A deeper dive into ApoE4

APOE4 is more than the “Alzheimer’s gene” nickname that it has been given. While APOE4 is considered the biggest genetic risk factor for Alzheimer’s disease, this is not true across all populations. Additionally, effects of this gene extend beyond Alzheimer’s, to other neurological issues, cardiovascular concerns, infectious diseases, aging, and more.

APOE was once considered just a fat (lipid) bucket, but it has roles beyond lipoprotein metabolism. A 2016 paper revealed that APOE4 enters the nucleus and tells 1700 different genes what to do in areas associated with neurotrophins, programmed cell death, synaptic function, sirtuins and aging, and insulin resistance. (Source: Direct Transcriptional Effects of Apolipoprotein E (Veena Theendakara et al, 20 Jan 2016)

Since APOE4 has so many different effects, references regarding it are diverse. This wiki is not a discussion on a certain subject rather it attempts to be an APOE4 “library” of mostly research papers, with a sprinkling of insightful articles, podcasts, etc.

For simplicity of wiki construction, these references are organized chronologically. Therefore, if searching for information on a specific subject, use a search function (control F, command F).

Also recognize this compilation is not complete.

2024

December 2024

November 2024

October 2024

September 2024

A cell-autonomous role for border-associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to white matter injury

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Antoine Anfray, Samantha Schaeffer, Yorito Hattori, Monica M. Santisteban, Nicole Casey, Gang Wang, Michael Strickland, Ping Zhou, David M. Holtzman, Josef Anrather, Laibaik Park & Costantino Iadecola
Nature Neuroscience (2024)
Published 18 September 2024
DOI: https://doi.org/10.1038/s41593-024-01757-6
Abstract
Apolipoprotein E4 (ApoE4), the strongest genetic risk factor for sporadic Alzheimer’s disease, is also a risk factor for microvascular pathologies leading to cognitive impairment, particularly subcortical white matter injury. These effects have been attributed to alterations in the regulation of the brain blood supply, but the cellular source of ApoE4 and the underlying mechanisms remain unclear. In mice expressing human ApoE3 or ApoE4, we report that border-associated macrophages (BAMs), myeloid cells closely apposed to neocortical microvessels, are both sources and effectors of ApoE4 mediating the neurovascular dysfunction through reactive oxygen species. ApoE4 in BAMs is solely responsible for the increased susceptibility to oligemic white matter damage in ApoE4 mice and is sufficient to enhance damage in ApoE3 mice. The data unveil a new aspect of BAM pathobiology and highlight a previously unrecognized cell-autonomous role of BAM in the neurovascular dysfunction of ApoE4 with potential therapeutic implications.
NOTE: The above paper is behind paywall, if interested in reading more, this article discusses the paper: Brain Macrophages with ApoE4 Play a Key Role in Damaging Blood Vessels and NeurodegenerationWeill Cornell Medicine

APOE4 and Infectious Diseases Jointly Contribute to Brain Glucose Hypometabolism, a Biomarker of Alzheimers Pathology: New findings from the ADNI

https://www.medrxiv.org/content/10.1101/2024.09.13.24313582v1 Aravind Lathika Rajendrakumar, Konstantin Arbeev, Olivia Bagley, Anatoliy I Yashin, Svetlana Ukraintseva
MedRxiv
Posted September 14, 2024 (preprint)
doi: https://doi.org/10.1101/2024.09.13.24313582
Abstract
Introduction
We investigated the interplay between infections and APOE4 on brain glucose hypometabolism, an early preclinical feature of Alzheimer's Disease (AD) pathology.
Methods
Multivariate linear regression analysis was performed on 1,509 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI). The outcomes were the rank-normalized hypometabolic convergence index (HCI) and statistical regions of interest (SROI) for AD and mild cognitive impairment (MCI). Further, the HCI and its change in the presence and absence of APOE4 were evaluated.
Results
Infections were associated with greater hypometabolism [0.15, 95% CI: 0.03, 0.27, p=0.01], with a more pronounced effect among APOE4 carriers, indicating an interaction effect. A higher HCI (0.44, p=0.01) was observed in APOE4 carriers with multiple infections, compared to (0.11, p=0.08) for those with a single infection, revealing a dose-response relationship. The corresponding estimates for the association of infections with SROI AD and SROI MCI were -0.01 (p=0.02) and -0.01 (p=0.04) respectively.
Conclusion
Our findings suggest that infections and APOE4 jointly contribute to brain glucose hypometabolism and AD pathology, supporting a "multi-hit" mechanism in AD development.

The biphasic impact of apolipoprotein E ε4 allele on age-related hearing loss

https://www.nature.com/articles/s41598-024-71774-9
Jae Sang Han, Sung goo Yoo, Sun jung Lee, Hyun Jin Lee, In Young Choi & Kyoung Ho Park
Scientific Reports volume 14, Article number: 21420 (2024)
Published: 13 September 2024
DOI: https://doi.org/10.1038/s41598-024-71774-9 Both the ε4 variant of the apolipoprotein E (APOE) gene and hearing loss are well-known risk factors for Alzheimer's disease. However, previous studies have produced inconsistent findings regarding the association between APOE genotypes and hearing levels, necessitating further investigation. The aim of this study was to investigate the relationship between APOE genotypes and hearing levels. This retrospective study analyzed clinical data from a clinical data warehouse of seven affiliated Catholic Medical Center hospitals. The study included 1,162 participants with records of APOE genotypes, audiometric tests, and cognitive function tests. In Generalized linear mixed model analysis, ε4 carriers exhibited lower pure tone audiometry thresholds with an estimate of -0.353 (SE = 0.126, p = 0.005). However, the interaction term for age and APOE ε4 had a coefficient of 0.577 (SE = 0.214 p = 0.006), suggesting that the APOE ε4 gene may accelerate hearing deterioration with age. Subgroup analysis based on an age cut-off of 75 revealed that ε4 carriers had better hearing at younger ages, but showed no significant difference at older ages. These results indicate that the ε4 allele may have a biphasic effect on hearing levels depending on age.

MicroRNAs: pioneering regulators in Alzheimer’s disease pathogenesis, diagnosis, and therapy

https://www.nature.com/articles/s41398-024-03075-8
Translational Psychiatry 14, Article number: 367 (2024)
Published: 10 September 2024
DOI: https://doi.org/10.1038/s41398-024-03075-8
Abstract
This article delves into Alzheimer’s disease (AD), a prevalent neurodegenerative condition primarily affecting the elderly. It is characterized by progressive memory and cognitive impairments, severely disrupting daily life. Recent research highlights the potential involvement of microRNAs in the pathogenesis of AD. MicroRNAs (MiRNAs), short non-coding RNAs comprising 20–24 nucleotides, significantly influence gene regulation by hindering translation or promoting degradation of target genes. This review explores the role of specific miRNAs in AD progression, focusing on their impact on β-amyloid (Aβ) peptide accumulation, intracellular aggregation of hyperphosphorylated tau proteins, mitochondrial dysfunction, neuroinflammation, oxidative stress, and the expression of the APOE4 gene. Our insights contribute to understanding AD’s pathology, offering new avenues for identifying diagnostic markers and developing novel therapeutic targets.

Circulating apoE4 protein levels from dried blood spots predict cognitive function in a large population-based survey setting

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.14224
Yacila I. Deza-Lougovski, Luzia M. Weiss, Hannah M. Horton, Aijing Sun, Nis Borbye-Lorenzen, Kristin Skogstrand, Solveig Holmgaard, Karen Andersen-Ranberg, Vania Panes Lundmark, Axel Börsch-Supan, Martina Börsch-Supan, Anna Rieckmann
Alheimer's & Dementia Online Version of Record before inclusion in an issue
First published: 05 September 2024
DOI: https://doi.org/10.1002/alz.14224
Abstract
INTRODUCTION
The apolipoprotein E (APOE) ε4 allele carries risk for cognitive impairment, but whether the level of circulating apoE4 protein in carriers affects cognition is unclear, as is how health and lifestyle impact circulating apoE4 levels.
METHODS
We assayed apoE4 protein levels in dried blood spots of 12,532 adults aged 50+. Regression analyses tested the likelihood of cognitive impairment between groups and within those with detected apoE4 protein. Predictors of circulating apoE4 were assessed.
RESULTS
We detected protein binding that indicates the presence of an APOE ε4 allele in 28.4% of this group. This group was more likely to have cognitive impairment, and this risk increases with age. However, higher apoE4 levels were associated with less likelihood of cognitive impairment within this group. Antihypertensive medication predicted apoE4 protein levels.
DISCUSSION
The apoE4 isoform is associated with a deficient protein and worse cognition. This association is modulated by the level of circulating apoE4 protein in ε4 carriers.
Highlights
•An assay to quantify apoE4 levels from dried blood spot samples was applied.
•The apoE4 protein was detected as specific binding at ≥30,000 pg/mL in 28.4% of samples.
•Having the apoE4 protein was associated with worse cognitive performance.
•Higher apoE4 protein levels in those who have it were associated with better cognition.
•Cardiovascular factors influenced levels of apoE4 protein.

Functional Glial Activation Mediates Phenotypic Effects of APOEɛ4 and Sex in Alzheimer’s Disease

https://www.mdpi.com/2571-6980/5/3/22
Roger M. Lane, Dan Li, and Taher Darreh-Shori
Neuroglia, 2024, 5(3), 323-343
Published: 5 September 2024
DOI: https://doi.org/10.3390/neuroglia5030022
Abstract
Background: This study examined the impact of apolipoprotein ɛ4 (APOEɛ4) allele frequency and sex on the phenotype of Alzheimer’s disease (AD).
Methods: This post hoc study evaluated the baseline characteristics, cerebrospinal fluid (CSF) and neuroimaging biomarkers, and cognition scores collected from 45 patients aged 50–74 years with CSF-biomarker-confirmed mild cognitive impairment or mild dementia due to AD from clinical trial NCT03186989.
Results: A phenotypic spectrum was observed from a predominant amyloid and limbic–amnestic phenotype in male APOEɛ4 homozygotes to a predominantly tau, limbic-sparing, and multidomain cognitive impairment phenotype in female APOEɛ4 noncarriers. Amyloid pathology was inversely correlated with tau pathophysiology, glial activation, and synaptic injury, with the strongest associations observed in male APOEɛ4 carriers. Tau pathophysiology was correlated with glial activation, synaptic injury, and neuroaxonal damage, with the strongest correlation observed in female APOEɛ4 noncarriers.
Conclusions: These data support the hypothesis that functional glial activation is influenced by apoE isoform and sex and might explain much

ApoE4 disrupts intracellular trafficking and iron homeostasis in an improved iPSC-based model of human brain endothelial cells

https://www.biorxiv.org/content/10.1101/2024.09.03.610802v1
Luisa Bell, Nadine Stokar-Regenscheit, Claire Simonneau, Angélique Augustin, Barbara Höllbacher, Lia D'Abate, Joanna Ficek-Pascual, Kim Schneider, Desiree Von Tell, Chiara Zanini, Christelle Zundel, Sabrina Golling, Christine Becker, Alex Odermatt, Martina Pigoni, Roberto Villaseñor
BioRxiv, 3 Sept 2024
3 Sept 2024 (preprint)
doi: https://doi.org/10.1101/2024.09.03.610802
Transferrin receptor in brain endothelial cells can deliver therapeutic antibodies to the brain via transcytosis across the blood-brain barrier. Whether receptor transport remains intact in Alzheimer's disease is still a major open question. Here, we investigated whether apolipoprotein E4 (ApoE4), the major genetic risk factor for Alzheimer's disease, altered intracellular transport in human brain endothelial cells. To achieve this, we first developed an optimized protocol for induced pluripotent stem cells based on a defined chemical cocktail and extracellular-matrix support to differentiate brain endothelial cells (iCE-BECs). Multi-omic profiling and functional transport assays showed that iCE-BECs have a brain endothelial gene signature and recapitulate receptor-mediated transcytosis of a clinically validated Brainshuttle™ antibody against transferrin receptor. Engineered iCE-BECs homozygous for ApoE4 had altered spatiotemporal organization of early endosomes, increased transferrin receptor expression and reduced cytoplasmic iron. Our data revealed that ApoE4 can impact intracellular transport and iron homeostasis at the BBB in a cell-autonomous manner. This finding could be relevant for the brain delivery of therapeutic antibodies for Alzheimer's disease.

APOE4 leads to Neurovascular dysfunction is an early change of Alzheimer's disease?

https://www.sciencedirect.com/science/article/pii/S2666245024000370
Mun Seong Cho
Cerebral Circulation - Cognition and Behavior Volume 6, Supplement 1, 2024, 100236
Version of Record 2 September 2024
DOI: https://doi.org/10.1016/j.cccb.2024.100236
Introduction
Vascular contributions to dementia & Alzheimer's disease are increasing recognized. Recent studies have suggested that blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction, including the early clinical stages of AD. Apolipoprotein E4(APOE4), the major AD susceptibility gene, leads to accelerated blood-brain barrier breakdown & degeneration of brain capillary pericyte that maintain blood-brain barrier integrity. Whether APOE4 cerebrovascular effects contribute to cognitive impairment remains, however, largely unknown.
Methods
A screening yielded publcations of which relevant articles were selected after an evaluation of their titles & abstracts. And then full text of these articles was obtained & compared about above respective subjects thoroughly.
Results
A recent meta-analysis of BBB peameability based on imaging & biochemical cerebrospinal fluid studies indicated that patients with AD have greater increase in BBB peameability compared with neurologically healthy human controls, which has also been confirmed by postmortem brain tissue (for review, see the articles by Zlocovic, & Sergillo et al). Impotantly, postmortem analysis indicated that the BBB breakdown is more pronounced in individuals with AD who carry the APOE4 allele. Astrocyte-derived human apoE2 & apoE3, leads to an age-dependent progressive BBB breakdown by activating a proinflammatory CypA-nuclear factor (NF)- κB-matrix- metalloproteinase-9 pathway (MMP-9) in brain capillary pericytes. The activation of MMP-9 in APOE mice leads to enzymatic degradation of the BBB tight junction & basement membrane proteins resulting in BBB breakdown followed by neuronal uptake of multiple blood-derived neurotoxic proteins (e.g., thrombin, fibrin), perivascular deposition of erythrocyte-derived hemosiderin & microvascular & CBF reductions. The vascular defects in APOE4-expressing mice precede neuronal dysfunction & can initiate neurodegenerative changes. Astrocyte secreated apoE3 & apoE2, but not apoE4, suppress the CypA-NF- κB-MMP-9 pathway in pericytes via the low density lipoprotein receptor related protein1(LRP1). There are apoE isoform-specific effects in the Aβ pathway. ApoE4 expression is assocated with a significant increase in amyloid plaques in brain at earlier ages compared with apoE3 or apoE2. ApoE4 impairs A β clearance from & across the BBB in animal models & patients at risk for developing AD.
Discussion
Future studies should explore whether similar early neuroimaging & biochemical markers of BBB disruption are present in humans carrying the apoE4.

August 2024

Finding That APOE4 Is Toxic in Alzheimer's Can Help Guide Targeted Therapies

https://mail.aol.com/d/list/referrer=newMail&folders=1&accountIds=1&listFilter=NEWMAIL/messages/AErLmpRTT6ugZtJBGQeNmB9rNbc
by Greg Laub
MedPage Today August 30, 2024
August 30, 2024
A working group of senior investigators, convened by the Alzheimer's Disease Sequencing Project opens in a new tab or window(ADSP), has reached a consensus that the APOE4 gene, long debated in Alzheimer's research, is definitively toxic. This breakthrough not only opens the door for targeted therapies but also underscores the gene's varying risk levels across different populations.
In this exclusive MedPage Today video, Jeffery Vance, MD, PhD, of the University of Miami Miller School of Medicine, describes the findings from the data analysis and how they might significantly reshape the future of Alzheimer's treatment strategies.

Identification of a specific APOE transcript and functional elements associated with Alzheimer’s disease

https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-024-00751-7
Qiang Chen, Luis Aguirre, Guoming Liang, Huanhuan Zhao, Tao Dong, Felix Borrego, Itziar de Rojas, Qichan Hu, Christopher Reyes, Ling-Yan Su, Bao Zhang, James D. Lechleiter, Harald H. H. Göring, Philip L. De Jager, Joel E. Kleinman, Thomas M. Hyde, Pan P. Li, Agustín Ruiz, Daniel R. Weinberger,Sudha Seshadri & Liang Ma
Molecular Neurodegeneration volume 19, Article number: 63 (2024)
Published: 29 August 2024
DOI: https://doi.org/10.1186/s13024-024-00751-7
Abstract
Background
The APOE gene is the strongest genetic risk factor for late-onset Alzheimer’s Disease (LOAD). However, the gene regulatory mechanisms at this locus remain incompletely characterized.
Methods
To identify novel AD-linked functional elements within the APOE locus, we integrated SNP variants with multi-omics data from human postmortem brains including 2,179 RNA-seq samples from 3 brain regions and two ancestries (European and African), 667 DNA methylation samples, and ChIP-seq samples. Additionally, we plotted the expression trajectory of APOE transcripts in human brains during development.
Results
We identified an AD-linked APOE transcript (jxn1.2.2) particularly observed in the dorsolateral prefrontal cortex (DLPFC). The APOE jxn1.2.2 transcript is associated with brain neuropathological features, cognitive impairment, and the presence of the APOE4 allele in DLPFC. We prioritized two independent functional SNPs (rs157580 and rs439401) significantly associated with jxn1.2.2 transcript abundance and DNA methylation levels. These SNPs are located within active chromatin regions and affect brain-related transcription factor-binding affinities. The two SNPs shared effects on the jxn1.2.2 transcript between European and African ethnic groups. Conclusion
The novel APOE functional elements provide potential therapeutic targets with mechanistic insight into the disease etiology.

APOE4-related differences in cortical thickness are modulated by sex in middle age

https://link.springer.com/article/10.1007/s11682-024-00911-9
Kaitlynne N. Leclaire, Jenna K. Blujus, Laura E. Korthauer & Ira Driscoll
Brain Imaging and Behavior 2024
Published 28 August 2024
DOI: https://doi.org/10.1007/s11682-024-00911-9
Abstract
Apolipoprotein E (APOE) ε4, the strongest genetic risk for late-onset Alzheimer’s disease (AD), confers greater risk in females than males. While APOE4-related modulation of structural brain integrity in AD is well documented, extant literature on sex-APOE interactions has focused on older adults. The understanding of the healthy brain as a part of the normal aging process and as distinct from explicit disease or pathology is essential before comparison can be made with pathological states. Hence, it is crucial to characterize and better understand these relationships in middle-age prior to the onset of overt clinical symptoms and advanced neurodegeneration. The present study examined the relationships between sex, APOE status, and cortical thickness in 128 healthy, cognitively unimpaired, middle-aged adults (ages 40–60, M(SD) = 49.97(6.04); 77 females). All participants underwent structural magnetic resonance imaging and were genotyped for APOE (APOE4 +  = 38; APOE4- = 90). Compared to males, females had thicker superior frontal cortices bilaterally, left middle temporal cortex, and left pars triangularis. APOE4 + had thinner left rostral middle frontal gyrus compared to APOE4-. Female compared to male APOE4- had thicker left banks of the superior temporal sulcus, left caudal anterior cingulate, left superior frontal, left superior parietal, and right precentral cortices. Female compared to male APOE4 + had thicker superior frontal cortices bilaterally. Female APOE4 + had thinner left rostral anterior cingulate cortex compared to female APOE4-. Overall, APOE-related differences in cortical thickness are more pronounced in females and detectable in middle age, well before the onset of overt clinical symptoms of AD.

C-Reactive Protein, the Gliovascular Unit, and Alzheimer’s Disease

https://www.cureus.com/articles/285659-c-reactive-protein-the-gliovascular-unit-and-alzheimers-disease?score_article=true#!/
Mihaela Straistă & Mark Slevin
Cureus 16(8): e67969
Published: August 27, 2024
DOI: 10.7759/cureus.67969
Abstract
Alzheimer's disease (AD) pathogenesis is conditioned by the presence of amyloid beta (Aβ) and neuroinflammation. The gliovascular unit (GVU) illustrates the relationship between the vascular components of the brain and glial cells, particularly astrocytes, which are seen as critical elements mainly affected in this disease. In AD patients, the impairment of the GVU is seen as blood-brain barrier breakdown, decreased clearance of Aβ, and chronic inflammatory status. C-reactive protein (CRP) and its monomeric form (mCRP) are associated with endothelial dysfunction and amyloid plaque instability, contributing to neuroinflammation and neurodegeneration. The interconnections between the GVU and the dissociated form of CRP were demonstrated by mCRP implication in vascular permeability that supports inflammation and extravasation of pro-inflammatory cytokines into the brain parenchyma. Astrocytic activation and endfeet function alterations can exacerbate the progression of AD by elevating pro-inflammatory agents and vascular amyloid accumulations. This review aims to emphasize the synergistic link between the GVU and monomers of CRP in the perpetuation of the inflammatory status, exacerbating neurodegeneration and neuroinflammation. Understanding their implication in AD can bring insights into novel therapeutic strategies to reduce AD progression.
AND FROM TEXT
This research aimed to uncover the roles of both mCRP and ApoE4 in the development of AD characteristics during chronic inflammation. Even though ApoE4 is considered a major genetic risk factor for AD, the mechanism through which ApoE4 contributes to AD is not fully understood, and future research directions should focus on personalized targeted therapeutic approaches.

Sex-Dependent Effects of Cardiometabolic Health and APOE4 on Brain Age A Longitudinal Cohort Study

https://www.neurology.org/doi/10.1212/WNL.0000000000209744?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
Sivaniya Subramaniapillai, PhD, Louise S. Schindler, MSc, Paul Redmond, MSc, Mark E. Bastin, DPhil, Joanna M. Wardlaw, MD, FRCR, Maria Valdés Hernández, PhD , Susana Muñoz Maniega, PhD, Benjamin Aribisala, PhD, Lars T. Westlye, PhD, William Coath, MSc, James Groves, MBBS, David M. Cash, PhD, Josephine Barnes, PhD, Sarah-Naomi James, PhD, Carole H. Sudre, PhD, Frederik Barkhof, MD, PhD, Marcus Richards, PhD, Janie Corley, PhD, Tom C. Russ, MD, PhD, Simon R. Cox, PhD, Jonathan M. Schott, MD, James H. Cole, PhD, and Ann-Marie G. de Lange, PhD
Neurology Volume 103, Number 6,September 24, 2024 issue
Online August 22, 2024
DOI: https://doi.org/10.1212/WNL.00000000002097
Abstract
Background and Objectives
The aging population is growing faster than all other demographic strata. With older age comes a greater risk of health conditions such as obesity and high blood pressure (BP). These cardiometabolic risk factors (CMRs) exhibit prominent sex differences in midlife and aging, yet their influence on brain health in females vs males is largely unexplored. In this study, we investigated sex differences in relationships between BP, body mass index (BMI), and brain age over time and tested for interactions with APOE ε4 genotype (APOE4), a known genetic risk factor of Alzheimer disease.
Methods
The sample included participants from 2 United Kingdom–based longitudinal birth cohorts, the Lothian Birth Cohort (1936) and Insight 46 (1946). Participants with MRI data from at least 1 time point were included to evaluate sex differences in associations between CMRs and brain age. The open-access software package brainageR 2.1 was used to estimate brain age for each participant. Linear mixed-effects models were used to assess the relationships between brain age, BMI, BP, and APOE4 status (i.e., carrier vs noncarrier) in males and females over time.
Results
The combined sample comprised 1,120 participants (48% female) with a mean age (SD) of 73 (0.72) years in the Lothian Birth Cohort and 71 (0.68) years in Insight 46 at the time point 1 assessment. Approximately 30% of participants were APOE4 carriers. Higher systolic and diastolic BP was significantly associated with older brain age in females only (β = 0.43–0.56, p < 0.05). Among males, higher BMI was associated with older brain age across time points and APOE4 groups (β = 0.72–0.77, p < 0.05). In females, higher BMI was linked to older brain age among APOE4 noncarriers (β = 0.68–0.99, p < 0.05), whereas higher BMI was linked to younger brain age among carriers, particularly at the last time point (β = −1.75, p < 0.05).
Discussion
This study indicates sex-dependent and time-dependent relationships between CMRs, APOE4 status, and brain age. Our findings highlight the necessity of sex-stratified analyses to elucidate the role of CMRs in individual aging trajectories, providing a basis for developing personalized preventive interventions.

Sex and APOE4-specific links between cardiometabolic risk factors and white matter alterations in individuals with a family history of Alzheimer's disease

https://www.biorxiv.org/content/10.1101/2024.08.21.608995v1
Stefanie A Tremblay, R. Nathan Spreng, Alfie Wearn, Zaki Alasmar, Amir Pirhadi, Christine L Tardif, Mallar Chakravarty, Sylvia Villeneuve, Ilana R Leppert, Felix Carbonell, Yasser Iturria-Medina, Christopher J Steele, Claudine J Gauthier, the PREVENT-AD Research Group
BioRxiv, 22 Aug 2024 (preprint)
22 Aug 2024
doi: https://doi.org/10.1101/2024.08.21.608995
Abstract INTRODUCTION: White matter (WM) alterations are among the earliest changes in Alzheimer's disease (AD), yet limited work has comprehensively characterized the effects of AD risk factors on WM. METHODS: In older adults with a family history of AD, we investigated the sex-specific and APOE genotype-related relationships between WM microstructure and risk factors. Multiple MRI-derived metrics were integrated using a multivariate approach based on the Mahalanobis distance (D2). The links between WM D2 and cognition were also explored. RESULTS: WM D2 in several regions was associated with high systolic blood pressure, BMI, and glycated hemoglobin, and low cholesterol, in both males and females. APOE4+ displayed a distinct risk pattern, with LDL-cholesterol having a detrimental effect only in carriers, and this pattern was linked to immediate memory performance. Myelination was the main mechanism underlying WM alterations. DISCUSSION: Our findings reveal that combined exposure to multiple cardiometabolic risk factors negatively impacts microstructural health, which may subsequently affect cognition. Notably, APOE4 carriers exhibited a different risk pattern, especially in the role of LDL, suggesting distinct underlying mechanisms in this group.

Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer’s disease

https://www.nature.com/articles/s43587-024-00693-1
Elisabet A. Frick, Valur Emilsson, Thorarinn Jonmundsson, Anna E. Steindorsdottir, Erik C. B. Johnson, Raquel Puerta, Eric B. Dammer, Anantharaman Shantaraman, Amanda Cano, Mercè Boada, Sergi Valero, Pablo García-González, Elias F. Gudmundsson, Alexander Gudjonsson, Rebecca Pitts, Xiazi Qiu, Nancy Finkel, Joseph J. Loureiro, Anthony P. Orth, Nicholas T. Seyfried, Allan I. Levey, Agustin Ruiz, Thor Aspelund, Lori L. Jennings, Lenore J. Launer, Valborg Gudmundsdottir & Vilmundur Gudnason
Nature Aging (2024)
Published: 21 August 2024
DOI: https://doi.org/10.1038/s43587-024-00693-1
Abstract
A deeper understanding of the molecular processes underlying late-onset Alzheimer’s disease (LOAD) could aid in biomarker and drug target discovery. Using high-throughput serum proteomics in the prospective population-based Age, Gene/Environment Susceptibility–Reykjavik Study (AGES) cohort of 5,127 older Icelandic adults (mean age, 76.6 ± 5.6 years), we identified 303 proteins associated with incident LOAD over a median follow-up of 12.8 years. Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status, were implicated in neuronal processes and overlapped with LOAD protein signatures in brain and cerebrospinal fluid. We identified 17 proteins whose associations with LOAD were strongly dependent on APOE-ε4 carrier status, with mostly consistent associations in cerebrospinal fluid. Remarkably, four of these proteins (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated due to LOAD, a finding replicated in external cohorts and possibly reflecting a response to disease onset. These findings highlight dysregulated pathways at the preclinical stages of LOAD, including those both independent of and dependent on APOE-ε4 status.

Herpes zoster and long-term risk of subjective cognitive decline

https://alzres.biomedcentral.com/articles/10.1186/s13195-024-01511-x
Tian-Shin Yeh, Gary C. Curhan, Barbara P. Yawn, Walter C. Willett & Sharon G. Curhan
Alzheimer's Research & Therapy 16, 180 (2024)
14 August 2024
DOI: https://doi.org/10.1186/s13195-024-01511-x
Abstract
Background
Herpes zoster (HZ), commonly known as “shingles,” may contribute to cognitive decline through mechanisms such as neuroinflammation or direct neuronal injury. However, evidence on the longitudinal association between HZ and cognitive decline is conflicting and whether the risk differs by APOE ε4-carrier status has not been studied; prospective cohort studies on the association between HZ vaccination and cognitive decline are also lacking.
Methods
We included 149,327 participants from three large cohorts—the Nurses’ Health Study (NHS), NHSII, and Health Professionals Follow-Up Study (HPFS)—to prospectively examine the association between HZ and subsequent subjective cognitive decline (SCD). Poisson regression was used to estimate the multivariable-adjusted relative risk (MVRR) of a 3-unit increment in SCD score according to years since HZ compared with participants with no history of HZ.
Results
Compared with individuals with no history of HZ, the MVRR (95% CI) of a 3-unit increment in SCD score was significantly and independently higher among individuals with a history of HZ, but the duration of time since HZ when the elevated risk of SCD was statistically significant differed among the cohorts. In NHS, HZ was associated with higher long-term risk of SCD; compared with individuals with no history of HZ, the MVRR (95% CI) of a 3-unit increment in SCD score was 1.14 (1.01, 1.32) for ≥ 13 years since HZ. In NHS II, HZ was associated with higher risk of SCD in both the short-term [MVRR 1.34 (1.18, 1.53) for 1–4 years] and long-term [MVRR 1.20 (1.08, 1.34) for ≥ 13 years since HZ]. In HPFS, an elevated risk of SCD was suggested across all time points. Among the subset of participants with information on APOE ε4, there was a suggestion that the association differed by APOE ε4 carrier status, but the results were not consistent between women and men. Among the subset of women with information on HZ vaccination, there was a suggestion that the long-term risk of SCD may be greater among women who were not vaccinated against HZ.
Conclusions
Data from three large independent cohorts of women and men showed that HZ was associated with higher long-term risk of SCD, and the risk may differ by APOE ε4-carrier status.

APOLLOE4 Phase 3 study of oral ALZ‐801/valiltramiprosate in APOE ε4/ε4 homozygotes with early Alzheimer's disease: Trial design and baseline characteristics

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11322500/
Susan Abushakra, Anton P. Porsteinsson, Marwan Sabbagh, David Watson, Aidan Power, Earvin Liang, Emer MacSweeney, Merce Boada, Susan Flint, Rosalind McLaine, J. Patrick Kesslak, John A. Hey, and Martin Tolar
Alzheimer’s & Dementia (N Y) 2024 Aug 13;10(3):e12498
Published online 13 Aug 2024
doi: 10.1002/trc2.12498
Abstract
INTRODUCTION
The approved amyloid antibodies for early Alzheimer's disease (AD) carry a boxed warning about the risk of amyloid‐related imaging abnormalities (ARIAs) that are highest in apolipoprotein E (APOE) ε4/ε4 homozygotes. ALZ‐801/valiltramiprosate, an oral brain‐penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD.
METHODS
This Phase 3 randomized, double‐blind, placebo‐controlled, 78‐week study of ALZ‐801 administered as 265 mg twice per day tablets, enrolled 50‐ to 80‐year‐old homozygotes with Mini‐Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating–Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug–placebo difference on the Alzheimer's Disease Assessment Scale 13‐item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating–Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes.
RESULTS
The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024.
DISCUSSION
APOLLOE4 is the first disease‐modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ‐801 has the potential to be the first effective and safe anti‐amyloid treatment for the high‐risk APOE ε4/ε4 population.
Highlights
• The APOLLOE4 Phase 3, placebo‐controlled, 78‐week study is designed to evaluate the efficacy and safety of ALZ‐801 265 mg twice per day in early Alzheimer's disease (AD) subjects with the apolipoprotein E (APOE) ε4/ε4 genotype.
• The enrolled early AD population (N = 325) has 51% females, a mean age = 69 years, and a mean Mini‐Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD).
• The primary outcome is the cognitive Alzheimer's Disease Assessment Scale 13‐item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating–Sum of Boxes, Amsterdam‐Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes.
• The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA).

Impaired cellular copper regulation in the presence of ApoE4

https://onlinelibrary.wiley.com/doi/10.1111/jnc.16198
Bryce Blades, Ya Hui Hung, Abdel A. Belaidi, Irene Volitakis, Aaron G. Schultz, Michael A. Cater, Nam Sang Cheung, Ashley I. Bush, Scott Ayton, Sharon La Fontaine
Journal of Nuerochemistry 12 August 2024 (Online before inclusion in an issue)
12 August 2024
https://doi.org/10.1111/jnc.16198
Abstract
The strongest genetic risk factor for late-onset Alzheimer's disease (AD) is allelic variation of the APOE gene, with the following risk structure: ε4 > ε3 > ε2. The biochemical basis for this risk profile is unclear. Here, we reveal a new role for the APOE gene product, apolipoprotein E (ApoE) in regulating cellular copper homeostasis, which is perturbed in the AD brain. Exposure of ApoE target replacement (TR) astrocytes (immortalised astrocytes from APOE knock-in mice) to elevated copper concentrations resulted in exacerbated copper accumulation in ApoE4- compared to ApoE2- and ApoE3-TR astrocytes. This effect was also observed in SH-SY5Y neuroblastoma cells treated with conditioned medium from ApoE4-TR astrocytes. Increased intracellular copper levels in the presence of ApoE4 may be explained by reduced levels and delayed trafficking of the copper transport protein, copper-transporting ATPase 1 (ATP7A/Atp7a), potentially leading to impaired cellular copper export. This new role for ApoE in copper regulation lends further biochemical insight into how APOE genotype confers risk for AD and reveals a potential contribution of ApoE4 to the copper dysregulation that is a characteristic pathological feature of the AD brain.

ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults A Randomized Clinical Trial

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2821809?utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_term=080124
Lynne H. Shinto, ND, MPH; Charles F. Murchison, PhD; Lisa C. Silbert, MD, MCR; Hiroko H. Dodge, PhD; David Lahna, MS; William Rooney, PhD; Jeffrey Kaye, MD; Joseph F. Quinn, MD; Gene L. Bowman, ND, MPH
JAMA Network Open 2024;7(8):e2426872
1 Aug 2024
doi:10.1001/jamanetworkopen.2024.26872
Abstract
Importance Older adults with lower intake and tissue levels of long-chain ω-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6) have more brain white matter lesions (WMLs), an association suggesting that small-vessel ischemic disease, a major contributor to the development of dementia, including Alzheimer disease, may be preventable through ω-3 treatment. Objective To determine whether ω-3 treatment reduces WML accumulation in older adults without dementia harboring WMLs and with suboptimal ω-3 status. Design, Setting, and Participants This quadruple-blinded, placebo-controlled, randomized clinical trial with treatment stratification by apolipoprotein E ε4 allele (APOE*E4) carrier status used linear mixed-effects models to estimate mean annual change between groups. The study was conducted at Oregon Health & Science University, a major academic medical center in the Pacific Northwest, from May 2014 to final participant visit in September 2019. Data analysis concluded in July 2022. Participants were adults without dementia aged 75 years and older with WMLs greater than or equal to 5 cm3 and plasma ω-3 PUFA less than 5.5 weight percentage of total. Intervention Three-year treatment with 1.65 g of ω-3 PUFA (975 mg of EPA and 650 mg of DHA) vs a soybean oil placebo matched for taste, smell, and appearance. Main Outcomes and Measures The primary outcome was annual WML progression measured using magnetic resonance imaging. Secondary outcomes included diffusion tensor imaging of fractional anisotropy (DTI-FA), representing neuronal integrity breakdown. Results A total of 102 participants (62 women [60.8%]; mean age, 81 years [range, 75-96 years]) were equally randomized, 51 per treatment group. Although the ω-3 group had less annual WML accumulation than the placebo group, the difference was not statistically significant (1.19 cm3 [95% CI, 0.64-1.74 cm3] vs 1.34 cm3 [95% CI, 0.80-1.88 cm3]; P = .30). Similarly, the ω-3 group had less annual DTI-FA decline than the placebo group, but the difference was not statistically significant (−0.0014 mm2/s [95% CI, −0.0027 to 0.0002 mm2/s] vs −0.0027 mm2/s [95% CI, −0.0041 to −0.0014 mm2/s]; P = .07). Among APOE*E4 carriers, the annual DTI-FA decline was significantly lower in the group treated with ω-3 than the placebo group (−0.0016 mm2/s [95% CI, −0.0032 to 0.0020 mm2/s] vs −0.0047 mm2/s [95% CI, −0.0067 to −0.0025 mm2/s]; P = .04). Adverse events were similar between treatment groups. Conclusions and Relevance In this 3-year randomized clinical trial, ω-3 treatment was safe and well-tolerated but failed to reach significant reductions in WML accumulation or neuronal integrity breakdown among all participants, which may be attributable to sample size limitations. However, neuronal integrity breakdown was reduced by ω-3 treatment in APOE*E4 carriers, suggesting that this treatment may be beneficial for this specific group.

Texture-based morphometry in relation to apolipoprotein ε4 genotype, ageing and sex in a midlife population

https://onlinelibrary.wiley.com/doi/10.1002/hbm.26798
Maria-Eleni Dounavi, Elijah Mak, Gregory Operto, Graciela Muniz-Terrera, Katie Bridgeman, Ivan Koychev, Paresh Malhotra, Lorina Naci, Brian Lawlor, Li Su, Carles Falcon, Karen Ritchie, Craig W Ritchie, Juan Domingo Gispert, John T O'Brien
Human Brain Mapping. 2024 Aug 1;45(11):e26798
1 Aug 2024
doi: 10.1002/hbm.26798
Abstract
Brain atrophy and cortical thinning are typically observed in people with Alzheimer's disease (AD) and, to a lesser extent, in those with mild cognitive impairment. In asymptomatic middle-aged apolipoprotein ε4 (ΑPOE4) carriers, who are at higher risk of future AD, study reports are discordant with limited evidence of brain structural differences between carriers and non-carriers of the ε4 allele. Alternative imaging markers with higher sensitivity at the presymptomatic stage, ideally quantified using typically acquired structural MRI scans, would thus be of great benefit for the detection of early disease, disease monitoring and subject stratification. In the present cross-sectional study, we investigated textural properties of T1-weighted 3T MRI scans in relation to APOE4 genotype, age and sex. We pooled together data from the PREVENT-Dementia and ALFA studies focused on midlife healthy populations with dementia risk factors (analysable cohort: 1585 participants; mean age 56.2 ± 7.4 years). Voxel-based and texture (examined features: contrast, entropy, energy, homogeneity) based morphometry was used to identify areas of volumetric and textural differences between APOE4 carriers and non-carriers. Textural maps were generated and were subsequently harmonised using voxel-wise COMBAT. For all analyses, APOE4, sex, age and years of education were used as model predictors. Interactions between APOE4 and age were further examined. There were no group differences in regional brain volume or texture based on APOE4 carriership or when age × APOE4 interactions were examined. Older people tended to have a less homogeneous textural profile in grey and white matter and a more homogeneous profile in the ventricles. A more heterogeneous textural profile was observed for females in areas such as the ventricles, frontal and parietal lobes and for males in the brainstem, cerebellum, precuneus and cingulate. Overall, we have shown the absence of volumetric and textural differences between APOE4 carriers and non-carriers at midlife and have established associations of textural features with ageing and sex.

Cholesterol imbalance and neurotransmission defects in neurodegeneration

https://www.nature.com/articles/s12276-024-01273-4
Kyung Chul Shin, Houda Yasmine Ali Moussa & Yongsoo Park
Experimental & Molecular Medicine 2024
Published 01 August 2024
DOI: https://doi.org/10.1038/s12276-024-01273-4
Abstract
The brain contains the highest concentration of cholesterol in the human body, which emphasizes the importance of cholesterol in brain physiology. Cholesterol is involved in neurogenesis and synaptogenesis, and age-related reductions in cholesterol levels can lead to synaptic loss and impaired synaptic plasticity, which potentially contribute to neurodegeneration. The maintenance of cholesterol homeostasis in the neuronal plasma membrane is essential for normal brain function, and imbalances in cholesterol distribution are associated with various neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. This review aims to explore the molecular and pathological mechanisms by which cholesterol imbalance can lead to neurotransmission defects and neurodegeneration, focusing on four key mechanisms: (1) synaptic dysfunction, (2) alterations in membrane structure and protein clustering, (3) oligomers of amyloid beta (Aβ) protein, and (4) α-synuclein aggregation.
From text under subheading: Possible therapeutic approaches for cholesterol imbalance
The apolipoprotein E (ApoE) gene is involved in the metabolism and transport of cholesterol79,80. There are three main variants or alleles of the APOE gene, namely, ApoE2, ApoE3, and ApoE481. The ApoE4 protein is the most important risk factor for late-onset AD82, i.e., the most common form of the disease that occurs after age 65. The molecular mechanisms by which ApoE4 contributes to AD are complex and not fully understood, but ApoE4 likely promotes Aβ aggregation by transporting cholesterol79,83. ApoE4 can induce cholesterol imbalance by transporting cholesterol from the plasma membrane in neurons to protein aggregates (Fig. 2). Given that cholesterol imbalance causes neurodegeneration, ApoE4 may be a possible target for mitigating Aβ aggregation and treating cholesterol imbalance.
Overall, the maintenance of cholesterol homeostasis is important for preventing or slowing the pathogenesis of neurodegenerative diseases. Strategies aimed at regulating cholesterol levels or targeting cholesterol-mediated pathways involved in protein aggregation might be potential therapeutic approaches to treating neurodegenerative diseases, although neurodegenerative diseases are complex and cholesterol imbalance is one of many contributing factors11,84.

July 2024

Linking APOE4/4 genotype to microglial lipid droplets and neurotoxicity in Alzheimer’s disease

https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-024-00433-w
Hao Huang, Rong Xiang & Riqiang Yan
Translational Neurodegeneration volume 13, Article number: 38 (2024)
Published 30 Jul 2024
DOI: https://doi.org/10.1186/s40035-024-00433-w
No abstract, from text:
In summary, the APOE4/4 genotype causes a lipid metabolic imbalance and has an impact on the development of AD. These insights pave the way for targeted therapies against LD accumulation in microglia during the progression of AD.

Traffic-related air pollution and APOE4 can synergistically affect hippocampal volume in older women: new findings from UK Biobank

https://www.frontiersin.org/journals/dementia/articles/10.3389/frdem.2024.1402091/full?utm_source=F-NTF&utm_medium=EMLX&utm_campaign=PRD_FEOPS_20170000_ARTICLE
Vladimir A. Popov, Svetlana V. Ukraintseva, Hongzhe Duan, Anatoliy I. Yashin, Konstantin G. Arbeev
Frontiers in Dementia, Volume 3 - 2024
28 July 2024
https://doi.org/10.3389/frdem.2024.1402091
A growing research body supports the connection between neurodegenerative disorders, including Alzheimer's disease (AD), and traffic-related air pollution (TRAP). However, the underlying mechanisms are not well understood. A deeper investigation of TRAP effects on hippocampal volume (HV), a major biomarker of neurodegeneration, may help clarify these mechanisms. Here, we explored TRAP associations with the HV in older participants of the UK Biobank (UKB), taking into account the presence of APOE e4 allele (APOE4), the strongest genetic risk factor for AD. Exposure to TRAP was approximated by the distance of the participant's main residence to the nearest major road (DNMR). The left/right HV was measured by magnetic resonance imaging (MRI) in cubic millimeters (mm3). Analysis of variance (ANOVA), Welch test, and regression were used to examine statistical significance. We found significant interactions between DNMR and APOE4 that influenced HV. Specifically, DNMR <50m (equivalent of a chronically high exposure to TRAP), and carrying APOE4 were synergistically associated with a significant (P = 0.01) reduction in the right HV by about 2.5% in women aged 60–75 years (results for men didn't reach a statistical significance). Results of our study suggest that TRAP and APOE4 jointly promote neurodegeneration in women. Living farther from major roads may help reduce the risks of neurodegenerative disorders, including AD, in female APOE4 carriers.

Protective alleles and precision healthcare in crewed spaceflight

https://www.nature.com/articles/s41467-024-49423-6
Lindsay A. Rutter, Matthew J. MacKay, Henry Cope, Nathaniel J. Szewczyk, JangKeun Kim, Eliah Overbey, Braden T. Tierney, Masafumi Muratani, Ben Lamm, Daniela Bezdan, Amber M. Paul, Michael A. Schmidt, George M. Church, Stefania Giacomello & Christopher E. Mason
Nature Communications 15, 6158 (2024)
22 Jul 2024
DOI: https://doi.org/10.1038/s41467-024-49423-6
In exploring genetic markers that confer potential risk in space, it is useful to further explore the APOE4/4 (APOE4) genotype in the context of novel exposures and cognitive changes. For example, there is a well-established phenomenon of chemotherapy-related cognitive impairment (CRCI), which appears to be increased in APOE4 carriers116. In survivors of breast cancer who had undergone chemotherapy, APOE4 carriers had worse visual memory and spatial ability when examined five years after diagnosis. In breast cancer survivors, those APOE4 carriers undergoing chemotherapy had significantly lower scores on measures of working memory and processing speed when examined at 1-, 6-, and 18-months post-treatment117. In another study, APOE4 breast cancer survivors treated with cytostatics had lower scores on executive function, attention, and processing speed at one- and two-years post-treatment118. Moreover, radiation-induced cognitive decline shows similar deficits in cognition. Cramer et al. showed that, among patients undergoing therapeutic brain irradiation, roughly 30% experience cognitive decline by 4 months. In those living over 6 months, the rate increases to 50% or greater119. Makale et al. have reported that 50-90% of those undergoing partial or whole brain cranial radiation experience disabling cognitive impairment (thought APOE status was not assessed by Cramer or Makale)120.

Metabolomic and Proteomic Analysis of ApoE4-Carrying H4 Neuroglioma Cells in Alzheimer’s Disease Using OrbiSIMS and LC-MS/MS

https://pubs.acs.org/doi/10.1021/acs.analchem.4c01201?fbclid=IwZXh0bgNhZW0CMTEAAR3lqO6Ue_hg0sjTKNCY4dtku78HYYie4HbuRsdyHketw7T8mkrS1KQ-yNw_aem_w_DBd4mO3KSBvuJ021bcxA
Li Lu, Anna M. Kotowska, Stefanie Kern, Min Fang, Timothy R. Rudd, Morgan R. Alexander, David J. Scurr, and Zheying Zhu
American Chemical Society 2024
11 Jul 2024
DOI: https://doi.org/10.1021/acs.analchem.4c01201
Abstract
Growing clinical evidence reveals that systematic molecular alterations in the brain occur 20 years before the onset of AD pathological features. Apolipoprotein E4 (ApoE4) is one of the most significant genetic risk factors for Alzheimer’s disease (AD), which is not only associated with the AD pathological features such as amyloid-β deposition, phosphorylation of tau proteins, and neuroinflammation but is also involved in metabolism, neuron growth, and synaptic plasticity. Multiomics, such as metabolomics and proteomics, are applied widely in identifying key disease-related molecular alterations and disease-progression-related changes. Despite recent advances in the development of analytical technologies, screening the entire profile of metabolites remains challenging due to the numerous classes of compounds with diverse chemical properties that require different extraction processes for mass spectrometry. In this study, we utilized Orbitrap Secondary Ion Mass Spectrometry (OrbiSIMS) as a chemical filtering screening tool to examine molecular alterations in ApoE4-carried neuroglioma cells compared to wild-type H4 cells. The findings were compared using liquid chromatography (LC)-MS/MS targeted metabolomics analysis for the confirmation of specific metabolite classes. Detected alterations in peptide fragments by OrbiSIMS provided preliminary indications of protein changes. These were extensively analyzed through proteomics to explore ApoE4’s impact on proteins. Our metabolomics approach, combining OrbiSIMS and LC-MS/MS, revealed disruptions in lipid metabolism, including glycerophospholipids and sphingolipids, as well as amino acid metabolism, encompassing alanine, aspartate, and glutamate metabolism; aminoacyl-tRNA biosynthesis; glutamine metabolism; and taurine and hypotaurine metabolism. Further LC-MS/MS proteomics studies confirmed the dysfunction in amino acid and tRNA aminoacylation metabolic processes, and highlighted RNA splicing alterations influenced by ApoE4

Apolipoprotein E polymorphisms and female fertility in a transgenic mouse model of Alzheimer’s disease

https://www.nature.com/articles/s41598-024-66489-w
Bani Medegan Fagla, Jason York, Amy Christensen, Cielo Dela Rosa, Deebika Balu, Christian J. Pike, Leon M. Tai & Irina A. Buhimschi
Scientific Reports 14, Article number: 15873 (2024)
10 Jul 2024
DOI: https://doi.org/10.1038/s41598-024-66489-w
Abstract
Apolipoprotein E (APOE) is a major cholesterol carrier responsible for lipid transport and injury repair in the brain. The human APOE gene (h-APOE) has 3 naturally occurring alleles: ε3, the common allele; ε4, which increases Alzheimer’s disease (AD) risk up to 15-fold; and ε2, the rare allele which protects against AD. Although APOE4 has negative effects on neurocognition in old age, its persistence in the population suggests a survival advantage. We investigated the relationship between APOE genotypes and fertility in EFAD mice, a transgenic mouse model expressing h-APOE. We show that APOE4 transgenic mice had the highest level of reproductive performance, followed by APOE3 and APOE2. Intriguingly, APOE3 pregnancies had more fetal resorptions and reduced fetal weights relative to APOE4 pregnancies. In conclusion, APOE genotypes impact fertility and pregnancy outcomes in female mice, in concordance with findings in human populations. These mouse models may help elucidate how h-APOE4 promotes reproductive fitness at the cost of AD in later life.

Associations of endogenous estrogens, plasma Alzheimer’s disease biomarkers, and APOE4 carrier status on regional brain volumes in postmenopausal women

https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2024.1426070/full
Katrina A. Wugalter, Rachel A. Schroeder, Rebecca C. Thurston, Minjie Wu, Howard J. Aizenstein, Ann D. Cohen, M. Ilyas Kamboh, Thomas K. Karikari, Carol A. Derby, Pauline M. Maki
Frontiers in Aging Neuroscience Volume 16 – 2024
08 July 2024
DOI: https://doi.org/10.3389/fnagi.2024.1426070
Background:
Women carrying the APOE4 allele are at greater risk of developing Alzheimer’s disease (AD) from ages 65–75 years compared to men. To better understand the elevated risk conferred by APOE4 carrier status among midlife women, we investigated the separate and interactive associations of endogenous estrogens, plasma AD biomarkers, and APOE4 carrier status on regional brain volumes in a sample of late midlife postmenopausal women.
Methods:
Participants were enrolled in MsBrain, a cohort study of postmenopausal women (n = 171, mean age = 59.4 years, mean MoCA score = 26.9; race = 83.2% white, APOE4 carriers = 40). Serum estrone (E1) and estradiol (E2) levels were assessed using liquid chromatography–tandem mass spectrometry. APOE genotype was determined using TaqMan SNP genotyping assays. Plasma AD biomarkers were measured using single molecule array technology. Cortical volume was measured and segmented by FreeSurfer software using individual T1w MPRAGE images. Multiple linear regression models were conducted to determine whether separate and interactive associations between endogenous estrogen levels, plasma AD biomarkers (Aβ42/Aβ40, Aβ42/p-tau181), and APOE4 carrier status predict regional brain volume (21 regions per hemisphere, selected a priori); and, whether significant interactive associations between estrogens and AD biomarkers on brain volume differed by APOE4 carrier status.
Results:
There was no main effect of APOE4 carrier status on regional brain volumes, endogenous estrogen levels, or plasma AD biomarkers. Estrogens did not associate with regional brain volumes, except for positive associations with left caudal middle frontal gyrus and fusiform volumes. The interactive association of estrogens and APOE4 carrier status on brain volume was not significant for any region. The interactive association of estrogens and plasma AD biomarkers predicted brain volume of several regions. Higher E1 and E2 were more strongly associated with greater regional brain volumes among women with a poorer AD biomarker profile (lower Aβ42/40, lower Aβ42/p-tau181 ratios). In APOE4-stratified analyses, these interactions were driven by non-APOE4 carriers.
Conclusion:
We demonstrate that the brain volumes of postmenopausal women with poorer AD biomarker profiles benefit most from higher endogenous estrogen levels. These findings are driven by non-APOE4 carriers, suggesting that APOE4 carriers may be insensitive to the favorable effects of estrogens on brain volume in the postmenopause.

The APOE isoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia in a xenotransplantation model of Alzheimer's disease

https://www.biorxiv.org/content/10.1101/2024.07.03.601874v1
Kitty B Murphy, Di Hu, Leen Wolfs, Renzo Mancuso, Bart De Strooper, Sarah J Marzi
bioRxiv 2024.07.03.601874
5 Jul 2024 PrePrint
doi: https://doi.org/10.1101/2024.07.03.601874
Microglia play a key role in the response to amyloid beta in Alzheimer's disease (AD). In this context, a major transcriptional response of microglia is the upregulation of APOE, the strongest late-onset AD risk gene. Of its three isoforms, APOE2 is thought to be protective, while APOE4 increases AD risk. We hypothesised that the isoforms functionally alter microglia by shaping their transcriptomic and chromatin landscapes. We used RNA- and ATAC-sequencing to profile gene expression and chromatin accessibility of human microglia isolated from a xenotransplantation model of AD. We identified widespread transcriptomic and epigenomic differences which are dependent on APOE genotype, and are corroborated across the profiling assays. Our results indicate that impaired microglial proliferation, migration and immune responses may contribute to the increased risk for late-onset AD in APOE4 carriers, while increased DNA-binding of the vitamin D receptor in APOE2 microglia may contribute to the isoform's protective role.

Sex-dependent APOE4 neutrophil–microglia interactions drive cognitive impairment in Alzheimer’s disease

https://www.nature.com/articles/s41591-024-03122-3
Neta Rosenzweig, Kilian L. Kleemann, Thomas Rust, Madison Carpenter, Madeline Grucci, Michael Aronchik, Nieske Brouwer, Isabel Valenbreder, Joya Cooper-Hohn, Malvika Iyer, Rajesh K. Krishnan, Kisha N. Sivanathan, Wesley Brandão, Taha Yahya, Ana Durao, Zhuoran Yin, Jean Paul Chadarevian, Michael J. Properzi, Roni Nowarski, Hayk Davtyan, Howard L. Weiner, Mathew Blurton-Jones, Hyun-Sik Yang, Bart J. L. Eggen, Reisa A. Sperling & Oleg Butovsky
Nature Medicine 2024
Published 03 July 2024
DOI: https://doi.org/10.1038/s41591-024-03122-3
Abstract
APOE4 is the strongest genetic risk factor for Alzheimer’s disease (AD), with increased odds ratios in female carriers. Targeting amyloid plaques shows modest improvement in male non-APOE4 carriers. Leveraging single-cell transcriptomics across APOE variants in both sexes, multiplex flow cytometry and validation in two independent cohorts of APOE4 female carriers with AD, we identify a new subset of neutrophils interacting with microglia associated with cognitive impairment. This phenotype is defined by increased interleukin (IL)-17 and IL-1 coexpressed gene modules in blood neutrophils and in microglia of cognitively impaired female APOE ε4 carriers, showing increased infiltration to the AD brain. APOE4 female IL-17+ neutrophils upregulated the immunosuppressive cytokines IL-10 and TGFβ and immune checkpoints, including LAG3 and PD-1, associated with accelerated immune aging. Deletion of APOE4 in neutrophils reduced this immunosuppressive phenotype and restored the microglial response to neurodegeneration, limiting plaque pathology in AD mice. Mechanistically, IL-17F upregulated in APOE4 neutrophils interacts with microglial IL-17RA to suppress the induction of the neurodegenerative phenotype, and blocking this axis supported cognitive improvement in AD mice. These findings provide a translational basis to target IL-17F in APOE ε4 female carriers with cognitive impairment.

Donanemab Approved for Alzheimer’s in the U.S.

https://www.alzforum.org/news/community-news/donanemab-approved-alzheimers-us
ALZForum 3 July 2024
3 July 2024
The FDA label for donanemab is similar to that of lecanemab, which was approved almost a year ago to the day (Jul 2023 news). It includes a boxed warning of the risk of ARIA, particularly for people who have two copies of the APOE4 allele, and it recommends APOE genotyping before prescribing the drug. To monitor for ARIA, the FDA suggests MRI at baseline and before the second, third, fourth, and seventh infusions. This is more frequent than before the fifth, seventh, and 14th infusions as recommended for lecanemab. Donanemab has about twice the risk of ARIA, with most serious reactions occurring early (Jun 2024 news). The label also discusses the increased risk of ARIA for people with cerebral amyloid angiopathy or other signs of cerebrovascular disease.

June 2024

Proteomic analysis of Alzheimer’s disease cerebrospinal fluid reveals alterations associated with APOE ε4 and atomoxetine treatment

https://www.science.org/doi/10.1126/scitranslmed.adn3504
ERIC B. DAMMER, ANANTHARAMAN SHANTARAMAN, LINGYAN PING, DUC M. DUONG EKATERINA S. GERASIMOV, SUDA PARIMALA RAVINDRAN, VALBORG GUDMUNDSDOTTIR, ELISABET A. FRICK, GABRIELA T. GOMEZ, KEENAN A. WALKER, VALUR EMILSSON, LORI L. JENNINGS, VILMUNDUR GUDNASON, DANIEL WESTERN, CARLOS CRUCHAGA, JAMES J. LAH, THOMAS S. WINGO, ALIZA P. WINGO, NICHOLAS T. SEYFRIED, ALLAN I. LEVEY, AND ERIK C. B. JOHNSON
Science Translational Medicine VOL. 16, NO. 753
26 June 2024
DOI: 10.1126/scitranslmed.adn3504
Editor’s summary
The use of fluid biomarkers to stratify patients and monitor treatment response can facilitate the development of therapeutics for Alzheimer’s disease (AD). To extend the AD marker toolkit, Dammer et al. established an integrated cerebrospinal fluid (CSF) proteomic network and showed that interconnected groups of proteins (modules) were associated with distinct disease aspects such as Aβ and tau pathology, cognitive dysfunction, or APOE E4 status. The M20 glycolysis/redox homeostasis module was elevated in AD and correlated with cognitive dysfunction. M20 was reduced after atomoxetine treatment in CSF from patients participating in a clinical trial. Together, these results could provide a useful resource for AD biomarker development. —Daniela Neuhofer
Abstract
Alzheimer’s disease (AD) is currently defined by the aggregation of amyloid-β (Aβ) and tau proteins in the brain. Although biofluid biomarkers are available to measure Aβ and tau pathology, few markers are available to measure the complex pathophysiology that is associated with these two cardinal neuropathologies. Here, we characterized the proteomic landscape of cerebrospinal fluid (CSF) changes associated with Aβ and tau pathology in 300 individuals using two different proteomic technologies—tandem mass tag mass spectrometry and SomaScan. Integration of both data types allowed for generation of a robust protein coexpression network consisting of 34 modules derived from 5242 protein measurements, including disease-relevant modules associated with autophagy, ubiquitination, endocytosis, and glycolysis. Three modules strongly associated with the apolipoprotein E ε4 (APOE ε4) AD risk genotype mapped to oxidant detoxification, mitogen-associated protein kinase signaling, neddylation, and mitochondrial biology and overlapped with a previously described lipoprotein module in serum. Alterations of all three modules in blood were associated with dementia more than 20 years before diagnosis. Analysis of CSF samples from an AD phase 2 clinical trial of atomoxetine (ATX) demonstrated that abnormal elevations in the glycolysis CSF module—the network module most strongly correlated to cognitive function—were reduced by ATX treatment. Clustering of individuals based on their CSF proteomic profiles revealed heterogeneity of pathological changes not fully reflected by Aβ and tau.

Sleep, 24-Hour Activity Rhythms, and Subsequent Amyloid-β Pathology

https://jamanetwork.com/journals/jamaneurology/fullarticle/2820395#:~:text=Findings%20In%20this%20cohort%20study,E4)%20carriers%20compared%20to%20noncarriers.
Phuong Thuy Nguyen Ho, BSc; Sanne J. W. Hoepel, MSc; Maria Rodriguez-Ayllon, PhD; Annemarie I. Luik, PhD; Meike W. Vernooij, MD, PhD; Julia Neitzel, PhD
JAMA Neurology
Published online June 24, 2024. doi:10.1001/jamaneurol.2024.1755
Key Points
Question
Are disturbances of 24-hour activity rhythms and sleep associated with subsequent brain amyloid-β deposition?
Findings
In this cohort study of 319 adults aged 48 to 80 years without dementia, a more fragmented 24-hour activity rhythm was associated with higher amyloid-β burden assessed 7.8 years later, and this association was stronger in Alzheimer disease (AD) genetic risk (apolipoprotein E4) carriers compared to noncarriers. Accounting for AD pathology at baseline did not notably change our findings.
Meaning
The findings suggest that rhythm disturbances can precede amyloid-β deposition and may be a modifiable risk factor for AD.
Abstract
Importance
Sleep disturbances are common among older adults and have been associated with the development of Alzheimer disease (AD), such as amyloid-β (Aβ) pathology. For effective AD prevention, it is essential to pinpoint the specific disturbances in sleep and the underlying 24-hour activity rhythms that confer the highest risk of Aβ deposition. Objective To determine the associations of 24-hour activity rhythms and sleep with Aβ deposition in adults without dementia, to evaluate whether disrupted 24-hour activity and sleep may precede Aβ deposition, and to assess the role of the apolipoprotein E ε4 (APOE4) genotype.
Design, Setting, and Participants
This was an observational cohort study using data from the Rotterdam Study. Of 639 participants without dementia who underwent Aβ positron emission tomography (PET) from September 2018 to November 2021, 319 were included in the current study. Exclusion criteria were no APOE genotyping and no valid actigraphy data at the baseline visits from 2004 to 2006 or from 2012 to 2014. The mean (SD) follow-up was 7.8 (2.4) years. Data were analyzed from March 2023 to April 2024.
Exposures
Actigraphy (7 days and nights, objective sleep, and 24-hour activity rhythms), sleep diaries (self-reported sleep), Aβ42/40, phosphorylated tau (p-tau)181 and p-tau217 plasma assays, 18F-florbetaben PET (mean standard uptake value ratio [SUVR] in a large cortical region of interest), and APOE4 genotype. Main Outcomes and Measures Association of objective and self-reported sleep and 24-hour activity rhythms at baseline with brain Aβ PET burden at follow-up.
Results
The mean (range) age in the study population was 61.5 (48-80) years at baseline and 69.2 (60-88) years at follow-up; 150 (47%) were women. Higher intradaily variability at baseline, an indicator of fragmented 24-hour activity rhythms, was associated with higher Aβ PET burden at follow-up (β, 0.15; bootstrapped 95% CI, 0.04 to 0.26; bootstrapped P = .02, false discovery rate [FDR] P = .048). APOE genotype modified this association, which was stronger in APOE4 carriers (β, 0.38; bootstrapped 95% CI, 0.05 to 0.64; bootstrapped P = .03) compared to noncarriers (β, 0.07; bootstrapped 95% CI, −0.04 to 0.18; bootstrapped P = .19). The findings remained largely similar after excluding participants with AD pathology at baseline, suggesting that a fragmented 24-hour activity rhythm may have preceded Aβ deposition. No other objective or self-reported measure of sleep was associated with Aβ.
Conclusions and Relevance
Among community-dwelling adults included in this study, higher fragmentation of the 24-hour activity rhythms was associated with greater subsequent Aβ burden, especially in APOE4 carriers. These results suggest that rest-activity fragmentation could represent a modifiable risk factor for AD.

Multifaceted roles of APOE in Alzheimer disease

https://www.nature.com/articles/s41582-024-00988-2
Rosemary J. Jackson, Bradley T. Hyman & Alberto Serrano-Pozo
Nature Reviews Neurology (2024)
Published 21 June 2024
https://doi.org/10.1038/s41582-024-00988-2
Abstract
For the past three decades, apolipoprotein E (APOE) has been known as the single greatest genetic modulator of sporadic Alzheimer disease (AD) risk, influencing both the average age of onset and the lifetime risk of developing AD. The APOEε4 allele significantly increases AD risk, whereas the ε2 allele is protective relative to the most common ε3 allele. However, large differences in effect size exist across ethnoracial groups that are likely to depend on both global genetic ancestry and local genetic ancestry, as well as gene–environment interactions. Although early studies linked APOE to amyloid-β — one of the two culprit aggregation-prone proteins that define AD — in the past decade, mounting work has associated APOE with other neurodegenerative proteinopathies and broader ageing-related brain changes, such as neuroinflammation, energy metabolism failure, loss of myelin integrity and increased blood–brain barrier permeability, with potential implications for longevity and resilience to pathological protein aggregates. Novel mouse models and other technological advances have also enabled a number of therapeutic approaches aimed at either attenuating the APOEε4-linked increased AD risk or enhancing the APOEε2-linked AD protection. This Review summarizes this progress and highlights areas for future research towards the development of APOE-directed therapeutics.
Key points
• The risk of Alzheimer disease associated with the APOE genotype is modulated by global and local genetic ancestries, other genetic risk loci and the lifetime exposome of an individual.
• APOE missense mutations are providing key insights into the pathophysiology of the classic three APOE isoforms.
• The APOE genotype might modulate the risk of other neurodegenerative diseases by influencing the pathobiology of their culprit aggregation-prone proteins.
• The APOE isoforms affect a wide range of molecular and cellular functions in multiple brain cell types via cell-autonomous and non-autonomous mechanisms.
• Several strategies to target APOE therapeutically have shown efficacy in preclinical studies and hold promise for translation into clinical trials.

Effects of Oral ALZ-801/Valiltramiprosate on Plasma Biomarkers, Brain Hippocampal Volume, and Cognition: Results of 2-Year Single-Arm, Open-Label, Phase 2 Trial in APOE4 Carriers with Early Alzheimer's Disease

https://pubmed.ncbi.nlm.nih.gov/38902571/
John A Hey, Susan Abushakra, Kaj Blennow, Eric M Reiman, Jakub Hort, Niels D Prins, Katerina Sheardova, Patrick Kesslak, Larry Shen, Xinyi Zhu, Adem Albayrak, Jijo Paul, Jean F Schaefer, Aidan Power, Martin Tolar
Drugs 2024 Jun 20
Epub ahead of print 20 Jun 2024
DOI: 10.1007/s40265-024-02067-8
Abstract
Introduction:
ALZ-801/valiltramiprosate is a small-molecule oral inhibitor of beta amyloid (Aβ) aggregation and oligomer formation being studied in a phase 2 trial in APOE4 carriers with early Alzheimer's disease (AD) to evaluate treatment effects on fluid and imaging biomarkers and cognitive assessments.
Methods:
The single-arm, open-label phase 2 trial was designed to evaluate the effects of the ALZ-801 265 mg tablet taken twice daily (after 2 weeks once daily) on plasma fluid AD biomarkers, hippocampal volume (HV), and cognition over 104 weeks in APOE4 carriers. The study enrolled subjects aged 50-80 years, with early AD [Mini-Mental State Examination (MMSE) ≥ 22, Clinical Dementia Rating-Global (CDR-G) 0.5 or 1], apolipoprotein E4 (APOE4) genotypes including APOE4/4 and APOE3/4 genotypes, and positive cerebrospinal fluid (CSF) AD biomarkers or prior amyloid scans. The primary outcome was plasma p-tau181, HV evaluated by magnetic resonance imaging (MRI) was the key secondary outcome, and plasma Aβ42 and Aβ40 were the secondary biomarker outcomes. The cognitive outcomes were the Rey Auditory Verbal Learning Test and the Digit Symbol Substitution Test. Safety and tolerability evaluations included treatment-emergent adverse events and amyloid-related imaging abnormalities (ARIA). The study was designed and powered to detect 15% reduction from baseline in plasma p-tau181 at the 104-week endpoint. A sample size of 80 subjects provided adequate power to detect this difference at a significance level of 0.05 using a two-sided paired t-test.
Results:
The enrolled population of 84 subjects (31 homozygotes and 53 heterozygotes) was 52% females, mean age 69 years, MMSE 25.7 [70% mild cognitive impairment (MCI), 30% mild AD] with 55% on cholinesterase inhibitors. Plasma p-tau181 reduction from baseline was significant (31%, p = 0.045) at 104 weeks and all prior visits; HV atrophy was significantly reduced (p = 0.0014) compared with matched external controls from an observational Early AD study. Memory scores showed minimal decline from baseline over 104 weeks and correlated significantly with decreased HV atrophy (Spearman's 0.44, p = 0.002). Common adverse events were COVID infection and mild nausea, and no drug-related serious adverse events were reported. Of 14 early terminations, 6 were due to nonserious treatment-emergent adverse events and 1 death due to COVID. There was no vasogenic brain edema observed on MRI over 104 weeks.
Conclusions:
The effect of ALZ-801 on reducing plasma p-tau181 over 2 years demonstrates target engagement and supports its anti-Aβ oligomer action that leads to a robust decrease in amyloid-induced brain neurodegeneration. The significant correlation between reduced HV atrophy and cognitive stability over 2 years suggests a disease-modifying effect of ALZ-801 treatment in patients with early AD. Together with the favorable safety profile with no events of vasogenic brain edema, these results support further evaluation of ALZ-801 in a broader population of APOE4 carriers, who represent two-thirds of patients with AD.

Analysis of Cerebrospinal Fluid, Plasma β-Amyloid Biomarkers, and Cognition from a 2-Year Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer’s Disease Using Quantitative Systems Pharmacology Model

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11289344/
John A. Hey, Jeremy Y. Yu, Susan Abushakra, Jean F. Schaefer, Aidan Power, Patrick Kesslak, and Martin Tolar
Drugs 2024; 84(7): 825–839
Published online 20 Jun 2024
doi: 10.1007/s40265-024-02068-7
Abstract
Introduction
ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of beta-amyloid (Aβ) aggregation and oligomer formation in late-stage development as a disease-modifying therapy for early Alzheimer’s disease (AD). The present investigation provides a quantitative systems pharmacology (QSP) analysis of amyloid fluid biomarkers and cognitive results from a 2-year ALZ-801 Phase 2 trial in APOE4 carriers with early AD.
Methods
The single-arm, open-label phase 2 study evaluated effects of ALZ-801 265 mg two times daily (BID) on cerebrospinal fluid (CSF) and plasma amyloid fluid biomarkers over 104 weeks in APOE4 carriers with early AD [Mini-Mental State Examination (MMSE) ≥ 22]. Subjects with positive CSF biomarkers for amyloid (Aβ42/Aβ40) and tau pathology (p-tau181) were enrolled, with serial CSF and plasma levels of Aβ42 and Aβ40 measured over 104 weeks. Longitudinal changes of CSF Aβ42, plasma Aβ42/Aβ40 ratio, and cognitive Rey Auditory Verbal Learning Test (RAVLT) were compared with the established natural disease trajectories in AD using a QSP approach. The natural disease trajectory data for amyloid biomarkers and RAVLT were extracted from a QSP model and an Alzheimer’s disease neuroimaging initiative population model, respectively. Analyses were stratified by disease severity and sex.
Results
A total of 84 subjects were enrolled. Excluding one subject who withdrew at the early stage of the trial, data from 83 subjects were used for this analysis. The ALZ-801 treatment arrested the progressive decline in CSF Aβ42 level and plasma Aβ42/Aβ40 ratio, and stabilized RAVLT over 104 weeks. Both sexes showed comparable responses to ALZ-801, whereas mild cognitive impairment (MCI) subjects (MMSE ≥ 27) exhibited a larger biomarker response compared with more advanced mild AD subjects (MMSE 22–26).
Conclusions
In this genetically defined and biomarker-enriched early AD population, the QSP analysis demonstrated a positive therapeutic effect of oral ALZ-801 265 mg BID by arresting the natural decline of monomeric CSF and plasma amyloid biomarkers, consistent with the target engagement to prevent their aggregation into soluble neurotoxic oligomers and subsequently into insoluble fibrils and plaques over 104 weeks. Accompanying the amyloid biomarker changes, ALZ-801 also stabilized the natural trajectory decline of the RAVLT memory test, suggesting that the clinical benefits are consistent with its mechanism of action. This sequential effect arresting the disease progression on biomarkers and cognitive decline was more pronounced in the earlier symptomatic stages of AD. The QSP analysis provides fluid biomarker and clinical evidence for ALZ-801 as a first-in-class, oral small-molecule anti-Aβ oligomer agent with disease modification potential in AD.

Cerebrospinal fluid proteome profiling using machine learning shows a unique protein signature associated with APOE4 genotype

https://www.biorxiv.org/content/10.1101/2024.04.18.590160v2
Artur Shvetcov, Shannon Thomson, Ann-Na Cho, Heather M. Wilkins, Joanne H. Reed, Russell H. Swerdlow, David A. Brown, the Alzheimer’s Disease Neuroimaging Initiative, Caitlin A. Finney
BioRxIV
6/16/2024 (preprint)
doi: https://doi.org/10.1101/2024.04.18.590160
Abstract
INTRODUCTION
Proteome changes associated with APOE4 variant carriage that are independent of Alzheimer’s disease (AD) pathology and diagnosis are unknown. This study investigated APOE4 proteome changes in people with AD, mild cognitive impairment, and no impairment.
METHODS
Clinical, APOE genotype, and cerebrospinal fluid (CSF) proteome and AD biomarker data was sourced from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Proteome profiling was done using supervised machine learning.
RESULTS
We found an APOE4-specific proteome signature that was independent of cognitive diagnosis and AD pathological biomarkers, and increased risk of progression to cognitive impairment. Proteins were enriched in brain regions including the caudate and cortex and cells including endothelial cells, oligodendrocytes, and astrocytes. Enriched peripheral immune cells included T cells, macrophages, and B cells.
DISCUSSION
APOE4 carriers have a unique CSF proteome signature associated with a strong brain and peripheral immune and inflammatory phenotype that likely underlies APOE4 carriers’ vulnerability to cognitive decline and AD.

mTOR inhibition enhances synaptic and mitochondrial function in Alzheimer’s disease in an APOE genotype-dependent manner

https://journals.sagepub.com/doi/10.1177/0271678X241261942
Basavaraju G Sanganahalli, Jelena M Mihailovic, Hemendra J Vekaria, Daniel Coman, Andrew T Yackzan, Abeoseh Flemister, Chetan Aware, Kathryn Wenger, W Brad Hubbard, Patrick G Sullivan, Fahmeed Hyder, Ai-Ling Lin
Journal of Cerebral Blood Flow & Metabolism 2024;0(0).
First published online June 16, 2024
DOI: https://doi.org/10.1177/0271678X241261942
Abstract
Apolipoprotein ε4 (APOE4) carriers develop brain metabolic dysfunctions decades before the onset of Alzheimer’s disease (AD). A goal of the study is to identify if rapamycin, an inhibitor for the mammalian target of rapamycin (mTOR) inhibitor, would enhance synaptic and mitochondrial function in asymptomatic mice with human APOE4 gene (E4FAD) before they showed metabolic deficits. A second goal is to determine whether there may be genetic-dependent responses to rapamycin when compared to mice with human APOE3 alleles (E3FAD), a neutral AD genetic risk factor. We fed asymptomatic E4FAD and E3FAD mice with control or rapamycin diets for 16 weeks from starting from 3 months of age. Neuronal mitochondrial oxidative metabolism and excitatory neurotransmission rates were measured using in vivo 1H-[13C] proton-observed carbon-edited magnetic resonance spectroscopy, and isolated mitochondrial bioenergetic measurements using Seahorse. We found that rapamycin enhanced neuronal mitochondrial function, glutamate-glutamine cycling, and TCA cycle rates in the asymptomatic E4FAD mice. In contrast, rapamycin enhances glycolysis, non-neuronal activities, and inhibitory neurotransmission of the E3FAD mice. These findings indicate that rapamycin might be able to mitigate the risk for AD by enhancing brain metabolic functions for cognitively intact APOE4 carriers, and the responses to rapamycin are varied by APOE genotypes. Consideration of precision medicine may be needed for future rapamycin therapeutics.

Relationship between sex, APOE genotype, endocannabinoids and cognitive change in older adults with metabolic syndrome during a 3-year Mediterranean diet intervention

https://nutritionj.biomedcentral.com/articles/10.1186/s12937-024-00966-w
Natalia Soldevila-Domenech, Beatriz Fagundo, Aida Cuenca-Royo, Laura Forcano, Maria Gomis-González, Anna Boronat, Antoni Pastor, Olga Castañer, Maria Dolores Zomeño, Albert Goday, Mara Dierssen, Khashayar Baghizadeh Hosseini, Emilio Ros, Dolores Corella, Miguel Ángel Martínez-González, Jordi Salas-Salvadó, Fernando Fernández-Aranda, Montserrat Fitó & Rafael de la Torre
Nutrition Journal volume 23, Article number: 61 (2024)
Published 12 June 2024
DOI: https://doi.org/10.1186/s12937-024-00966-w
Abstract
Background
The Mediterranean diet (MedDiet) has demonstrated efficacy in preventing age-related cognitive decline and modulating plasma concentrations of endocannabinoids (eCBs) and N-acylethanolamines (NAEs, or eCB-like compounds), which are lipid mediators involved in multiple neurological disorders and metabolic processes. Hypothesizing that eCBs and NAEs will be biomarkers of a MedDiet intervention and will be related to the cognitive response, we investigated this relationship according to sex and apolipoprotein E (APOE) genotype, which may affect eCBs and cognitive performance.
Methods
This was a prospective cohort study of 102 participants (53.9% women, 18.8% APOE-ɛ4 carriers, aged 65.6 ± 4.5 years) from the PREDIMED-Plus-Cognition substudy, who were recruited at the Hospital del Mar Research Institute (Barcelona). All of them presented metabolic syndrome plus overweight/obesity (inclusion criteria of the PREDIMED-Plus) and normal cognitive performance at baseline (inclusion criteria of this substudy). A comprehensive battery of neuropsychological tests was administered at baseline and after 1 and 3 years. Plasma concentrations of eCBs and NAEs, including 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and N-docosahexaenoylethanolamine (DHEA), were also monitored. Baseline cognition, cognitive changes, and the association between eCBs/NAEs and cognition were evaluated according to gender (crude models), sex (adjusted models), and APOE genotype.
Results
At baseline, men had better executive function and global cognition than women (the effect size of gender differences was − 0.49, p = 0.015; and − 0.42, p = 0.036); however, these differences became nonsignificant in models of sex differences. After 3 years of MedDiet intervention, participants exhibited modest improvements in memory and global cognition. However, greater memory changes were observed in men than in women (Cohen’s d of 0.40 vs. 0.25; p = 0.017). In men and APOE-ε4 carriers, 2-AG concentrations were inversely associated with baseline cognition and cognitive changes, while in women, cognitive changes were positively linked to changes in DHEA and the DHEA/AEA ratio. In men, changes in the OEA/AEA and OEA/PEA ratios were positively associated with cognitive changes.
Conclusions
The MedDiet improved participants’ cognitive performance but the effect size was small and negatively influenced by female sex. Changes in 2-AG, DHEA, the OEA/AEA, the OEA/PEA and the DHEA/AEA ratios were associated with cognitive changes in a sex- and APOE-dependent fashion. These results support the modulation of the endocannabinoid system as a potential therapeutic approach to prevent cognitive decline in at-risk populations.
And from text:
Effect of APOE genotype
APOE differences in cognition
At baseline, there were no differences in cognitive performance based on APOE genotype (Supplementary Table 4). After 1 year of MedDiet intervention, both APOE-ε4 carriers and noncarriers exhibited improvements in global cognition and memory (p < 0.05), with no significant differences between groups (Supplementary Table 5). However, the Cohen’s d effect size of differences ranged 0.30 to 0.57, favoring APOE-ε4 carriers. After 3 years, global cognition and executive functioning composites improved in APOE-ε4 noncarriers but, on average, there was no significant change in these composites in APOE-ε4 carriers. However, although the Cohen’s d effect size of differences in cognitive change was moderate (-0.52 for global cognition and − 0.46 for memory), multivariable-adjusted models showed no significant differences between groups, except for the specific domain of visuoconstructive praxis and attention favoring APOE-ε4 noncarriers (Cohen’s d of -0.74, p = 0.010).
APOE differences in eCBs and NAEs
At baseline, the concentrations of eCBs and NAEs did not differ according to APOE genotype (Supplementary Table 6). After 6 months of MedDiet intervention, 2-AG, AEA, and several NAEs (OEA, PEA, DHEA, DGLEA, LEA, POEA, and SEA) decreased in APOE-ε4 noncarriers but remained unchanged in APOE-ε4 carriers (Supplementary Table 7). Larger differences between groups were observed for OEA (Cohen’s d = 1.08, p = 0.009) and PEA (Cohen’s d = 1.09, p = 0.009), and smaller differences were detected for AEA (Cohen’s d = 0.34, p = 0.003), LEA (Cohen’s d = 0.38, p = 0.007) and DEA (Cohen’s d = 0.14, p = 0.006) and DGLEA (Cohen’s d = 0.10, p = 0.048). After 1 year, APOE-ε4 noncarriers exhibited greater increases in the PEA/AEA ratio (Cohen’s d=-1.02, p = 0.031). Similarly, APOE-ε4 noncarriers showed greater increases in the DHEA/AEA ratio after 1 year (Cohen’s d=-0.36, p = 0.083) and 3 years (Cohen’s d=-0.30, p = 0.015).
APOE differences in cardiovascular and lifestyle risk factors
At baseline, cardiovascular and lifestyle risk factors did not differ according to APOE genotype (Supplementary Table 8). Between-group differences in changes in these factors were detected in terms of diastolic blood pressure and total cholesterol (Supplementary Table 9). Accordingly, after 6 months, APOE-ε4 carriers showed greater reductions in diastolic blood pressure than noncarriers (mean change of -8.0 vs. -3.6 mmHg, Cohen’s d= -1.64, p = 0.053). Similarly, after 1 year, APOE-ε4 carriers experienced greater reductions in total cholesterol than noncarriers (mean change of -9.0 vs. 3.7 mg/dL, Cohen’s d= -2.09, p = 0.045).
Association between eCBs and cognition by APOE genotype
As shown in Fig. 4A-B, within-subject changes in 2-AG concentrations after 1 year were negatively associated with changes in global cognition (β = -0.02, 95%CI -0.04, 0.00; pGAM = 0.012) and executive functions (β = -0.03, 95%CI -0.06, 0.00; pGAM =0.043) among APOE-ε4 carriers. In turn, within-subject change in the OEA/AEA ratio after 3 years was positively associated with change in executive function among APOE-ε4 noncarriers (Fig. 4C), and this relationship was linear (β = 0.05, 95%CI 0.00, 0.10; pGAM = 0.010).

Neuromodulatory subcortical nucleus integrity is associated with white matter microstructure, tauopathy and APOE status

https://www.nature.com/articles/s41467-024-48490-z
Alfie Wearn, Stéfanie A. Tremblay, Christine L. Tardif, Ilana R. Leppert, Claudine J. Gauthier, Giulia Baracchini, Colleen Hughes, Patrick Hewan, Jennifer Tremblay-Mercier, Pedro Rosa-Neto, Judes Poirier, Sylvia Villeneuve, Taylor W. Schmitz, Gary R. Turner, R. Nathan Spreng
Nature Communications 15, 4706 (2024)
Published 03 June 2024
https://doi.org/10.1038/s41467-024-48490-z
The neuromodulatory subcortical nuclei within the isodendritic core (IdC) are the earliest sites of tauopathy in Alzheimer’s disease (AD). They project broadly throughout the brain’s white matter. We investigated the relationship between IdC microstructure and whole-brain white matter microstructure to better understand early neuropathological changes in AD. Using multiparametric quantitative magnetic resonance imaging we observed two covariance patterns between IdC and white matter microstructure in 133 cognitively unimpaired older adults (age 67.9 ± 5.3 years) with familial risk for AD. IdC integrity related to 1) whole-brain neurite density, and 2) neurite orientation dispersion in white matter tracts known to be affected early in AD. Pattern 2 was associated with CSF concentration of phosphorylated-tau, indicating AD specificity. Apolipoprotein-E4 carriers expressed both patterns more strongly than non-carriers. IdC microstructure variation is reflected in white matter, particularly in AD-affected tracts, highlighting an early mechanism of pathological development.

Neuronal APOE4-induced Early Hippocampal Network Hyperexcitability in Alzheimers Disease Pathogenesis

https://www.biorxiv.org/content/10.1101/2023.08.28.555153v3
Dennis RTabuena, Sung-SoomJang, Brian Grone, Oscar Yip, Emily Aster Aery Jones, Jessica Blumenfeld, Zherui Liang, Nicole Koutsodendris, Antara Rao, Leonardo Ding, Alex R Zhang, Yanxia Hao, Qin Xu, Seo Yeon Yoon, Samuel De Leon, Yadong Huang, Misha Zilberter
bioRxiv 2023.08.28.555153
3 June 2024 (preprint)
doi: https://doi.org/10.1101/2023.08.28.555153
The full impact of apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on neuronal and network function remains unclear. We found hippocampal region-specific network hyperexcitability in young APOE4 knock-in (E4-KI) mice which predicted cognitive deficits at old age. Network hyperexcitability in young E4-KI mice was mediated by hippocampal region-specific subpopulations of smaller and hyperexcitable neurons that were eliminated by selective removal of neuronal APOE4. Aged E4-KI mice exhibited hyperexcitable granule cells, a progressive inhibitory deficit, and E/I imbalance in the dentate gyrus, exacerbating hippocampal hyperexcitability. Single-nucleus RNA-sequencing revealed neuronal cell type-specific and age-dependent transcriptomic changes, including Nell2 overexpression in E4-KI mice. Reducing Nell2 expression in specific neuronal types of E4-KI mice with CRISPRi rescued their abnormal excitability phenotypes, implicating Nell2 overexpression as a cause of APOE4-induced hyperexcitability. These findings highlight the early transcriptomic and electrophysiological alterations underlying APOE4-induced hippocampal network dysfunction and its contribution to AD pathogenesis with aging.

APOE4 increases energy metabolism in APOE-isogenic iPSC-derived neurons

https://www.biorxiv.org/content/10.1101/2024.06.03.597106v1
Vanessa Budny, Yannic Knoepfli, Debora Meier, Kathrin Zuercher, Chantal Bodenmann, Siri L Peter, Terry Mueller, Marie Tardy, Cedric Cortijo, Christian Tackenberg
bioRxiv 2024.06.03.597106
Posted June 03, 2024 (preprint)
doi: https://doi.org/10.1101/2024.06.03.597106
Abstract
The apolipoprotein E4 (APOE4) allele represents the major genetic risk factor for Alzheimers disease (AD). In contrast, APOE2 is known to lower the AD risk while APOE3 is defined as risk neutral. APOE plays a prominent role in the bioenergetic homeostasis of the brain, and early-stage metabolic changes have been detected in brains of AD patients. Although APOE is primarily expressed by astrocytes in the brain, neurons also have been shown as source for APOE. However, little is known about the differential role of the three APOE isoforms for neuronal energy homeostasis. In this study, we generated pure human neurons (iN cells) from APOE-isogenic induced pluripotent stem cells (iPSCs), expressing either APOE2, APOE3, APOE4 or carrying an APOE-knockout (KO) to investigate APOE isoform-specific effects on neuronal energy metabolism. We showed that endogenously produced APOE4 enhanced mitochondrial ATP production in APOE-isogenic iN cells but not in the corresponding iPS cell line. This effect neither correlated with the expression levels of mitochondrial fission or fusion proteins, nor with the intracellular or secreted levels of APOE, which were similar for APOE2, APOE3 and APOE4 iN cells. ATP production and basal respiration in APOE-KO iN cells strongly differed from APOE4 and more closely resembled APOE2 and APOE3 iN cells indicating a gain-of-function mechanism of APOE4 rather than a loss-of-function. Taken together, our findings in APOE isogenic iN cells reveal an APOE genotype-dependent and neuron-specific regulation of oxidative energy metabolism.

Neuromodulatory subcortical nucleus integrity is associated with white matter microstructure, tauopathy and APOE status

https://www.nature.com/articles/s41467-024-48490-z
Alfie Wearn, Stéfanie A. Tremblay, Christine L. Tardif, Ilana R. Leppert, Claudine J. Gauthier, Giulia Baracchini, Colleen Hughes, Patrick Hewan, Jennifer Tremblay-Mercier, Pedro Rosa-Neto, Judes Poirier, Sylvia Villeneuve, Taylor W. Schmitz, Gary R. Turner, R. Nathan Spreng
Nature Communications volume 15, Article number: 4706 (2024)
Published: 03 June 2024
DOI: https://doi.org/10.1038/s41467-024-48490-z
The neuromodulatory subcortical nuclei within the isodendritic core (IdC) are the earliest sites of tauopathy in Alzheimer’s disease (AD). They project broadly throughout the brain’s white matter. We investigated the relationship between IdC microstructure and whole-brain white matter microstructure to better understand early neuropathological changes in AD. Using multiparametric quantitative magnetic resonance imaging we observed two covariance patterns between IdC and white matter microstructure in 133 cognitively unimpaired older adults (age 67.9 ± 5.3 years) with familial risk for AD. IdC integrity related to 1) whole-brain neurite density, and 2) neurite orientation dispersion in white matter tracts known to be affected early in AD. Pattern 2 was associated with CSF concentration of phosphorylated-tau, indicating AD specificity. Apolipoprotein-E4 carriers expressed both patterns more strongly than non-carriers. IdC microstructure variation is reflected in white matter, particularly in AD-affected tracts, highlighting an early mechanism of pathological development.

==== Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease
https://www.nature.com/articles/s41467-024-49028-z
==== Zengjie Xia, Emily E. Prescott, Agnieszka Urbanek, Hollie E. Wareing, Marianne C. King, Anna Olerinyova, Helen Dakin, Tom Leah, Katy A. Barnes, Martyna M. Matuszyk, Eleni Dimou, Eric Hidari, Yu P. Zhang, Jeff Y. L. Lam, John S. H. Danial, Michael R. Strickland, Hong Jiang, Peter Thornton, Damian C. Crowther, Sohvi Ohtonen, Mireia Gómez-Budia, Simon M. Bell, Laura Ferraiuolo, Heather Mortiboys, Adrian Higginbottom, Stephen B. Wharton, David M. Holtzman, Tarja Malm, Rohan T. Ranasinghe, David Klenerman & Suman De
Nature Communications volume 15, Article number: 4695 (2024)
Published: 01 June 2024
DOI: https://doi.org/10.1038/s41467-024-49028-z
Abstract
Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer’s Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% of the mass of diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related functions of Aβ aggregates throughout the course of aggregation. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.

Retinal Dysfunction in Alzheimer's Disease (AD): A Dual Investigation into the Impact of APOE4 and Diabetes

https://iovs.arvojournals.org/article.aspx?articleid=2796269
Surabhi Abhyankar; Qianyi Luo; Neha Mahajan; Gabriella Hartman; Timothy William Corson; Adrian Oblak; Bruce Lamb; Ashay D Bhatwadekar
Investigative Ophthalmology & Visual Science June 2024, Vol.65, 334
June 2024
Abstract
Purpose :
The global impact of Alzheimer’s Disease (AD) is profound, affecting more than 33 million individuals worldwide. Late-onset AD (LOAD) is the predominant form, and the apolipoprotein e4 (APOE4) variant significantly contributes to its genetic underpinnings. The coexistence of diabetes further amplifies cognitive decline and dementia risks, and together, these comorbidities may exacerbate retinal dysfunction. To investigate the effects of the APOE4 gene and diabetes on retinal function,, we conducted two studies in APOE4-knock in (KI) (LOAD-risk) and APOE3-KI (LOAD-neutral) mice: 1) To evaluate the retinal phenotype and function and 2) To evaluate whether diabetes with the APOE4 genotype accelerates diabetic retinopathy (DR, a major complication of diabetes) phenotype. This research explores how the retina could serve as a model to examine the adverse impacts of APOE4.
Methods :
All the experiments were performed on twelve-month-old mice. Retina structure and function was assessed by optical coherence tomography (OCT), fundus photography, fluorescein angiography (FA), electroretinogram (ERG), and optokinetic reflex (OKR). A second group of mice were fed a control diet (CD) or western diet (WD) for 12 months to induce diabetes. All the experiments were performed longitudinally after two, six, and twelve months of diet treatment. The effect of WD on body weight (BW) and glucose metabolism was monitored, and the retinal phenotype and function were assessed as mentioned above.
Results :
APOE4-KI mice showed reduced retinal thickness and increased vascular tortuosity. ERG studies revealed functional deficits in the retinas of APOE4-KI animals. The APOE4-KI mice displayed lower visual acuity and contrast sensitivity. Both APOE4-KI and APOE3-KI mice subjected to a WD exhibited higher BW and elevated fasting blood glucose levels than their counterparts treated with a CD. Notably, the WD-treated APOE4-KI mice showed decrease in inner retinal thickness, increased tortuosity and reduction in a- and b-wave amplitudes in their retinas and lower visual acuity and contrast sensitivity after six months of diet treatment.
Conclusions :
The APOE4 allele is associated with retinal vascular changes, functional deficits, and increased susceptibility to retinal degeneration compared to the APOE3 allele. WD accelerates DR phenotype in the presence of the APOE4 allele.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

May 2024

Association of LIfestyle for BRAin health risk score (LIBRA) and genetic susceptibility with incident dementia and cognitive decline

https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.13801
Jeanne Neuffer, Maude Wagner, Elisa Moreno, Quentin Le Grand, Aniket Mishra, David-Alexandre Trégouët, Karen Leffondre, Cécile Proust-Lima, Alexandra Foubert-Samier, Claudine Berr, Christophe Tzourio, Catherine Helmer, Stéphanie Debette, Cécilia Samieri
Alzheimer's & Dementia Online before inclusion in an issue
First published: 22 May 2024
DOI: https://doi.org/10.1002/alz.13801
Abstract
INTRODUCTION
Evaluating whether genetic susceptibility modifies the impact of lifestyle-related factors on dementia is critical for prevention. METHODS
We studied 5170 participants from a French cohort of older persons free of dementia at baseline and followed for up to 17 years. The LIfestyle for BRAin health risk score (LIBRA) including 12 modifiable factors was constructed at baseline (higher score indicating greater risk) and was related to both subsequent cognitive decline and dementia incidence, according to genetic susceptibility to dementia (reflected by the apolipoprotein E [APOE] ε4 allele and a genetic risk score [GRS]). RESULTS
The LIBRA was associated with higher dementia incidence, with no significant effect modification by genetics (hazard ratio for one point score = 1.09 [95% confidence interval, 1.05; 1.13]) in APOE ε4 non-carriers and = 1.15 [1.08; 1.22] in carriers; P = 0.15 for interaction). Similar findings were obtained with the GRS and with cognitive decline. DISCUSSION
Lifestyle-based prevention may be effective whatever the genetic susceptibility to dementia.

Exploring the link between comorbidities and Alzheimer's dementia in the Australian Imaging, Biomarker & Lifestyle (AIBL) study

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/dad2.12593
Catherine Quynh Nhu Nguyen, Liwei Ma, Yi Ling Clare Low, Edwin C. K. Tan, Christopher Fowler, Colin L. Masters, Liang Jin, Yijun Pan
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume16, Issue2 April‐June 2024, e12593
First published: 20 May 2024
DOI: https://doi.org/10.1002/dad2.12593
Abstract
INTRODUCTION
Mounting evidence suggests that certain comorbidities may influence the clinical evolution of Alzheimer's dementia (AD).
METHODS
We conducted logistic regression analyses on the medical history and cognitive health diagnoses of participants in the Australian Imaging, Biomarker & Lifestyle study (n = 2443) to investigate cross-sectional associations between various comorbidities and mild cognitive impairment (MCI)/AD.
RESULTS
A mixture of associations were observed. Higher comorbidity of anxiety and other neurological disorders was associated with higher odds of AD, while arthritis, cancer, gastric complaints, high cholesterol, joint replacement, visual defect, kidney and liver disease were associated with lower odds of AD.
DISCUSSION
This study underscores the links between specific comorbidities and MCI/AD. Further research is needed to elucidate the longitudinal comorbidity-MCI/AD associations and underlying mechanisms of these associations.
Highlights
• Comorbidities that significantly increased AD odds included anxiety and other neurological disorders.
• Arthritis, cancer, gastric complaints, high cholesterol, joint replacement, visual defect, kidney and liver disease were associated with lower odds of AD.
• Alcohol consumption had the most significant confounding effect in the study.
• Visual-AD association was modified by age, sex, and APOE ε4 allele status.
• Anxiety-AD and depression-AD associations were modified by sex.

Alzheimer’s disease as a women’s health challenge: a call for action on integrative precision medicine approaches

https://www.nature.com/articles/s44294-024-00021-3
S. Miramontes, C. Pereda Serras, S. R. Woldemariam, U. Khan, Y. Li, A. S. Tang, E. Tsoy, T. T. Oskotsky & M. Sirota
npj Womens Health 2, 17 (2024)
Published 20 May 2024
DOI: https://doi.org/10.1038/s44294-024-00021-3
Alzheimer’s Disease (AD) is marked by pronounced sex differences in pathophysiology and progression. However, the field has yet to fully recognize AD as a women’s health issue, delaying the development of targeted preventative strategies and treatments. This perspective explores the elements impacting AD in women, identifying sex specificity in risk factors, highlighting new diagnostic approaches with electronic health records, and reviewing key molecular studies to underscore the need for integrative precision medicine approaches. Established AD risk factors such as advancing age, the apolipoprotein E4 allele, and poorer cardiovascular health affect women differently. We also shed light on sociocultural risk factors, focusing on the gender disparities that may play a role in AD development. From a biological perspective, sex differences in AD are apparent in biomarkers and transcriptomics, further emphasizing the need for targeted diagnostics and treatments. The convergence of novel multiomics data and cutting-edge computational tools provides a unique opportunity to study the molecular underpinnings behind sex dimorphism in AD. Thus, precision medicine emerges as a promising framework for understanding AD pathogenesis through the integration of genetics, sex, environment, and lifestyle. By characterizing AD as a women’s health challenge, we can catalyze a transformative shift in AD research and care, marked by improved diagnostic accuracy, targeted interventions, and ultimately, enhanced clinical outcomes.

Does a Rare Fibronectin Variant Protect Against APOE4?

https://www.alzforum.org/news/research-news/does-rare-fibronectin-variant-protect-against-apoe4
AlzForum, 16 May 2024
16 May 2024
• Some APOE4 carriers are resilient to Alzheimer’s.
• A glycine to glutamic acid substitution at amino acid 357 of fibronectin reduces their risk of AD.
• Resilient E4 carriers had limited fibronectin surrounding blood vessels and minimal gliosis in the brain

Dr. Kellyann Niotis - ApoE4 Alleles and Alzheimer's

https://www.youtube.com/watch?v=YfhOgcY6dxM
16 May 2024
Short YouTube video where Dr Kellyann Niotis, preventative Neurologist addresses the Nature article, “APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease” published on 6 May 2024. From the notes: “I know this Nature Medicine paper has gotten a lot of press, but let’s be careful with the conclusion we draw. Having two copies of the ApoE4 allele does NOT guarantee you will develop AD. According to population-based studies, the lifetime risk of mild cognitive impairment or dementia for ApoE4 homozygotes is 30-67% and this depends on multiple factors: age, sex, other genes, ethnicity, and environmental and lifestyle factors. - We know amyloid is insufficient to cause cognitive impairment or dementia due AD - Based on prior work, pTau217 tracks best with cognitive trajectory - AD is a CLINICO-Pathological condition. No clinical decrement in cognitive function = NO DISEASE! It cannot be diagnosed based on the presence of biomakers alone. ApoE genotyping can help empower patients to improve their health by applying personalized prevention strategies and early interventions.”

Suppressing APOE4-induced mortality and cellular damage by targeting VHL

https://www.biorxiv.org/content/10.1101/2024.02.28.582664v2?fbclid=IwZXh0bgNhZW0CMTEAAR1abVcYPWCoU3NamKTV-44g6TP_BiVt3nSoYqZ2rP_PHprK-6jwJrKQS1I_aem_AWnCEQ4e741ASns0OB40MQtAQi8bQ3ARdwlV3HHUVFcBsrA5jO8ZOtIOGtI6rVBVePX43K7cqwJHoobVwKvfmsDX
Wei Jiang, Yimin Cao, Yue Xue, Yichun Ji, Benjamin Y. Winer, Mengqi Zhang, Neel S Singhal, Jonathan Pierce, Song Chen, View Dengke K. Ma
bioRxiv 2024.02.28.582664
version 2: 10 May 2024 (preprint)
doi: https://doi.org/10.1101/2024.02.28.582664
Abstract
Mortality rate increases with age and can accelerate upon extrinsic or intrinsic damage to individuals. Identifying factors and mechanisms that curb the population mortality rate has wide-ranging implications. Here, we show that targeting the VHL-1 (Von Hippel-Lindau) protein suppresses C. elegans mortality caused by distinct factors, including elevated reactive oxygen species, temperature, and APOE4, the genetic variant that confers high risks of neurodegeneration in Alzheimer's diseases and all-cause mortality in humans. These mortality factors are of different physical-chemical nature, yet result in similar cellular dysfunction and damage that are suppressed by deleting VHL-1. Stabilized HIF-1 (hypoxia-inducible factor), a transcription factor normally targeted for degradation by VHL-1, recapitulates the protective effects of deleting VHL-1. HIF-1 orchestrates a genetic program that defends against mitochondrial abnormalities, excess oxidative stress, cellular proteostasis dysregulation, and endo-lysosomal rupture, all events that lead to mortality. Genetic inhibition of Vhl also alleviates cerebral vascular injury and synaptic lesions in APOE4 mice, supporting an evolutionarily conserved mechanism. Collectively, we identify the VHL-HIF axis as a potent modifier of APOE4 and propose that targeting VHL-HIF in non-proliferative animal tissues may suppress tissue injuries and mortality by broadly curbing cellular damage.

Blood Pressure Variability, Central Autonomic Network Dysfunction, and Cerebral Small‐Vessel Disease in APOE4 Carriers

https://www.ahajournals.org/doi/epub/10.1161/JAHA.123.034116?fbclid=IwZXh0bgNhZW0CMTEAAR0vkMkOsj4rxDfhF_hN6ZJ3ePLvXVWPozyu611qEPxQ4X-9SzRGPo4Wo2Y_aem_AaCDJQQOUO9RECHmbUWUBAtaAAj8AbudytEh2MgrJXroHo17uoYs-WQmXmLuCu6-IyUQ84rCZKqkBWu42qe81tgn
Trevor Lohman, Isabel Sible, Arunima Kapoor, Allison C. Engstrom, Fatemah Shenasa, John Paul M. Alitin, Aimee Gaubert, Kathleen E. Rodgers, David Bradford, Mara Mather, S. Duke Han, Julian F. Thayer and Daniel A. Nation
Journal of the American Heart AssociationVolume 13, Issue 9
7 May 2024
https://doi.org/10.1161/JAHA.123.034116
No significant differences in age, sex, vascular risk factors, blood pressure, CSVD features, or CAN connectivity were observed between APOE4 carrier status group. In subgroup linear and logistic regression analysis, higher BPV, quantified as variability independent of the mean,2 was associated with increased log odds of CSVD presence (B=18.92, P=0.02), and was also associated with increased WML volume fraction (B=0.003, P=0.04) in APOE4 carriers, independent of age, sex, CAN connectivity, average blood pressure, and vascular risk factor burden. A similar relationship was not observed in noncarriers. Any potential mediation effect of CAN connectivity on the relationship between BPV and CSVD was not statistically significant in this analysis (Figure [B]). Instead, CAN connectivity was a statistically significant moderator of the relationship between BPV and CSVD in APOE4 carriers, whereby BPV effects on CSVD presence (B=36.43, P=0.02) and WML volume fraction (B=0.0006, P=0.01) were greater in those with lower CAN connectivity (−1 SD). The conditional effect of BPV on odds of CSVD presence and WML volume illustrates how BPV is more strongly correlated with CSVD as CAN connectivity diminishes (Figure [C]). Mediation and moderation analyses were performed in R (R Foundation for Statistical Computing, Vienna, Austria) using Hayes PROCESS macro model 1 (simple moderation) and model 4 (simple mediation) with x (independent variable)=BPV, y (dependent variable)=WML/IC fraction/Presence of CSVD, and w (moderator)/m (mediator)=CAN connectivity. Older APOE4 carriers with elevated beat‐to‐beat BPV exhibited increased CSVD presence and severity, independent of age, average blood pressure, vascular risk factor burden, and CAN function. To our knowledge, this is the first study to report a relationship between BPV and CSVD specifically in APOE4 carriers. These findings are consistent with prior studies indicating stronger links between BPV and neuropathologic change in APOE4 carriers versus noncarriers.2 These findings could also suggest that BPV and central autonomic dysfunction may have synergistic effects on CSVD in older APOE4 carriers, which may be related to their higher risk of cerebral amyloid angiopathy and blood–brain barrier disruption. These results add to mounting evidence for the role of BPV as a risk factor for cerebrovascular disease, raising the question of what drives BPV elevation in older adults. There are multiple regulatory mechanisms underlying age‐related changes in BPV, including autonomic functions controlled by the CAN. CSVD could damage white matter connections that link central autonomic nodes, potentially disrupting blood pressure regulation.3, 4 However, causal mediation analysis showed that changes in the CAN could not account for the relationship between BPV and CSVD presence or extent, suggesting that increased BPV is more likely a cause rather than a consequence of CSVD.1 Nevertheless, the relationship between higher BPV and greater CSVD burden was driven by APOE4 carriers with lower CAN connectivity. These findings could suggest that BPV and central autonomic dysfunction may have synergistic effects on CSVD in older APOE4 carriers. The mechanism is unclear, but autonomic dysfunction may hamper the ability of the cerebrovasculature to adapt to increased BPV.5 Further study of autonomic and cerebrovascular autoregulatory functions related to CAN connectivity and BPV may yield further insights into potential treatments. A strength of the present study is the use of a CAN definition derived from a voxel‐level meta‐analysis.4 Additional strengths include use of multimodal imaging to characterize CSVD presence and severity. Examination of APOE4 gene effects and mediation/moderation analyses are further strengths. Future studies should evaluate the potential mediating and moderating effects of subsystems with the broader CAN. Study limitations include the cross‐sectional design, which limits causal inference, and the relatively small sample size.

APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease

https://www.nature.com/articles/s41591-024-02931-w?fbclid=IwZXh0bgNhZW0CMTEAAR3Z7DQDDHkNke47NjkrEOG4AyzrhbQczOs98Y61qxBvO4jd-LJTfO-EAeI_aem_AVuG8aMZ2lqFMczHpSL1z5_T0ti-s9dZ-FcQpR0yYuvQhcNTZPubyR9cGs6OFlkBKkc4tSaERJ8kWIdQ4vcflw2-
Juan Fortea, Jordi Pegueroles, Daniel Alcolea, Olivia Belbin, Oriol Dols-Icardo, Lídia Vaqué-Alcázar, Laura Videla, Juan Domingo Gispert, Marc Suárez-Calvet, Sterling C. Johnson, Reisa Sperling, Alexandre Bejanin, Alberto Lleó & Víctor Montal
Nature Medicine volume 30, pages1284–1291 (2024)
06 May 2024
https://doi.org/10.1038/s41591-024-02931-w
Abstract
This study aimed to evaluate the impact of APOE4 homozygosity on Alzheimer’s disease (AD) by examining its clinical, pathological and biomarker changes to see whether APOE4 homozygotes constitute a distinct, genetically determined form of AD. Data from the National Alzheimer’s Coordinating Center and five large cohorts with AD biomarkers were analyzed. The analysis included 3,297 individuals for the pathological study and 10,039 for the clinical study. Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3 homozygotes. By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating near-full penetrance of AD biology in APOE4 homozygotes. The age of symptom onset was earlier in APOE4 homozygotes at 65.1, with a narrower 95% prediction interval than APOE3 homozygotes. The predictability of symptom onset and the sequence of biomarker changes in APOE4 homozygotes mirrored those in autosomal dominant AD and Down syndrome. However, in the dementia stage, there were no differences in amyloid or tau positron emission tomography across haplotypes, despite earlier clinical and biomarker changes. The study concludes that APOE4 homozygotes represent a genetic form of AD, suggesting the need for individualized prevention strategies, clinical trials and treatments.

Human APOE allelic variants suppress the formation of diffuse and fibrillar Aβ deposits relative to mouse Apoe in transgenic mouse models of Alzheimer amyloidosis

https://www.biorxiv.org/content/10.1101/2024.04.30.591932v1?fbclid=IwZXh0bgNhZW0CMTEAAR1TdUoTnFjSd8Hy_sGYlfBvEXTyjZXnguJZIbv6QtsDhexoypOsYU4mMBk_aem_Ae7E3IzY0d5f2Y2hCpcm-DkrMbVCMCIEzdpvhgFhb51Jf1WXeeT0TZddKnMC1DkHuQXfQMGhtInd467CmsH_EVo6
Guilian Xu, Patricia Sacilotto, Carmelina Gorski, Parul Bali, Susan Fromholt, Quan Vo, Karen N McFarland, Qing Lu, David R Borchelt, Paramita Chakrabarty
bioRxiv 2024.04.30.591932
May 1, 2024 (preprint)
doi: https://doi.org/10.1101/2024.04.30.591932
Abstract
Background Apolipoprotein E (apoE) modulates the deposition of amyloid β (Aβ) aggregates in Alzheimer’s disease (AD) in an isoform-dependent manner. In transgenic mouse models of AD-amyloidosis, replacing mouse Apoe alleles with human APOE variants suppresses fibrillar Aβ deposits. In the PD-APP transgenic mouse model, deletion of the Apoe gene led to selective reduction of fibrillar deposits with increased diffuse deposits. This finding suggested that apoE may have differential effects on different types of amyloid pathology. Methods Here, we investigated the interaction between the type of Aβ pathology in the brain and human apoE isoforms in different transgenic mouse models. Results In the APPsi model that develops predominantly diffuse Aβ plaques late in life, we determined that replacing mouse Apoe with human APOE3 or APOE4 genes potently suppressed diffuse amyloid formation, with apoE3 exhibiting a greater activity relative to apoE4. Relative to apoE4, apoE3 appeared to suppress Aβ deposition in the cerebral vasculature. In a second cohort, we accelerated the deposition of diffuse Aβ pathology by seeding, finding that seeded APPsi mice harboring APOE4 or APOE3 developed equal burdens of diffuse parenchymal Aβ. Finally, in the recently developed SAA-APP model that has a mix of dense-core and fibrous Aβ plaques, we found that replacing mouse apoE with human apoE suppressed deposition significantly, with the amyloid burden following the trend of Apoe>>APOE4> APOE3∼APOE2. In the SAA-APP and seeded APPsi models, we found evidence of apoE protein associated with Aβ plaques. Conclusions Overall, these observations demonstrate a capacity for human apoE to suppress the deposition of both diffuse and fibrillar-cored deposits, relative to mouse apoE. Notably, in the seeded paradigm, the suppressive activity of human apoE3 and apoE4 appeared to be overwhelmed. Taken together, this study demonstrates that APOE genotype influences the deposition of both cored-fibrillar and diffuse amyloid.

April 2024

Blood Pressure Variability, Central Autonomic Network Dysfunction, and Cerebral Small‐Vessel Disease in APOE4 Carriers

https://www.ahajournals.org/doi/10.1161/JAHA.123.034116
Trevor Lohman, Isabel Sible, Arunima Kapoor, Allison C. Engstrom, Fatemah Shenasa, John Paul M. Alitin, Aimee Gaubert, Kathleen E. Rodgers, David Bradford, Mara Mather, S. Duke Han, Julian F. Thayer and Daniel A. Nation
Journal of the American Heart Association Vol. 13, No. 9, 2024
Originally published 30 Apr 2024
DOI: https://doi.org/10.1161/JAHA.123.034116
Increased blood pressure variability (BPV) is a risk factor for Alzheimer disease and cerebral small‐vessel disease (CSVD),1 independent of blood pressure. Studies suggest BPV‐associated risk for Alzheimer disease may be more prominent in apolipoprotein E4 (APOE4) carriers,2 but no studies to date have examined BPV‐associated risk for CSVD in APOE4 carriers. It also remains uncertain whether BPV elevation is a cause or a consequence of CSVD3 or to what degree central autonomic network (CAN) dysfunction may contribute to BPV‐associated risk for CSVD. Seventy independently living older adults (65.7% women) aged 55 to 89 years (70±7.31) with no history of stroke or Alzheimer disease underwent 5 minutes of resting beat‐to‐beat BPV monitoring, genetic testing for APOE genotype, and brain structural/functional magnetic resonance imaging to determine CSVD burden and CAN resting‐state functional connectivity. CSVD presence was defined by visual rating of the presence and extent of white matter lesions (WMLs), microbleeds, lacunes, and perivascular spaces. The CAN was based on a meta‐analysis of 43 studies4 (Figure [A]). Causal mediation and simple moderation analysis evaluated BPV and CAN connectivity effects on CSVD in APOE4 carriers (n=37) and noncarriers (n=33) using a cross‐sectional study design. This study was approved by the University of Southern California and University of California, Irvine Institutional Review Boards, and all participants gave informed consent. The data that support the findings of this study are available upon reasonable request from the corresponding author.
And from text:
No significant differences in age, sex, vascular risk factors, blood pressure, CSVD features, or CAN connectivity were observed between APOE4 carrier status group.

Estradiol improves behavior in FAD transgenic mice that express APOE3 but not APOE4 after ovariectomy

https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1374825/full?utm_tsource=F-NTF&utm_medium=EMLX&utm_campaign=PRD_FEOPS_20170000_ARTICLE&fbclid=IwZXh0bgNhZW0CMTEAAR3LFbIA2g7GgVd_p_hSSJS15yVZKn7rOAf8-NSEeB78ZJA3QSTH73QUGQI_aem_AWoaTNFWxRl2T9m4Tss-qIfqyHTjqOJ5CGlGZe4mqKTGfgM5JtdZ-tAe0-s7w1Px5P8z0pq_IdTqS6lMZGxm5rgu
Deebika Balu ,Ana C. Valencia-Olvera, Ashwini Deshpande, Saharsh Narayanam, Sravya Konasani, Shreya Pattisapu, Jason M. York, Gregory, R. J. Thatcher,Mary Jo LaDu,Leon M. Tai
Frontiers in Endocrinology, Sec. Translational Endocrinology Volume 15 - 2024
28 April 2024
DOI: https://doi.org/10.3389/fendo.2024.1374825
Increasing evidence suggests that female individuals have a higher Alzheimer’s disease (AD) risk associated with post-menopausal loss of circulating estradiol (E2). However, clinical data are conflicting on whether E2 lowers AD risk. One potential contributing factor is APOE. The greatest genetic risk factor for AD is APOE4, a factor that is pronounced in female individuals post-menopause. Clinical data suggests that APOE impacts the response of AD patients to E2 replacement therapy. However, whether APOE4 prevents, is neutral, or promotes any positive effects of E2 is unclear. Therefore, our goal was to determine whether APOE modulates the impact of E2 on behavior and AD pathology in vivo. To that end, mice that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce Aβ42 were ovariectomized at either 4 months (early) or 8 months (late) and treated with vehicle or E2 for 4 months. In E3FAD mice, we found that E2 mitigated the detrimental effect of ovariectomy on memory, with no effect on Aβ in the early paradigm and only improved learning in the late paradigm. Although E2 lowered Aβ in E4FAD mice in the early paradigm, there was no impact on learning or memory, possibly due to higher Aβ pathology compared to E3FAD mice. In the late paradigm, there was no effect on learning/memory and Aβ pathology in E4FAD mice. Collectively, these data support the idea that, in the presence of Aβ pathology, APOE impacts the response to E2 supplementation post-menopause.

Impact of Apolipoprotein E4 on the Locus Coeruleus Functional Connectivity in Preclinical Alzheimer's Disease

https://content.iospress.com/articles/journal-of-alzheimers-disease/jad240065
Um, Yoo Hyun | Wang, Sheng-Min | Kang, Dong Woo | Kim, Sunghwan | Lee, Chang Uk | Kim, Donghyeond | Choe, Yeong Simd | Kim, Regina E.Y.| Lee, Soyounge; | Lee, Min-Kyungg | Lim, Hyun Kookb
Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2024
Published: 26 April 2024
DOI: 10.3233/JAD-240065
Abstract:
Background:
Recent interest has surged in the locus coeruleus (LC) for its early involvement in Alzheimer’s disease (AD), notably concerning the apolipoprotein ɛ4 allele (APOE4).
Objective:
This study aimed to discern LC functional connectivity (FC) variations in preclinical AD subjects, dissecting the roles of APOE4 carrier status and amyloid-β (Aβ) deposition.
Methods:
A cohort of 112 cognitively intact individuals, all Aβ-positive, split into 70 APOE4 noncarriers and 42 carriers, underwent functional MRI scans, neuropsychological assessments, and APOE genotyping. The research utilized seed to voxel analysis for illustrating LC rsFC discrepancies between APOE4 statuses and employed a general linear model to examine the interactive influence of APOE4 carrier status and Aβ deposition on LC FC values.
Results:
The investigation revealed no significant differences in sex, age, or SUVR between APOE4 carriers and noncarriers. It found diminished LC FC with the occipital cortex in APOE4 carriers and identified a significant interaction between APOE4 carrier status and temporal lobe SUVR in LC FC with the occipital cortex. This interaction suggested a proportional increase in LC FC for APOE4 carriers. Additional notable interactions were observed affecting LC FC with various brain regions, indicating a proportional decrease in LC FC for APOE4 carriers.
Conclusions:
These findings confirm that APOE4 carrier status significantly influences LC FC in preclinical AD, showcasing an intricate relationship with regional Aβ deposition. This underscores the critical role of genetic and pathological factors in early AD pathophysiology, offering insights into potential biomarkers for early detection and intervention strategies.

Large-scale Deep Proteomic Analysis in Alzheimer’s Disease Brain Regions Across Race and Ethnicity

https://www.biorxiv.org/content/10.1101/2024.04.22.590547v1
Fatemeh Seifar, Edward J. Fox, Anantharaman Shantaraman, Yue Liu, Eric B. Dammer, Erica Modeste, Duc M. Duong, Luming Yin, Adam N. Trautwig, Qi Guo, Kaiming Xu, Lingyan Ping, Joseph S. Reddy, Mariet Allen, Zachary Quicksall, Laura Heath, Jo Scanlan, Erming Wang, Minghui Wang, Abby Vander Linden, William Poehlman, Xianfeng Chen, Saurabh Baheti, Charlotte Ho, Thuy Nguyen, Geovanna Yepez, Adriana O. Mitchell, Stephanie R. Oatman, Xue Wang, Minerva M. Carrasquillo, Alexi Runnels, Thomas Beach, Geidy E. Serrano, Dennis W. Dickson, Edward B. Lee, Todd E. Golde, Stefan Prokop, Lisa L. Barnes, Bin Zhang, Varham Haroutunian, Marla Gearing, James J. Lah, Philip De Jager, David A Bennett, Anna Greenwood, Nilüfer Ertekin-Taner, Allan I. Levey, Aliza Wingo, Thomas Wingo, Nicholas T. Seyfried
bioRxiv 2024.04.22.590547
April 26, 2024 (Preprint)
DOI: https://doi.org/10.1101/2024.04.22.590547
Abstract
Introduction
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within the non-Hispanic White (NHW) population. Here we aimed to provide comprehensive insights into the proteomic landscape of AD across diverse racial and ethnic groups.
Methods
Dorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) brain tissues were donated from multiple centers (Mayo Clinic, Emory University, Rush University, Mt. Sinai School of Medicine) and were harmonized through neuropathological evaluation, specifically adhering to the Braak staging and CERAD criteria. Among 1105 DLPFC tissue samples (998 unique individuals), 333 were from African American donors, 223 from Latino Americans, 529 from NHW donors, and the rest were from a mixed or unknown racial background. Among 280 STG tissue samples (244 unique individuals), 86 were African American, 76 Latino American, 116 NHW and the rest were mixed or unknown ethnicity. All tissues were uniformly homogenized and analyzed by tandem mass tag mass spectrometry (TMT-MS).
Results
As a Quality control (QC) measure, proteins with more than 50% missing values were removed and iterative principal component analysis was conducted to remove outliers within brain regions. After QC, 9,180 and 9,734 proteins remained in the DLPC and STG proteome, respectively, of which approximately 9,000 proteins were shared between regions. Protein levels of microtubule-associated protein tau (MAPT) and amyloid-precursor protein (APP) demonstrated AD-related elevations in DLPFC tissues with a strong association with CERAD and Braak across racial groups. APOE4 protein levels in brain were highly concordant with APOE genotype of the individuals.
Discussion
This comprehensive region resolved large-scale proteomic dataset provides a resource for the understanding of ethnoracial-specific protein differences in AD brain.

Cerebrospinal fluid proteome profiling using machine learning shows a unique protein signature associated with APOE4 genotype

https://www.biorxiv.org/content/10.1101/2024.04.18.590160v1?fbclid=IwZXh0bgNhZW0CMTEAAR0Dx7xj1FZYQ9gaBmdeYmSszflpCgHM77btKkvhYR0QjaKjwk_sImxrPg0_aem_Afc8n_mso7j25bPTe6L5HmLIUUqCiofvojWj9tJ31XgzqgFaO0Oob1qhTBCjHD7X4JKTTCDyZTaMSW7EHEnw50L0
Artur Shvetcov, PhD, Shannon Thomson, PhD, Ann-Na Cho, PhD, Heather M. Wilkins, PhD, Joanne H. Reed, PhD, Russell H. Swerdlow, MD, David A. Brown, PhD, and Caitlin A. Finney, PhD
bioRxiv 2024.04.18.590160
April 22, 2024 (preprint)
doi : https://doi.org/10.1101/2024.04.18.590160
Abstract
APOE4 is the biggest genetic risk factor for Alzheimer’s disease (AD). Proteome-wide changes independent of AD brain pathology and whether these extend to APOE4 carriers irrespective of cognitive status remain unknown. To investigate APOE4-associated proteome changes in people with and without AD. Patient clinical, APOE genotype, and cerebrospinal fluid (CSF) proteome data for 735 participants was sourced from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Participants with no cognitive impairment, mild cognitive impairment (MCI), and AD were included. Diagnosis was defined using cognitive assessments. Supervised machine learning (classification and regression trees; CART) was used for proteome profiling to identify protein signatures. Enrichment analyses for brain regions and cells and peripheral immune cells were performed using NetworkAnalyst 3.0 and the Human Protein Atlas. CART revealed an APOE4 specific proteome signature consisting of 7 proteins that were independent predictors of APOE4 carriers (sensitivity, specificity, PPV, NPV, and AUC = 1.0) and 50 proteins that interacted together for prediction (sensitivity = 0.99, specificity = 0.74, PPV = 0.86, NPV = 0.98, AUC = 0.92). This signature was found across APOE4 carriers independently of diagnosis and was associated with an increased risk of progression to cognitive impairment over time. Proteins within the signature were enriched in brain regions including the caudate and cortex. Enriched brain cells included endothelial cells, oligodendrocytes, and astrocytes. Enriched peripheral immune cells included T cells, macrophages, and B cells. We identified an APOE4 specific CSF proteome signature of 57 proteins that was independent of cognitive status and was associated with an increased risk of progression to cognitive impairment. It was also associated with a strong immune and inflammatory phenotype across the brain and periphery. Our findings suggest that the APOE4 proteome signature is independent of AD-specific brain pathology and likely underlies APOE4 carriers’ vulnerability to cognitive decline and AD.

Association between abnormal lipid metabolism and Alzheimer's disease: New research has revealed significant findings on the APOE4 genotype in microglia

https://www.jstage.jst.go.jp/article/bst/18/2/18_2024.01092/_article/-char/en
Xiqi Hu, Ya-nan Ma, Ying Xia
BioScience Trends, 2024, Volume 18, Issue 2, Pages 195-197
Advance online publication April 17, 2024
DOI: https://doi.org/10.5582/bst.2024.01092
Abstract:
APOE4 is widely recognized as a genetic risk factor for Alzheimer's disease (AD), implicated in 60–80% of all AD cases. Recent research suggests that microglia carrying the APOE4 genotype display abnormal lipid metabolism and accumulate lipid droplets, which may exacerbate the pathology of AD. Microglia play a critical role in immune surveillance within the central nervous system and are responsible for removing harmful particles and preserving neuronal function. The APOE4 genotype causes abnormal lipid metabolism in microglia, resulting in excessive accumulation of lipid droplets. This accumulation not only impairs the phagocytic and clearance capabilities of microglia but also disrupts their interactions with neurons, resulting in disorganization and neurodegenerative alterations at the neuronal network level. In addition, the presence of APOE4 modifies the metabolic landscape of microglia, particularly affecting purinergic signaling and lipid metabolism, thereby exacerbating the pathological processes of AD. In conclusion, the accumulation of lipid droplets and abnormal lipid metabolism may be critical mechanisms in the progression of AD in microglia carrying the APOE4 genotype.

Triglyceride metabolism controls inflammation and APOE4-associated disease states in microglia

https://www.biorxiv.org/content/10.1101/2024.04.11.589145v1?fbclid=IwZXh0bgNhZW0CMTEAAR2C4jiuexAOS4EXwkb68wMyJlcOpl3fIwzeNYkC7GHbGIDuXPoKjnEN2Zg_aem_ATucwiojxsoYVWQ5Vi3hwyOjKyDC8bxltG0BUXBXAbDv0f-q0VP02x1x5wjrG58ciiGYIz9-5kwJW6mjdv8oa04d
Roxan A. Stephenson, Kory R. Johnson, Linling Cheng, Linda G. Yang, Jessica T. Root, Jaanam Gopalakrishnan, Han-Yu Shih, Priyanka S. Narayan
bioRxiv 2024.04.11.589145
April 13, 2024 (preprint)
doi https://doi.org/10.1101/2024.04.11.589145
Abstract
Microglia modulate their cell state in response to various stimuli. Changes to cellular lipids often accompany shifts in microglial cell state, but the functional significance of these metabolic changes remains poorly understood. In human induced pluripotent stem cell-derived microglia, we observed that both extrinsic activation (by lipopolysaccharide treatment) and intrinsic triggers (the Alzheimer’s disease-associated APOE4 genotype) result in accumulation of triglyceride-rich lipid droplets. We demonstrate that lipid droplet accumulation is not simply concomitant with changes in cell state but rather necessary for microglial activation. We discovered that both triglyceride biosynthesis and catabolism are needed for the transcription and secretion of proinflammatory cytokines and chemokines in response to extrinsic stimuli. Additionally, we reveal that triglyceride biosynthesis and catabolism are necessary for the activation-associated phagocytosis of multiple substrates including the disease-associated amyloid-beta peptide. In microglia harboring the Alzheimer’s disease risk APOE4 genotype, triglyceride-rich lipid droplets accumulate even in the absence of any external stimuli. Inhibiting triglyceride biosynthesis in APOE4 microglia not only modifies the transcription of immune response genes but also attenuates disease-associated transcriptional states. This work establishes that triglyceride metabolism is necessary for microglia to respond to extrinsic activation. In APOE4 microglia, this metabolic process modulates both immune signaling and a disease-associated transcriptional state. Importantly, our work identifies metabolic pathways that can be used to tune microglial immunometabolism in APOE4-associated disease.

Effects of APOE4 on omega-3 brain metabolism across the lifespan

https://www.cell.com/trends/endocrinology-metabolism/abstract/S1043-2760(24)00065-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1043276024000651%3Fshowall%3Dtrue
Brandon Ebright, Marlon V. Duro, Kai Chen, Stan Louie, Hussein N. Yassine
Trends in Endocrinology & Metabolism
Published:April 11, 2024
DOI: https://doi.org/10.1016/j.tem.2024.03.003
Highlights
• Inconsistencies between Alzheimer’s disease (AD) clinical trials and prevention studies using omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation can be largely attributed to differences in age, environmental factors, genetic factors, baseline n-3/n-6 intake, and disease stage.
• Changes in docosahexaenoic acid (DHA) brain uptake throughout AD progression are influenced by the apolipoprotein E ε4 (APOE4) allele and lifestyle factors, such as DHA intake or exercise, and can be monitored by DHA positron emission tomography (PET) brain imaging.
• APOE4 carriers are more susceptible to blood–brain barrier dysfunction, oxidative stress, neuroinflammation, and fatty acid oxidation with aging compared to noncarriers.
• We hypothesize that increasing n-3 PUFA intake provides APOE4 carriers with the highest potential for protection against AD dementia when implemented early in life, many years before the onset of cognitive decline.
• During the AD dementia phase, alternative strategies targeting neuroinflammation and PUFA metabolism may offer potential benefits.
Abstract
Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), have important roles in human nutrition and brain health by promoting neuronal functions, maintaining inflammatory homeostasis, and providing structural integrity. As Alzheimer’s disease (AD) pathology progresses, DHA metabolism in the brain becomes dysregulated, the timing and extent of which may be influenced by the apolipoprotein E ε4 (APOE4) allele. Here, we discuss how maintaining adequate DHA intake early in life may slow the progression to AD dementia in cognitively normal individuals with APOE4, how recent advances in DHA brain imaging could offer insights leading to more personalized preventive strategies, and how alternative strategies targeting PUFA metabolism pathways may be more effective in mitigating disease progression in patients with existing AD dementia.

Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer's disease.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11006751/
Bhattarai P, Gunasekaran TI, Belloy ME, Reyes-Dumeyer D, Jülich D, Tayran H, Yilmaz E, Flaherty D, Turgutalp B, Sukumar G, Alba C, McGrath EM, Hupalo DN, Bacikova D, Le Guen Y, Lantigua R, Medrano M, Rivera D, Recio P, Nuriel T, Ertekin-Taner N, Teich AF, Dickson DW, Holley S, Greicius M, Dalgard CL, Zody M, Mayeux R, Kizil C, Vardarajan BN
Acta Neuropathol. 2024 Apr 10;147(1):70
Published online 2024 Apr 10
doi: 10.1007/s00401-024-02721-1
The risk of developing Alzheimer’s disease (AD) significantly increases in individuals carrying the APOEε4 allele. Elderly cognitively healthy individuals with APOEε4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects of APOEε4; however, these mechanisms are unknown. We hypothesized that APOEε4 carriers without dementia might carry genetic variations that could protect them from developing APOEε4-mediated AD pathology. To test this, we leveraged whole-genome sequencing (WGS) data in the National Institute on Aging Alzheimer's Disease Family Based Study (NIA-AD FBS), Washington Heights/Inwood Columbia Aging Project (WHICAP), and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) cohorts and identified potentially protective variants segregating exclusively among unaffected APOEε4 carriers. In homozygous unaffected carriers above 70 years old, we identified 510 rare coding variants. Pathway analysis of the genes harboring these variants showed significant enrichment in extracellular matrix (ECM)-related processes, suggesting protective effects of functional modifications in ECM proteins. We prioritized two genes that were highly represented in the ECM-related gene ontology terms, (FN1) and collagen type VI alpha 2 chain (COL6A2) and are known to be expressed at the blood–brain barrier (BBB), for postmortem validation and in vivo functional studies. An independent analysis in a large cohort of 7185 APOEε4 homozygous carriers found that rs140926439 variant in FN1 was protective of AD (OR = 0.29; 95% CI [0.11, 0.78], P = 0.014) and delayed age at onset of disease by 3.37 years (95% CI [0.42, 6.32], P = 0.025). The FN1 and COL6A2 protein levels were increased at the BBB in APOEε4 carriers with AD. Brain expression of cognitively unaffected homozygous APOEε4 carriers had significantly lower FN1 deposition and less reactive gliosis compared to homozygous APOEε4 carriers with AD, suggesting that FN1 might be a downstream driver of APOEε4-mediated AD-related pathology and cognitive decline. To validate our findings, we used zebrafish models with loss-of-function (LOF) mutations in fn1b—the ortholog for human FN1. We found that fibronectin LOF reduced gliosis, enhanced gliovascular remodeling, and potentiated the microglial response, suggesting that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with FN1 LOF. Our study suggests that vascular deposition of FN1 is related to the pathogenicity of APOEε4, and LOF variants in FN1 may reduce APOEε4-related AD risk, providing novel clues to potential therapeutic interventions targeting the ECM to mitigate AD risk.

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers

https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-024-03611-5?fbclid=IwAR2fG6CkUolQleVADQutsa5ZNonniYkj2d-LEWnPV9GYy9nT2dux3XCdLYQ
Lane, R.M., Darreh-Shori, T., Junge, C. et al.
BMC Neurol 24, 116 (2024)
Published 09 April 2024
DOI: https://doi.org/10.1186/s12883-024-03611-5
Abstract
Background
The authors sought to examine the impact of the K-variant of butyrylcholinesterase (BCHE-K) carrier status on age-at-diagnosis of Alzheimer disease (AD) in APOE4 carriers. Methods
Patients aged 50–74 years with cerebrospinal fluid (CSF) biomarker-confirmed AD, were recruited to clinical trial (NCT03186989 since June 14, 2017). Baseline demographics, disease characteristics, and biomarkers were evaluated in 45 patients according to BCHE-K and APOE4 allelic status in this post-hoc study. Results
In APOE4 carriers (N = 33), the mean age-at-diagnosis of AD in BCHE-K carriers (n = 11) was 6.4 years earlier than in BCHE-K noncarriers (n = 22, P < .001, ANOVA). In APOE4 noncarriers (N = 12) there was no observed influence of BCHE-K. APOE4 carriers with BCHE-K also exhibited slightly higher amyloid and tau accumulations compared to BCHE-K noncarriers. A predominantly amyloid, limited tau, and limbic-amnestic phenotype was exemplified by APOE4 homozygotes with BCHE-K. In the overall population, multiple regression analyses demonstrated an association of amyloid accumulation with APOE4 carrier status (P < .029), larger total brain ventricle volume (P < .021), less synaptic injury (Ng, P < .001), and less tau pathophysiology (p-tau181, P < .005). In contrast, tau pathophysiology was associated with more neuroaxonal damage (NfL, P = .002), more synaptic injury (Ng, P < .001), and higher levels of glial activation (YKL-40, P = .01). Conclusion
These findings have implications for the genetic architecture of prognosis in early AD, not the genetics of susceptibility to AD. In patients with early AD aged less than 75 years, the mean age-at-diagnosis of AD in APOE4 carriers was reduced by over 6 years in BCHE-K carriers versus noncarriers. The functional status of glia may explain many of the effects of APOE4 and BCHE-K on the early AD phenotype.

Repetitive head trauma and apoE4 induce chronic cerebrovascular alterations that impair tau elimination from the brain

https://www.sciencedirect.com/science/article/abs/pii/S0014488624000281?fbclid=IwAR0obFQ4WGD1GCbp2l9NKLQkBjvcTnQep4gFqn6k4RIM_wiA-h3bbW7P9Tg
Maxwell Eisenbaum, Andrew Pearson, Camila Ortiz, Milica Koprivica, Arianna Cembran, Michael Mullan, Fiona Crawford, Joseph Ojo, Corbin Bachmeier
Experimental Neurology, Volume 374, 2024,114702
DOI: https://doi.org/10.1016/j.expneurol.2024.114702.
April 2024
Abstract: Repetitive mild traumatic brain injuries (r-mTBI) sustained in the military or contact sports have been associated with the accumulation of extracellular tau in the brain, which may contribute to the pathogenesis of neurodegenerative tauopathies. The expression of the apolipoprotein E4 (apoE4) isoform has been associated with higher levels of tau in the brain, and worse clinical outcomes after r-mTBI, though the influence of apoE genotype on extracellular tau dynamics in the brain is poorly understood. We recently demonstrated that extracellular tau can be eliminated across blood-brain barrier (BBB), which is progressively impaired following r-mTBI. The current studies investigated the influence of repetitive mild TBI (r-mTBI) and apoE genotype on the elimination of extracellular solutes from the brain. Following intracortical injection of biotin-labeled tau into humanized apoE-Tr mice, the levels of exogenous tau residing in the brain of apoE4 mice were elevated compared to other isoforms, indicating reduced tau elimination. Additionally, we found exposure to r-mTBI increased tau residence in apoE2 mice, similar to our observations in E2FAD animals. Each of these findings may be the result of diminished tau efflux via LRP1 at the BBB, as LRP1 inhibition significantly reduced tau uptake in endothelial cells and decreased tau transit across an in vitro model of the BBB (basolateral-to-apical). Notably, we showed that injury and apoE status, (particularly apoE4) resulted in chronic alterations in BBB integrity, pericyte coverage, and AQP4 polarization. These aberrations coincided with an atypical reactive astrocytic gene signature indicative of diminished CSF-ISF exchange. Our work found that CSF movement was reduced in the chronic phase following r-mTBI (>18 months post injury) across all apoE genotypes. In summary, we show that apoE genotype strongly influences cerebrovascular homeostasis, which can lead to age-dependent deficiencies in the elimination of toxic proteins from the brain, like tau, particularly in the aftermath of head trauma.

March 2024

Humanin variant P3S is associated with longevity in APOE4 carriers and resists APOE4-induced brain pathology

https://onlinelibrary.wiley.com/doi/10.1111/acel.14153
Brendan Miller, Su-Jeong Kim, Kevin Cao, Hemal H. Mehta, Neehar Thumaty, Hiroshi Kumagai, Tomomitsu Iida, Cassandra McGill, Christian J. Pike, Kamila Nurmakova, Zachary A. Levine, Patrick M. Sullivan, Kelvin Yen, Nilüfer Ertekin-Taner, Gil Atzmon, Nir Barzilai, Pinchas Cohen
Aging Cell, e14153, Online Version of Record before inclusion in an issue
First published: 22 March 2024
https://doi.org/10.1111/acel.14153
Researchers at the USC Leonard Davis School of Gerontology have discovered a genetic mutation in a small mitochondrial protein that may promote longevity, preserve cognitive function, and protect against Alzheimer's disease among carriers of APOE4
Abstract
The APOE4 allele is recognized as a significant genetic risk factor to Alzheimer's disease (AD) and influences longevity. Nonetheless, some APOE4 carriers exhibit resistance to AD even in advanced age. Humanin, a mitochondrial-derived peptide comprising 24 amino acids, has variants linked to cognitive resilience and longevity. Our research uncovered a unique humanin variant, P3S, specifically enriched in centenarians with the APOE4 allele. Through in silico analyses and subsequent experimental validation, we demonstrated a strong affinity between humanin P3S and APOE4. Utilizing an APOE4-centric mouse model of amyloidosis (APP/PS1/APOE4), we observed that humanin P3S significantly attenuated brain amyloid-beta accumulation compared to the wild-type humanin. Transcriptomic assessments of mice treated with humanin P3S highlighted its potential mechanism involving the enhancement of amyloid beta phagocytosis. Additionally, in vitro studies corroborated humanin P3S's efficacy in promoting amyloid-beta clearance. Notably, in the temporal cortex of APOE4 carriers, humanin expression is correlated with genes associated with phagocytosis. Our findings suggest a role of the rare humanin variant P3S, especially prevalent among individuals of Ashkenazi descent, in mitigating amyloid beta pathology and facilitating phagocytosis in APOE4-linked amyloidosis, underscoring its significance in longevity and cognitive health among APOE4 carriers.

ApoE4 dysregulation incites depressive symptoms and mitochondrial impairments in mice

https://onlinelibrary.wiley.com/doi/10.1111/jcmm.18160?fbclid=IwAR1LqON6o70cJJD9ymfllufWW7PAbQqxgSEX3qNLj0itPAbOBLa2wHGvWS0
Weifen Li, Tahir Ali, Kaiwu He, Chengyou Zheng, Ningning Li, Zhi-Jian Yu, Shupeng Li
First published: 20 March 2024
https://doi.org/10.1111/jcmm.18160
Abstract
Apolipoprotein E4 (ApoE4) is involved in the stress-response processes and is hypothesized to be a risk factor for depression by means of mitochondrial dysfunction. However, their exact roles and underlying mechanisms are largely unknown. ApoE4 transgenic mice (B6. Cg-ApoEtm1UncCdh18Tg(GFAP−APOE i4)1Hol/J) were subjected to stress (lipopolysaccharides, LPS) to elucidate the aetiology of ApoE4-induced depression. LPS treatment significantly aggravated depression-like behaviours, concurrent with neuroinflammation and impaired mitochondrial changes, and melatonin/Urolithin A (UA) + 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) reversed these effects in ApoE4 mice. Concurrently, ApoE4 mice exhibited mitophagy deficits, which could be further exacerbated by LPS stimulation, as demonstrated by reduced Atg5, Beclin-1 and Parkin levels, while PINK1 levels were increased. However, these changes were reversed by melatonin treatment. Additionally, proteomic profiling suggested mitochondria-related signalling and network changes in ApoE4 mice, which may underlie the exaggerated response to LPS. Furthermore, HEK 293T cells transfected with ApoE4 showed mitochondria-associated protein and mitophagy defects, including PGC-1α, TFAM, p-AMPKα, PINK1 and LC3B impairments. Additionally, it aggravates mitochondrial impairment (particularly mitophagy), which can be attenuated by triggering autophagy. Collectively, ApoE4 dysregulation enhanced depressive behaviour upon LPS stimulation.

Sex, Body Mass Index, and APOE4 Increase Plasma Phospholipid–Eicosapentaenoic Acid Response During an ω-3 Fatty Acid Supplementation: A Secondary Analysis

https://jn.nutrition.org/article/S0022-3166(24)00162-7/fulltext
Insaf Loukil, Ester Cisneros Aguilera, Annick Vachon, Pauline Léveillé, Mélanie Plourde
The Journal of Nutrition Volume 154, Issue 5, May 2024, Pages 1561-1570
Published: March 18, 2024
DOI: https://doi.org/10.1016/j.tjnut.2024.03.013
Abstract
Background
The brain is concentrated with omega (ω)-3 (n–3) fatty acids (FAs), and these FAs must come from the plasma pool. The 2 main ω-3 FAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), must be in the form of nonesterified fatty acid (NEFA) or esterified within phospholipids (PLs) to reach the brain. We hypothesized that the plasma concentrations of these ω-3 FAs can be modulated by sex, body mass index (BMI, kg/m2), age, and the presence of the apolipoprotein (APO) E-ε4 allele in response to the supplementation. Objectives
This secondary analysis aimed to determine the concentration of EPA and DHA within plasma PL and in the NEFA form after an ω-3 FA or a placebo supplementation and to investigate whether the factors change the response to the supplement. Methods
A randomized, double-blind, placebo-controlled trial was conducted. Participants were randomly assigned to either an ω-3 FA supplement (DHA 0.8 g and EPA 1.7 g daily) or to a placebo for 6 mo. FAs from fasting plasma samples were extracted and subsequently separated into PLs with esterified FAs and NEFAs using solid-phase extraction. DHA and EPA concentrations in plasma PLs and as NEFAs were quantified using gas chromatography. Results
EPA and DHA concentrations in the NEFA pool significantly increased by 31%−71% and 42%−82%, respectively, after 1 and 6 mo of ω-3 FA supplementation. No factors influenced plasma DHA and EPA responses in the NEFA pool. In the plasma PL pool, DHA increased by 83%−109% and EPA by 387%−463% after 1 and 6 mo of ω-3 FA supplementation. APOE4 carriers, females, and individuals with a BMI of ≤25 had higher EPA concentrations than noncarriers, males, and those with a BMI of >25, respectively. Conclusions
The concentration of EPA in plasma PLs are modulated by APOE4, sex, and BMI. These factors should be considered when designing clinical trials involving ω-3 FA supplementation.

Protection against APOE4-associated aging phenotypes with the longevity-promoting intervention 17α-estradiol in male mice

https://www.biorxiv.org/content/10.1101/2024.03.12.584678v1
Cassandra J. McGill, Amy Christensen, Wenjie Qian, Max A. Thorwald, Jose Godoy Lugo, Sara Namvari, Olivia S. White, Caleb E. Finch, Bérénice A. Benayoun, Christian J. Pike
bioRxiv 2024.03.12.584678
Posted March 14, 2024
doi: https://doi.org/10.1101/2024.03.12.584678
Summary
The apolipoprotein ε4 allele (APOE4) is associated with decreased longevity, increased vulnerability to age-related declines, and disorders across multiple systems. Interventions that promote healthspan and lifespan represent a promising strategy to attenuate the development of APOE4-associated aging phenotypes. Here we studied the ability of the longevity-promoting intervention 17α-estradiol (17αE2) to protect against age-related impairments in APOE4 versus the predominant APOE3 genotype using early middle-aged mice with knock-in of human APOE alleles. Beginning at age 10 months, male APOE3 or APOE4 mice were treated for 20 weeks with 17αE2 or vehicle then compared for indices of aging phenotypes body-wide. Across peripheral and neural measures, APOE4 was associated with poorer outcomes. Notably, 17αE2 treatment improved outcomes in a genotype-dependent manner favoring APOE4 mice. These data demonstrate a positive APOE4 bias in 17αE2-mediated healthspan actions, suggesting that longevity-promoting interventions may be useful in mitigating deleterious age-related risks associated with APOE4 genotype.

APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10990924/
Haney MS, Pálovics R, Munson CN, Long C, Johansson PK, Yip O, Dong W, Rawat E, West E, Schlachetzki JC, Tsai A, Guldner IH, Lamichhane BS, Smith A, Schaum N, Calcuttawala K, Shin A, Wang YH, Wang C, Koutsodendris N, Serrano GE, Beach TG, Reiman EM, Glass CK, Abu-Remaileh M, Enejder A, Huang Y, Wyss-Coray T
Nature 2024 Apr;628(8006):154-161.
Epub 2024 Mar 13
DOI: 10.1038/s41586-024-07185-7
Abstract
Several genetic risk factors for Alzheimer’s disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer’s disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer’s disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer’s disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer’s disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer’s disease.

APOE4 genotype and aging impair injury-induced microglial behavior in brain slices, including toward Aβ, through P2RY12

https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-024-00714-y?fbclid=IwAR328Rn2wGEOJwaqHkaQKi-jUDP07Byoe0-bOlZ_cUNDKoz4sTM23SvnrpY
Sepulveda, J., Kim, J.Y., Binder, J. et al.
Molecular Neurodegeneration 19, 24 (2024)
Published 11 March 2024
DOI: https://doi.org/10.1186/s13024-024-00714-y
Abstract
Microglia are highly dynamic cells that play a critical role in tissue homeostasis through the surveillance of brain parenchyma and response to cues associated with damage. Aging and APOE4 genotype are the strongest risk factors for Alzheimer’s disease (AD), but how they affect microglial dynamics remains unclear. Using ex vivo confocal microscopy, we analyzed microglial dynamic behaviors in the entorhinal cortex (EC) and hippocampus CA1 of 6-, 12-, and 21-month-old mice APOE3 or APOE4 knock-in mice expressing GFP under the CX3CR1 promoter. To study microglia surveillance, we imaged microglia baseline motility for 20 min and measured the extension and retraction of processes. We found that APOE4 microglia exhibited significantly less brain surveillance (27%) compared to APOE3 microglia in 6-month-old mice; aging exacerbated this deficit. To measure microglia response to damage, we imaged process motility in response to ATP, an injury-associated signal, for 30 min. We found APOE4 microglia extended their processes significantly slower (0.9 µm/min, p < 0.005) than APOE3 microglia (1.1 μm/min) in 6-month-old animals. APOE-associated alterations in microglia motility were observed in 12- and 21-month-old animals, and this effect was exacerbated with aging in APOE4 microglia. We measured protein and mRNA levels of P2RY12, a core microglial receptor required for process movement in response to damage. We found that APOE4 microglia express significantly less P2RY12 receptors compared to APOE3 microglia despite no changes in P2RY12 transcripts. To examine if the effect of APOE4 on the microglial response to ATP also applied to amyloid β (Aβ), we infused locally Hi-Lyte Fluor 555-labeled Aβ in acute brain slices of 6-month-old mice and imaged microglia movement for 2 h. APOE4 microglia showed a significantly slower (p < 0.0001) process movement toward the Aβ, and less Aβ coverage at early time points after Aβ injection. To test whether P2RY12 is involved in process movement in response to Aβ, we treated acute brain slices with a P2RY12 antagonist before Aβ injection; microglial processes no longer migrated towards Aβ. These results provide mechanistic insights into the impact of APOE4 genotype and aging in dynamic microglial behaviors prior to gross Aβ pathology and could help explain how APOE4 brains are more susceptible to AD pathogenesis.

Leading Neurologist: This Gene Raises Your Risk of Alzheimer’s—and Drug Side Effects

https://www.beingpatient.com/apoe4-raises-alzheimers-risk-risk-of-aria-side-effect-from-dementia-drugs/?fbclid=IwAR1B7ogVoEgG2OYRQVoXG-QcaSxzZjYJnkCklZnkeHwbO1MLBgfCT6V029g
By Alexandra Marvar Being Patient March 6th, 2024
Studies show that in some people, the inherited genetic variant ApoE4 could not only multiply your risk of developing Alzheimer's disease, but also your risk of experiencing brain bleeds from taking monoclonal antibody treatments for Alzheimer's, like Leqembi. Article includes video.

How are APOE4, changes in body weight, and longevity related? Insights from a causal mediation analysis

https://www.frontiersin.org/articles/10.3389/fragi.2024.1359202/full?utm_source=F-NTF&utm_medium=EMLX&utm_campaign=PRD_FEOPS_20170000_ARTICLE&fbclid=IwAR0qZmpgfhlKdupFBoId86zU4oN0ZU9ti44-jBqkUNDSS3h3ujegjWvtmB4
Rachel Holmes, Hongzhe Duan, Deqing Wu, Yury Loika, Anatoliy Yashin, Konstantin Arbeev, Svetlana Ukraintseva
Frontiers in Aging, 01 March 2024 Sec. Genetics, Genomics and Epigenomics of Aging Volume 5 - 2024
01 March 2024
DOI: https://doi.org/10.3389/fragi.2024.1359202
The ε4 allele of the APOE gene (APOE4) is known for its negative association with human longevity; however, the mechanism is unclear. APOE4 is also linked to changes in body weight, and the latter changes were associated with survival in some studies. Here, we explore the role of aging changes in weight in the connection between APOE4 and longevity using the causal mediation analysis (CMA) approach to uncover the mechanisms of genetic associations. Using the Health and Retirement Study (HRS) data, we tested a hypothesis of whether the association of APOE4 with reduced survival to age 85+ is mediated by key characteristics of age trajectories of weight, such as the age at reaching peak values and the slope of the decline in weight afterward. Mediation effects were evaluated by the total effect (TE), natural indirect effect, and percentage mediated. The controlled direct effect and natural direct effect are also reported. The CMA results suggest that APOE4 carriers have 19%–22% (TE p = 0.020–0.039) lower chances of surviving to age 85 and beyond, in part, because they reach peak values of weight at younger ages, and their weight declines faster afterward compared to non-carriers. This finding is in line with the idea that the detrimental effect of APOE4 on longevity is, in part, related to the accelerated physical aging of ε4 carriers.

Cognitively healthy APOE4/4 carriers show white matter impairment associated with serum NfL and amyloid-PET

https://www.sciencedirect.com/science/article/pii/S096999612400038X
Claudia Tato-Fernández, Laura L. Ekblad, Elina Pietilä, Virva Saunavaara, Semi Helin, Riitta Parkkola, Henrik Zetterberg, Kaj Blennow, Juha O. Rinne, Anniina Snellman
Neurobiology of Disease, Volume 192, 106439
March 2024
DOI: https://doi.org/10.1016/j.nbd.2024.106439
Highlights
• Differences in white matter microstructure appear in healthy APOE4 homozygotes.
• APOE4 homozygotes showed higher diffusivity in corpus callosum and right cingulum.
• MD, RD and AxD correlate with the amyloid load assessed by PET in APOE4 carriers.
• MD, RD and AxD correlate with serum neurofilament light chain in APOE4 carriers.
Abstract
Except for aging, carrying the APOE ε4 allele (APOE4) is the most important risk factor for sporadic Alzheimer's disease. APOE4 carriers may have reduced capacity to recycle lipids, resulting in white matter microstructural abnormalities. In this study, we evaluated whether white matter impairment measured by diffusion tensor imaging (DTI) differs between healthy individuals with a different number of APOE4 alleles, and whether white matter impairment associates with brain beta-amyloid (Aβ) load and serum levels of neurofilament light chain (NfL). We studied 96 participants (APOE3/3, N = 37; APOE3/4, N = 39; APOE4/4, N = 20; mean age 70.7 (SD 5.22) years, 63% females) with a brain MRI including a DTI sequence (N = 96), Aβ-PET (N = 89) and a venous blood sample for the serum NfL concentration measurement (N = 88). Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) in six a priori-selected white matter regions-of-interest (ROIs) were compared between the groups using ANCOVA, with sex and age as covariates. A voxel-weighted average of FA, MD, RD and AxD was calculated for each subject, and correlations with Aβ-PET and NfL levels were evaluated. APOE4/4 carriers exhibited a higher MD and a higher RD in the body of corpus callosum than APOE3/4 (p = 0.0053 and p = 0.0049, respectively) and APOE3/3 (p = 0.026 and p = 0.042). APOE4/4 carriers had a higher AxD than APOE3/4 (p = 0.012) and APOE3/3 (p = 0.040) in the right cingulum adjacent to cingulate cortex. In the total sample, composite MD, RD and AxD positively correlated with the cortical Aβ load (r = 0.26 to 0.33, p < 0.013 for all) and with serum NfL concentrations (r = 0.31 to 0.36, p < 0.0028 for all). In conclusion, increased local diffusivity was detected in cognitively unimpaired APOE4/4 homozygotes compared to APOE3/4 and APOE3/3 carriers, and increased diffusivity correlated with biomarkers of Alzheimer's disease and neurodegeneration. White matter impairment seems to be an early phenomenon in the Alzheimer's disease pathologic process in APOE4/4 homozygotes.

February 2024

Leqembi’s “Brain Bleeds” Side Effect, Explained

https://www.youtube.com/watch?v=tAdrDZ-fNFo
Being Patient, Feb 23, 2024
In this video, we dive into the fascinating world of groundbreaking Alzheimer's treatments known as anti-amyloid monoclonal antibodies. Join us as we explore the journey of Leqembi (Lecanemab) and Aduhelm (Aducanumab), two drugs designed to target beta-amyloid protein plaques in the brain. Discover the risks and benefits associated with these medications, including a side effect known as ARIA (Amyloid Related Imaging Abnormalities). We hear from experts like neurologist Dr. Marwan Sabbagh and neurologist-turned-patient Daniel Gibbs, who provide valuable insights and personal experiences. Learn about the ongoing clinical trials of Donanemab and what the future holds for Alzheimer's treatment. Don't miss this informative video that sheds light on the latest advancements in Alzheimer's research.

Associations between regional blood-brain barrier disruption, aging, and Alzheimer’s disease biomarkers in cognitively normal older adults

https://www.biorxiv.org/content/10.1101/2024.02.16.580788v1?fbclid=IwAR0BcSz_Jc4rMFhxv85rY-yhx3BRNwYWsDKJxtxHM62ugBE4pAYLpL_76eI
Marisa Denkinger, Suzanne Baker, Ben Inglis, SarahmKobayashi, Alexis Juarez, Suzanne Mason, William Jagust
February 21, 2024 (preprint)
doi: https://doi.org/10.1101/2024.02.16.580788
Abstract
Background
Blood-brain barrier disruption (BBBd) has been hypothesized as a feature of aging that may lead to the development of Alzheimer’s disease (AD). We sought to identify the brain regions most vulnerable to BBBd during aging and examine their regional relationship with neuroimaging biomarkers of AD.
Methods
We studied 31 cognitively normal older adults (OA) and 10 young adults (YA) from the Berkeley Aging Cohort Study (BACS). Both OA and YA received dynamic contrast-enhanced MRI (DCE-MRI) to quantify Ktrans values, as a measure of BBBd, in 37 brain regions across the cortex. The OA also received Pittsburgh compound B (PiB)-PET to create distribution volume ratios (DVR) images and flortaucipir (FTP)-PET to create partial volume corrected standardized uptake volume ratios (SUVR) images. Repeated measures ANOVA assessed the brain regions where OA showed greater BBBd than YA. In OA, Ktrans values were compared based on sex, Aβ positivity status, and APOE4 carrier status within a composite region across the areas susceptible to aging. We used linear models and sparse canonical correlation analysis (SCCA) to examine the relationship between Ktrans and AD biomarkers.
Results
OA showed greater BBBd than YA predominately in the temporal lobe, with some involvement of parietal, occipital and frontal lobes. Within an averaged ROI of affected regions, there was no difference in Ktrans values based on sex or Aβ positivity, but OA who were APOE4 carriers had significantly higher Ktrans values. There was no direct relationship between averaged Ktrans and global Aβ pathology, but there was a trend for an Aβ status by tau interaction on Ktrans in this region. SCCA showed increased Ktrans was associated with increased PiB DVR, mainly in temporal and parietal brain regions. There was not a significant relationship between Ktrans and FTP SUVR.
Discussion
Our findings indicate that the BBB shows regional vulnerability during normal aging that overlaps considerably with the pattern of AD pathology. Greater BBBd in brain regions affected in aging is related to APOE genotype and may also be related to the pathological accumulation of Aβ.

APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size

https://rupress.org/jcb/article-abstract/223/4/e202305003/276556/APOE-traffics-to-astrocyte-lipid-droplets-and?redirectedFrom=fulltext
Ian A. Windham, Alex E. Powers, Joey V. Ragusa, E. Diane Wallace, Maria Clara Zanellati, Victoria H. Williams, Colby H. Wagner, Kristen K. White, Sarah Cohen
Journal of Cell Biology (2024) 223 (4): e202305003
February 09 2024
DOI: https://doi.org/10.1083/jcb.202305003
The E4 variant of APOE strongly predisposes individuals to late-onset Alzheimer’s disease. We demonstrate that in response to lipogenesis, apolipoprotein E (APOE) in astrocytes can avoid translocation into the endoplasmic reticulum (ER) lumen and traffic to lipid droplets (LDs) via membrane bridges at ER–LD contacts. APOE knockdown promotes fewer, larger LDs after a fatty acid pulse, which contain more unsaturated triglyceride after fatty acid pulse-chase. This LD size phenotype was rescued by chimeric APOE that targets only LDs. Like APOE depletion, APOE4-expressing astrocytes form a small number of large LDs enriched in unsaturated triglyceride. Additionally, the LDs in APOE4 cells exhibit impaired turnover and increased sensitivity to lipid peroxidation. Our data indicate that APOE plays a previously unrecognized role as an LD surface protein that regulates LD size and composition. APOE4 causes aberrant LD composition and morphology. Our study contributes to accumulating evidence that APOE4 astrocytes with large, unsaturated LDs are sensitized to lipid peroxidation, which could contribute to Alzheimer’s disease risk.
Full paper in preprint form available at this link:
https://www.biorxiv.org/content/10.1101/2023.04.28.538740v1.full.pdf

January 2024

Apolipoprotein E isoforms and their Cys-thiol modifications impact LRP1-mediated metabolism of triglyceride-rich lipoproteins

https://febs.onlinelibrary.wiley.com/doi/full/10.1002/1873-3468.14803
Hiroto Matsuura, Shogo Akahane, Takahiro Kaido, Tomu Kamijo, Kenta Sakamoto, Kazuyoshi Yamauchi
FEBS Letters Volume598, Issue3 February 2024 Pages 347-362
First published: 27 January 2024
DOI: https://doi.org/10.1002/1873-3468.14803
Abstract
The low-density lipoprotein (LDL) receptor-related protein (LRP)1 participates in the metabolism of apolipoprotein (apo) E-containing lipoproteins (apoE-LP). We investigated the effects of modifications of cysteine (Cys)-thiol of apoE on LRP1-mediated metabolism. Among the three isoforms, apoE2-LP exhibited the lowest affinity for LRP1 but was significantly catabolized, whereas apoE4-LP was sufficiently bound to LRP1 but showed the lowest catabolic capability. The reduction enhanced the binding and suppressed the catabolism of apoE3-LP, but had no effect on apoE2-LP. The formation of disulfide-linked complexes with apoAII suppressed binding, but enhanced the catabolism of apoE2-LP. Redox modifications of apoE-Cys-thiol may modulate the LRP1-mediated metabolism of apoE2- or apoE3-LP, but not apoE4-LP. The failure of this function may be involved in the pathophysiology of dyslipidemia.

Apolipoprotein E-ε2 and Resistance to Atherosclerosis in Midlife: The PESA Observational Study

https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.123.323921
Raquel Toribio-Fernández, Catarina Tristão-Pereira, Juan Carlos Silla-Castro, Sergio Callejas, Belen Oliva, Irene Fernandez-Nueda, Ines Garcia-Lunar, Cristina Perez-Herreras, José María Ordovás, Pilar Martin, Fiona Blanco-Kelly, Carmen Ayuso, Enrique Lara-Pezzi, Antonio Fernandez-Ortiz, Ana Garcia-Alvarez, Ana Dopazo, Fatima Sanchez-Cabo, Borja Ibanez, Marta Cortes-Canteli and Valentin Fuster
Circulation Research. 2024;134:411–424
Originally published 23 Jan 2024
https://doi.org/10.1161/CIRCRESAHA.123.323921
Abstract
BACKGROUND:
APOE is a known genetic contributor to cardiovascular disease, but the differential role APOE alleles play in subclinical atherosclerosis remains unclear.
METHODS:
The PESA (Progression of Early Subclinical Atherosclerosis) is an observational cohort study that recruited 4184 middle-aged asymptomatic individuals to be screened for cardiovascular risk and multiterritorial subclinical atherosclerosis. Participants were APOE-genotyped, and omics data were additionally evaluated.
RESULTS:
In the PESA study, the frequencies for APOE -ε2, -ε3, and -ε4 alleles were 0.060, 0.844, and 0.096, respectively. This study included a subcohort of 3887 participants (45.8±4.3 years of age; 62% males). As expected, APOE-ε4 carriers were at the highest risk for cardiovascular disease and had significantly greater odds of having subclinical atherosclerosis compared with ε3/ε3 carriers, which was mainly explained by their higher levels of low-density lipoprotein (LDL)-cholesterol. In turn, APOE-ε2 carriers were at the lowest risk for cardiovascular disease and had significantly lower odds of having subclinical atherosclerosis in several vascular territories (carotids: 0.62 [95% CI, 0.47–0.81]; P=0.00043; femorals: 0.60 [0.47–0.78]; P=9.96×10−5; coronaries: 0.53 [0.39–0.74]; P=0.00013; and increased PESA score: 0.58 [0.48–0.71]; P=3.16×10−8). This APOE-ε2 atheroprotective effect was mostly independent of the associated lower LDL-cholesterol levels and other cardiovascular risk factors. The protection conferred by the ε2 allele was greater with age (50–54 years: 0.49 [95% CI, 0.32–0.73]; P=0.00045), and normal (<150 mg/dL) levels of triglycerides (0.54 [0.44–0.66]; P=4.70×10−9 versus 0.90 [0.57–1.43]; P=0.67 if ≥150 mg/dL). Omics analysis revealed an enrichment of several canonical pathways associated with anti-inflammatory mechanisms together with the modulation of erythrocyte homeostasis, coagulation, and complement activation in ε2 carriers that might play a relevant role in the ε2’s atheroprotective effect.
CONCLUSIONS:
This work sheds light on the role of APOE in cardiovascular disease development with important therapeutic and prevention implications on cardiovascular health, especially in early midlife.

Phase 3 Trials of Aducanumab Highlight High Risk of Amyloid-Related Imaging Abnormalities in APOE Carriers

https://www.neurologylive.com/view/phase-3-trials-aducanumab-highlight-high-risk-amyloid-related-imaging-abnormalities-apoe-carriers?ekey=RUtJRDpBM0QwMjA0Qy03NzY3LTQwQTgtOTk5Ri04QjNEMzMzNzYxMDU%3D&_hsmi=290574822&utm_medium=email&utm_content=290574822&utm_source=hs_email&_hsenc=p2ANqtz-83AykpDd6IwnfPFOEfIUwMfea0bOMjxMQAzDnlhCxxxG05tdk-ZPXsP0TyDM74O2X846bCPaaRMvdTw0j7YeeVVDEBWQ&fbclid=IwAR1WMzatgDl-kZImNg5OGSIj0T4k5EEWiuHOqYNWHTHiLulh_dvQ0bFBkUY
Marco Meglio Neurology Live January 18, 2024
Newly published in Neurology, a genome-wide association study (GWAS) of the phase 3 ENGAGE (NCT02477800) and EMERGE (NCT02484547) trials of aducanumab (Aduhelm; Biogen) revealed a strong, significant link between apolipoprotein (APOE) carrier status and the risk of amyloid-related imaging abnormalities (ARIA). The sample observed had a mean age of 70.3 years, with all participants of European ancestry. When compared with ε3/ε3 homozygotes, results showed a dose-dependent association between APOE ε4/ε4 and ARIA. All told, participants homozygous for APOE ε4 exhibited 4.28 greater odds of experiencing AIRA-H, 4.58 greater odds of experiencing ARIA-H microhemorrhage, and 7.84 greater odds of experiencing ARIA-H superficial siderosis.

Synthesis and biophysical evaluation of carbosilane dendrimers as therapeutic siRNA carriers

https://www.nature.com/articles/s41598-024-51238-w
Serafin Zawadzki, Ángela Martín-Serrano, Elżbieta Okła, Marta Kędzierska, Sandra Garcia-Gallego, Paula O. López, Francisco J. de la Mata, Sylwia Michlewska, Tomasz Makowski, Maksim Ionov, Elżbieta Pędziwiatr-Werbicka, Maria Bryszewska & Katarzyna Miłowska
Scientific Reports 14, 1615 (2024)
Published: 18 January 2024
DOI: https://doi.org/10.1038/s41598-024-51238-w
Abstract
Gene therapy presents an innovative approach to the treatment of previously incurable diseases. The advancement of research in the field of nanotechnology has the potential to overcome the current limitations and challenges of conventional therapy methods, and therefore to unlocking the full potential of dendrimers for use in the gene therapy of neurodegenerative disorders. The blood–brain barrier (BBB) poses a significant challenge when delivering therapeutic agents to the central nervous system. In this study, we investigated the biophysical properties of dendrimers and their complexes with siRNA directed against the apolipoprotein E (APOE) gene to identify an appropriate nanocarrier capable of safely delivering the cargo across the BBB. Our study yielded valuable insights into the complexation process, stability over time, the mechanisms of interaction, the influence of dendrimers on the oligonucleotide's spatial structure, and the potential cytotoxic effects on human cerebral microvascular endothelium cells. Based on our findings, we identified that the dendrimer G3Si PEG6000 was an optimal candidate for further research, potentially serving as a nanocarrier capable of safely delivering therapeutic agents across the BBB for the treatment of neurodegenerative disorders.

This Common Supplement Fights Cognitive Decline

https://www.spring.org.uk/2024/01/supplem-dec.php
Dr Jeremy Dean, PsyBlog, January 16, 2024
Omega-3 fatty acids may enhance brain function in middle age, research finds.
Among over 2,000 people in the study, those with higher concentrations of omega-3 in their blood had a range of cognitive advantages:
• Larger hippocampi: a brain structure central to learning and memory.
• Better abstract reasoning skills: the ability to think logically.
• Carriers of the APOE4 gene, who are at greater genetic risk of dementia, had fewer signs of small-vessel disease.

Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status

https://alzres.biomedcentral.com/articles/10.1186/s13195-023-01380-w
Reas, E.T., Triebswetter, C., Banks, S.J Emilie T. Reas, Curtis Triebswetter, Sarah J. Banks & Linda K. McEvoy
Alzheimer's Research & Therapy volume 16, 7 (2024).
11 January 2024
DOI: https://doi.org/10.1186/s13195-023-01380-w
Abstract
Background
APOE4 is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD), whereas APOE2 confers protection. However, effects of APOE on neurodegeneration in cognitively intact individuals, and how these associations evolve with cognitive decline, are unclear. Furthermore, few studies have evaluated whether effects of APOE on neurodegenerative changes are modified by other AD key risk factors including age and sex.
Methods
Participants included older adults (57% women; 77 ± 7 years) from the Rancho Bernardo Study of Health Aging and the University of California San Diego Alzheimer’s Disease Research Center, including 192 cognitively normal (CN) individuals and 33 with mild cognitive impairment. Participants underwent diffusion MRI, and multicompartment restriction spectrum imaging (RSI) metrics were computed in white matter, gray matter, and subcortical regions of interest. Participants were classified as APOE4 carriers, APOE2 carriers, and APOE3 homozygotes. Analysis of covariance among CN (adjusting for age, sex, and scanner) assessed differences in brain microstructure by APOE, as well as interactions between APOE and sex. Analyses across all participants examined interactions between APOE4 and cognitive status. Linear regressions assessed APOE by age interactions.
Results
Among CN, APOE4 carriers showed lower entorhinal cortex neurite density than non-carriers, whereas APOE2 carriers showed lower cingulum neurite density than non-carriers. Differences in entorhinal microstructure by APOE4 and in entorhinal and cingulum microstructure by APOE2 were present for women only. Age correlated with lower entorhinal restricted isotropic diffusion among APOE4 non-carriers, whereas age correlated with lower putamen restricted isotropic diffusion among APOE4 carriers. Differences in microstructure between cognitively normal and impaired participants were stronger for APOE4-carriers in medial temporal regions, thalamus, and global gray matter, but stronger for non-carriers in caudate.
Conclusions
The entorhinal cortex may be an early target of neurodegenerative changes associated with APOE4 in presymptomatic individuals, whereas APOE2 may support beneficial white matter and entorhinal microstructure, with potential sex differences that warrant further investigation. APOE modifies microstructural patterns associated with aging and cognitive impairment, which may advance the development of biomarkers to distinguish microstructural changes characteristic of normal brain aging, APOE-dependent pathways, and non-AD etiologies.

Rescue of ApoE4-related lysosomal autophagic failure in Alzheimer’s disease by targeted small molecules

https://www.nature.com/articles/s42003-024-05767-9?fbclid=IwAR1e4BKpoO3ufM7KgJ2svamtRybkEqMhMkMoW_-D0ccXt5XK6-29Dgf6aP8
Meenakshisundaram Balasubramaniam, Jagadeesh Narasimhappagari, Ling Liu, Akshatha Ganne, Srinivas Ayyadevara, Ramani Atluri, Haarika Ayyadevara, Guy Caldwell, Robert J. Shmookler Reis, Steven W. Barger & W. Sue T. Griffin
Communications Biology 7, 60 (2024)
Published: 08 January 2024
DOI: https://doi.org/10.1038/s42003-024-05767-9
Abstract
Homozygosity for the ε4 allele of APOE increases the odds of developing Alzheimer’s by 12 to 15 times relative to the most common ε3;ε3 genotype, and its association with higher plaque loads comports with evidence that APOEε4 compromises autophagy. The ApoE4 protein specifically binds a cis element (“CLEAR”) in the promoters of several autophagy genes to block their transcription. We used a multifaceted approach to identify a druggable site in ApoE4, and virtual screening of lead-like compounds identified small molecules that specifically bind to this site to impede ApoE4::DNA binding. We validated these molecules both in vitro and in vivo with models expressing ApoE4, including ApoE4 targeted-replacement mice. One compound was able to significantly restore transcription of several autophagy genes and protected against amyloid-like aggregation in a C. elegans AD model. Together, these findings provide proof-of-principle evidence for pharmacological remediation of lysosomal autophagy by ApoE4 via ApoE4-targeted lead molecules that represent a novel tack on neurodegenerative disorders.

2023

December 2023

An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer’s brains

https://www.cell.com/immunity/abstract/S1074-7613(23)00532-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1074761323005320%3Fshowall%3Dtrue
Ion Millet, Jose Henrique Ledo, Sohail F. Tavazoie
Immunity (2023)
Published: December 29, 2023
DOI: https://doi.org/10.1016/j.immuni.2023.12.001
Highlights
• Age and APOE4 enrich for TIM, microglia co-expressing stress and inflammatory markers
• TIM are present in human AD and spatially colocalize with Aβ plaques in the cortex
• TIM are an exhausted-like population with impaired function and signaling
• Aducanumab treatment alters TIM heterogeneity and state in an APOE-dependent manner
Summary
The dominant risk factors for late-onset Alzheimer’s disease (AD) are advanced age and the APOE4 genetic variant. To examine how these factors alter neuroimmune function, we generated an integrative, longitudinal single-cell atlas of brain immune cells in AD model mice bearing the three common human APOE alleles. Transcriptomic and chromatin accessibility analyses identified a reactive microglial population defined by the concomitant expression of inflammatory signals and cell-intrinsic stress markers whose frequency increased with age and APOE4 burden. An analogous population was detectable in the brains of human AD patients, including in the cortical tissue, using multiplexed spatial transcriptomics. This population, which we designate as terminally inflammatory microglia (TIM), exhibited defects in amyloid-β clearance and altered cell-cell communication during aducanumab treatment. TIM may represent an exhausted-like state for inflammatory microglia in the AD milieu that contributes to AD risk and pathology in APOE4 carriers and the elderly, thus presenting a potential therapeutic target for AD.

Genome-Wide Association Studies of ARIA From the Aducanumab Phase 3 ENGAGE and EMERGE Studies

https://www.neurology.org/doi/10.1212/WNL.0000000000207919?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
Stephanie J.Loomis, PhD, MPH, Ryan Miller, MD, Carmen Castrillo-Viguera, MD, Kimberly Umans, PhD, Wenting Cheng, PhD, MA, John O'Gorman, PhD, MS, Richard Hughes, MD, Samantha Budd Haeberlein, PhD, and Christopher D. Whelan, MSc, PhD
Neurology February 13, 2024 issue 102 (3)
December 28, 2023
DOI: https://doi.org/10.1212/WNL.0000000000207919
Abstract
Background and Objectives
Amyloid-related imaging abnormalities (ARIA) were the most common adverse events reported in the phase 3 ENGAGE and EMERGE trials of aducanumab, an anti-amyloid monoclonal antibody. APOE ε4 carrier status has been shown to increase risk of ARIA in prior trials of aducanumab and other anti-amyloid therapies; however, the remainder of the human genome has not been evaluated for ARIA risk factors. Therefore, we sought to determine in a hypothesis-free manner whether genetic variants beyond APOE influence risk of ARIA in aducanumab-treated patients.
Methods
We performed genome-wide association studies (GWAS) of ARIA in participants in the ENGAGE and EMERGE trials. Participants had mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia and were amyloid-positive on PET scans. All participants underwent regular MRI monitoring to detect and diagnose ARIA.
Results
Of the 3,285 participants in the intent-to-treat population, this analysis included 1,691 with genotyping array data who received at least one dose of aducanumab with at least one post-baseline MRI. All participants in the study cohort were of European ancestry; 51% were female. The mean age was 70.3 years. 31% had ARIA-E, 19% had ARIA-H microhemorrhage, and 14% had ARIA-H superficial siderosis. We identified one genome-wide significant (p < 5.0 × 10−8) association at the chromosome 19 locus encompassing APOE. The APOE association with ARIA was stronger in ε4/ε4 homozygotes (OR = 4.28, 4.58, 7.84; p < 2.9 × 10−14 for ARIA-E, ARIA-H microhemorrhage, and ARIA-H superficial siderosis, respectively) than in ε3/ε4 heterozygotes (OR = 1.74, 1.46, 3.14; p ≤ 0.03). We found greater odds of radiographically severe ARIA (OR = 7.04–24.64, p ≤ 2.72 × 10−5) than radiographically mild ARIA (OR = 3.19–5.00, p ≤ 1.37 × 10−5) among ε4/ε4 homozygotes. APOE ε4 was also significantly associated with both symptomatic (ε4/ε4 OR = 3.64–9.52; p < 0.004) and asymptomatic (ε4/ε4 OR = 4.20–7.94, p < 1.7 × 10−11) cases, although among ARIA cases, APOE did not appear to modulate symptomatic status. No other genome-wide significant associations were found.
Discussion
We identified a strong, genome-wide significant association between APOE and risk of ARIA. Future, larger studies may be better powered to detect associations beyond APOE. These findings indicate that APOE is the strongest genetic risk factor of ARIA incidence, with implications for patient management and risk-benefit treatment decisions.

APOE4 impairs microglia-astrocyte response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.076510
Oleg Butovsky, Zhuoran Yin, Neta Rosenzweig, Kilian Kleemann, Xiaoming Zhang, Wesley N Brandao, Milica Margeta, Caitlin M Schroeder, Sebastian Silveira, Christian Gauthier, Dania Mallah, Kristen Pitts, Ana Durao, Shawn Herron, Hannah Shorey, Yiran Cheng, Jen-Li Barry, Sam Wakelin, Jared Rhee, Anthony Yung, Michael Aronchik, Chao Wang, Nimansha Jain, Xin Bao, Emma Gerrits, Nieske Brouwer, Amy Deik, Daniel G. Tenen, Tsuneya Ikezu, Nicolas G. Santander, Gabriel L. McKinsey, Caroline Baufeld, Dean Sheppard, Susanne Krasemann, Bart Eggen, Clary Clish, Rudolph E. Tanzi, Charlotte Madore, Thomas D. Arnold, David M. Holtzman Alzheimer’s & Dementia Volume19, IssueS1 Supplement: Basic Science and Pathogenesis – Part 1, December 2023
First published: 25 December 2023
DOI: https://doi.org/10.1002/alz.076510
Abstract
Background
APOE ε4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD). Method
Generation of CX3CR1-CREERT2 mice crossed to APOE-KI(E3 and E4)fl/fl: APP/PS1 and APOE-KI(E3 and E4)fl/fl: P301S mice. Microglia and astrocytes were isolated and sequenced using either bulk RNA-seq (MGnD-Paradigm) or single-cell RNA-seq. Crosstalk between cells was determined using the NichenetR database and validated using 1) recombinant Lgals3 intracranial injection into APP/PS1 mice and 2) adoptive transfer of microglia, from APOE3-KI, APOE4-KI, and APOE4-cKO mice challenged with labeled apoptotic neurons, into WT mice and isolation of astrocytes. Validation in the brain of AD donors carrying the APOE e3/3 and e3/4 alleles. Result
Here we show, in mice and in humans, a negative role of microglial APOE4 in the induction of MGnD response to neurodegeneration. Deletion of microglial APOE4 restores MGnD phenotype, associated with neuroprotection in P301S tau transgenic mice, and decreases pathology in APP/PS1 mice. MGnD-astrocyte crosstalk associated with b-amyloid (Ab) plaque encapsulation and clearance is mediated via Lgals3 signaling following microglial APOE4 deletion. In the brain of AD donors carrying the APOE ε4 allele, we found a sex-dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, as compared to APOE ε3/3 carriers. Mechanistically, APOE4-mediated induction of ITGB8-TGFb signaling impairs MGnD response via upregulation of TGFb-mediated microglial homeostatic checkpoints, including INPP5D. Microglial deletion of Inpp5d restores MGnD-astrocyte crosstalk and facilitates plaque clearance in APP/PS1 mice. Genetic and pharmacological blocking of ITGB8-TGFb signaling enhanced MGnD response associated with increased plaque clearance in AD mice. Conclusion
We identify the microglial APOE4-ITGB8-TGFb pathway as a negative regulator of microglia-astrocyte response to AD pathology, and restoring MGnD phenotype via blocking ITGB8-TGFb signaling may provide new molecular targets to modulate and restore functional microglia in AD.

Cerebral perfusion is elevated in a novel model of aged hAβKI APOE4 mice

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.081750
Andre Obenaus, Aditya Singh, Rojina Pad, Anika Iyer, Tia Ketsan, Amandine Jullienne
Alzheimer's Imaging Consortium Volume19, IssueS10 December 2023
First published: 24 December 2023
DOI: https://doi.org/10.1002/alz.081750
Abstract
Background
The Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease (MODEL-AD) Consortium is developing the next generation of Alzheimer’s disease (AD) models based on human genomic and imaging data. Recently, MODEL-AD has generated a new human Aß Knock-In (hAßKI) mouse carrying the APOE4 allele. APOE4 carriers are at increased risk for AD. Previous studies have demonstrated altered cerebrovascular integrity and function. We examined the cerebrovascular function in the hAßKI APOE4 mice at 18mo of age using perfusion-weighted magnetic resonance imaging (PWI). We investigated brain-wide perfusion alterations in conjunction with histopathological vessel painting.
Method
Contrast-enhanced PWI MRI (9.4T) was undertaken from hAßKI APOE4 (n = 6) and WT (n = 5) mice at 18mo of age following tail vein cannulation for Gadolinium infusion. Imaging sequences included: T1-pre and post-infusion, PWI (10min) and susceptibility-weighted imaging (SWI) for blood extravasation and iron content. All data were processed using JIM v9 software for maps of cerebral blood flow (CBF), volumes (CBV), time to peak, mean transit time and dynamic susceptibility measures for blood-brain barrier dysfunction. Manual regions of interest (ROI) were performed for cortex, temporal lobe cortex, dorsal hippocampus and thalamus, and semi-automatic 30+ regions based on the Allen mouse brain atlas. At the end of the in vivo experiments all mice underwent vessel painting followed by microscopic analyses.
Result
Compared to WT mice at 18mo of age, hAßKI APOE4 mice exhibited elevated CBF in virtually all regions examined. CBF was elevated approx. 16%, 11%, 4% and 23% in the cortex, hippocampus, thalamus and temporal lobe cortex, respectively. CBF was significantly elevated in the retrosplenial and temporal lobe cortices (p<0.05). CBV was also significantly increased in temporal lobe. Ongoing analyses will correlate vascular network measures (density, junctions, length) to PWI metrics as well as to hAßKI only mice.
Conclusion
The 18mo hAßKI APOE4 mouse compared to WT exhibited consistent brain-wide elevations in cerebrovascular measures. This increase may represent a compensatory mechanism to maintain decreased metabolism that occurs with aging. The MODEL-AD consortium (UCI/IUSM/JAX) continues to develop new and novel AD mouse models. All data will be made available to AD researchers via the Sage Knowledge Network (https://adknowledgeportal.synapse.org/).

Flavonoids and fibrate modulate apoE4-induced processing of amyloid precursor protein in neuroblastoma cells

https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1245895/full?utm_source=F-NTF&utm_medium=EMLX&utm_campaign=PRD_FEOPS_20170000_ARTICLE
Viralkumar Davra, Kenza E. Benzeroual
Frontiers in Neuroscience, VOLUME 17, 2023
21 December 2023
DOI: https://doi.org/10.3389/fnins.2023.1245895
Introduction:
Apolipoprotein (apo) E4, being a major genetic risk factor for Alzheimer’s disease (AD), is actively involved in the proteolytic processing of amyloid precursor protein (APP) to amyloid β (Aβ) peptide, the principle constituent of amyloid plaques in Alzheimer Disease (AD) patients. ApoE4 is believed to affect APP processing through intracellular cholesterol homeostasis, whereas lowering the cholesterol level by pharmacological agents has been suggested to reduce Aβ production. This study has investigated the effects of hypolipidemic agents fenofibrate, and the flavonoids–naringenin and diosmetin–on apoE4-induced APP processing in rat neuroblastoma cells stably transfected with human wild-type APP 695 (B103-hAPP695wt). Results:
B103-hAPP695wt cells were pretreated with different doses of flavonoids and fenofibrate for 1 h prior to apoE4 exposure for 24 h. ApoE4-induced production of intra- and extracellular Aβ peptides has been reduced with fenofibrate, naringenin, and diosmetin treatments. Pretreatment with diosmetin has significantly reduced apoE4-induced full-length APP (fl- APP) expression, whereas naringenin and fenofibrate had no effect on it. In addition, the increase in the apoE4-induced secretion of sAPPtotal and sAPPα has been dose-dependently reduced with drug pretreatment. On the other hand, the decrease in the expression of both APP-carboxy terminal fragments (CTF)-α and –β (generated by the α- or β-secretase cleavage of APP) by apoE4 was dose-dependently increased in cells pretreated with fenofibrate and naringenin but not diosmetin. Conclusion:
Thus, we suggest that fenofibrate, naringenin, and diosmetin treatments can reduce apoE4- induced Aβ production by distinct mechanisms that may prove useful in developing drugs for AD patients.

Microglial APOE4: more is less and less is more

https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-023-00693-6?fbclid=IwAR0Qb9ltiBAgzCjLeghTXW6g-D_phvRm7yLMCo187Vr3VM3KxfrB5DejC_M
Ghazaleh Eskandari-Sedighi & Mathew Blurton-Jones Molecular Neurodegeneration 18, Article 99 (2023)
Published: 19 December 2023
Abstract
Apolipoprotein E (APOE) is the single greatest genetic risk factor for late onset Alzheimer’s disease (AD). Yet, the cell-specific effects of APOE on microglia function have remained unclear. Fortunately, two comprehensive new studies published in the latest issue of Nature Immunology have employed complementary gain-of-function and loss-of-function approaches to provide critical new insight into the impact of microglial APOE on AD pathogenesis.

Fatal iatrogenic cerebral β-amyloid-related arteritis in a woman treated with lecanemab for Alzheimer’s disease

https://www.nature.com/articles/s41467-023-43933-5?fbclid=IwAR2MAwIx777xRptgJdJ64ewbpojgtzjgZfwM4oc4kf_7kpenDWOVY5qan4w
Elena Solopova, Wilber Romero-Fernandez, Hannah Harmsen, Lissa Ventura-Antunes, Emmeline Wang, Alena Shostak, Jose Maldonado, Manus J. Donahue, Daniel Schultz, Thomas M. Coyne, Andreas Charidimou & Matthew Schrag
Nature Communications 14, Article number 8220 (2023)
Published: 12 December 2023
DOI: https://doi.org/10.1038/s41467-023-43933-5
Abstract
We report the case of a 79-year-old woman with Alzheimer’s disease who participated in a Phase III randomized controlled trial called CLARITY-AD testing the experimental drug lecanemab. She was randomized to the placebo group and subsequently enrolled in an open-label extension which guaranteed she received the active drug. After the third biweekly infusion, she suffered a seizure characterized by speech arrest and a generalized convulsion. Magnetic resonance imaging revealed she had multifocal swelling and a marked increase in the number of cerebral microhemorrhages. She was treated with an antiepileptic regimen and high-dose intravenous corticosteroids but continued to worsen and died after 5 days. Post-mortem MRI confirmed extensive microhemorrhages in the temporal, parietal and occipital lobes. The autopsy confirmed the presence of two copies of APOE4, a gene associated with a higher risk of Alzheimer’s disease, and neuropathological features of moderate severity Alzheimer’s disease and severe cerebral amyloid angiopathy with perivascular lymphocytic infiltrates, reactive macrophages and fibrinoid degeneration of vessel walls. There were deposits of β-amyloid in meningeal vessels and penetrating arterioles with numerous microaneurysms. We conclude that the patient likely died as a result of severe cerebral amyloid-related inflammation.

Synthesis and Preclinical Evaluation of 22-[18F]Fluorodocosahexaenoic Acid as a Positron Emission Tomography Probe for Monitoring Brain Docosahexaenoic Acid Uptake Kinetics

https://pubs.acs.org/doi/10.1021/acschemneuro.3c00681
Marlon Vincent V. Duro, Juno Van Valkenburgh, Diana E. Ingles, Jenny Tran, Zhiheng Cai, Brandon Ebright, Shaowei Wang, Bilal E. Kerman, Jasmin Galvan, Sung Hee Hwang, Naomi S. Sta Maria, Francesca Zanderigo, Etienne Croteau, Stephen C. Cunnane, Stanley I. Rapoport, Stan G. Louie, Russell E. Jacobs, Hussein N. Yassine, and Kai Chen
ACS Chemical Neuroscience, 2023, 14, 24, 4409–4418
Publication Date: December 4, 2023
Doi: https://doi.org/10.1021/acschemneuro.3c00681
Abstract
Docosahexaenoic acid [22:6(n-3), DHA], a polyunsaturated fatty acid, has an important role in regulating neuronal functions and in normal brain development. Dysregulated brain DHA uptake and metabolism are found in individuals carrying the APOE4 allele, which increases the genetic risk for Alzheimer’s disease (AD), and are implicated in the progression of several neurodegenerative disorders. However, there are limited tools to assess brain DHA kinetics in vivo that can be translated to humans. Here, we report the synthesis of an ω-radiofluorinated PET probe of DHA, 22-[18F]fluorodocosahexaenoic acid (22-[18F]FDHA), for imaging the uptake of DHA into the brain. Using the nonradiolabeled 22-FDHA, we confirmed that fluorination of DHA at the ω-position does not significantly alter the anti-inflammatory effect of DHA in microglial cells. Through dynamic PET-MR studies using mice, we observed the accumulation of 22-[18F]FDHA in the brain over time and estimated DHA’s incorporation coefficient (K*) using an image-derived input function. Finally, DHA brain K* was validated using intravenous administration of 15 mg/kg arecoline, a natural product known to increase the DHA K* in rodents. 22-[18F]FDHA is a promising PET probe that can reveal altered lipid metabolism in APOE4 carriers, AD, and other neurologic disorders. This new probe, once translated into humans, would enable noninvasive and longitudinal studies of brain DHA dynamics by guiding both pharmacological and nonpharmacological interventions for neurodegenerative diseases.

November 2023

Associations of ApoE Polymorphisms with Postoperative Atrial Fibrillation and Cardiac Injury in Patients with Coronary Artery Bypass Graft Surgery

https://www.jstage.jst.go.jp/article/ihj/64/6/64_23-245/_article?fbclid=IwAR0idnmsAwpnJv54ddfeNrgrc7kut2LyuGeZI1CoXbAgU4y0qRkhQN_gelU
Hui Xue, Lixin Fan, Chen Liu
International Heart Journal, 2023, Volume 64, Issue 6, Pages 1049-1053
November 30, 2023
DOI: https://doi.org/10.1536/ihj.23-245
Abstract
Genetic factors may be involved in postoperative atrial fibrillation (PoAF) development and cardiac injury. However, the associations of the apolipoprotein E (ApoE) gene polymorphisms with PoAF and cardiac injury after coronary artery bypass graft surgery (CABG) remain unclear. We recruited 150 patients with CABG, comprising 92 and 58 cases for the ApoE4 and ApoE3 groups, respectively, and analyzed PoAF incidence and the levels of cardiac biomarkers, including N-terminal prohormone of brain natriuretic peptide, cardiac troponin T (cTnT), and cardiac troponin I (cTnI). The linear regression model or logistic regression analysis was applied to investigate the associations of ApoE gene polymorphisms with PoAF and biomarkers for cardiac injury. A total of 58 (38.7%) patients with CABG developed PoAF, with 40 and 18 cases in the ApoE4 and ApoE3 groups (43.5% versus 31.0%, P < 0.05), respectively. Logistic regression analysis revealed that the ApoE4 allele was an independent risk factor for PoAF (OR = 3.340, P = 0.001), while the ApoE3 allele was a protective factor for the PoAF (OR = 0.841, P = 0.043). Patients carrying the ApoE4 allele had higher levels of cTnT and cTnI than those carrying the ApoE3 allele. ApoE3 was a protective factor for cardiac injury (β = −0.220, P = 0.001), whereas ApoE4 was a risk factor for cTnI (β = 0.335, P = 0.015). Our study reveals that the ApoE allele contributes to the occurrence of PoAF and severity of cardiac injury in an allele-dependent manner, with the ApoE4 allele increasing the risk and the ApoE3 allele reducing the risk.

Ceramides Mediate Insulin-Induced Impairments in Cerebral Mitochondrial Bioenergetics in ApoE4 Mice

https://www.mdpi.com/1422-0067/24/23/16635?fbclid=IwAR3OHWWV97Xo_GbxEI5aNZqYnMIscSE5t3-22BLhkzCYLxXlhmcVoXMSj7U
Carr, S.T.; Saito, E.R.; Walton, C.M.; Saito, J.Y.; Hanegan, C.M.; Warren, C.E.; Trumbull, A.M.; Bikman, B.T.
International Journal of Molecular Sciences 2023, 24, 16635
Published: 23 November 2023
DOI: https://doi.org/10.3390/ijms242316635
Abstract
Alzheimer’s disease (AD) is the most common form of neurodegenerative disease worldwide. A large body of work implicates insulin resistance in the development and progression of AD. Moreover, impairment in mitochondrial function, a common symptom of insulin resistance, now represents a fundamental aspect of AD pathobiology. Ceramides are a class of bioactive sphingolipids that have been hypothesized to drive insulin resistance. Here, we describe preliminary work that tests the hypothesis that hyperinsulinemia pathologically alters cerebral mitochondrial function in AD mice via accrual of the ceramides. Homozygous male and female ApoE4 mice, an oft-used model of AD research, were given chronic injections of PBS (control), insulin, myriocin (an inhibitor of ceramide biosynthesis), or insulin and myriocin over four weeks. Cerebral ceramide content was assessed using liquid chromatography–mass spectrometry. Mitochondrial oxygen consumption rates were measured with high-resolution respirometry, and H2O2 emissions were quantified via biochemical assays on brain tissue from the cerebral cortex. Significant increases in brain ceramides and impairments in brain oxygen consumption were observed in the insulin-treated group. These hyperinsulinemia-induced impairments in mitochondrial function were reversed with the administration of myriocin. Altogether, these data demonstrate a causative role for insulin in promoting brain ceramide accrual and subsequent mitochondrial impairments that may be involved in AD expression and progression.

Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist

https://www.cell.com/neuron/abstract/S0896-6273(23)00804-8
Alexandra Litvinchuk, Jung H. Suh, Jing L. Guo, Karin Lin, Sonnet S. Davis, Nga Bien-Ly, Eric Tycksen, G. Travis Tabor, Javier Remolina Serrano, Melissa Manis, Xin Bao, Choonghee Lee, Megan Bosch, Enmanuel J. Perez, Carla M. Yuede, Anil G. Cashikar, Jason D. Ulrich, Gilbert Di Paolo, David M. Holtzman
Neuron Volume 112, Issue 3, P384-403.E8, FEBRUARY 07, 2024
Published: November 22, 2023
DOI: https://doi.org/10.1016/j.neuron.2023.10.023
Summary
Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer’s disease (LOAD). APOE4 increases and APOE2 decreases risk relative to APOE3. In the P301S mouse model of tauopathy, ApoE4 increases tau pathology and neurodegeneration when compared with ApoE3 or the absence of ApoE. However, the role of ApoE isoforms and lipid metabolism in contributing to tau-mediated degeneration is unknown. We demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation and perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via an LXR agonist or Abca1 overexpression strongly attenuates tau pathology and neurodegeneration in P301S/ApoE4 mice. We also demonstrate reductions in reactive astrocytes and microglia, as well as changes in cholesterol biosynthesis and metabolism in glia of tauopathy mice in response to LXR activation. These data suggest that promoting efflux of glial lipids may serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration.

Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer’s Disease Model

https://www.biorxiv.org/content/10.1101/2023.11.10.566510v1?fbclid=IwAR3LN5-6Err0C6DvoCSmdrhrmzPSjqAqIxvxABwRpUszsDf5iKIN-DTjDyc
Antara Rao, Nuo Chen, Min Joo Kim, Jessica Blumenfeld, Oscar Yip, Yanxia Hao, Zherui Liang, Maxine R. Nelson, Nicole Koutsodendris, Brian Grone, Leo Ding, Seo Yeon Yoon, Patrick Arriola, Yadong Huang
bioRxiv 2023.11.10.566510
Posted November 14, 2023 (preprint)
doi: https://doi.org/10.1101/2023.11.10.566510
SUMMARY
Despite strong evidence supporting the involvement of both apolipoprotein E4 (APOE4) and microglia in Alzheimer’s Disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-driven AD pathogenesis remain elusive. Here, we examined such effects utilizing microglial depletion in a chimeric model with human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) induced pluripotent stem cell (iPSC)-derived human neurons into the hippocampus of human APOE3 or APOE4 knock-in mice, and depleted microglia in half the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of Aβ and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA-sequencing analysis identified two pro-inflammatory microglial subtypes with high MHC-II gene expression that are enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis.
HIGHLIGHTS
• Transplanted human APOE4 neurons generate Aβ and p-tau aggregates in APOE4-KI mouse hippocampus.
• Human neuronal APOE4 promotes the formation of dense-core Aβ plaques and p-tau aggregates.
• Microglia is required for human neuronal APOE4-driven formation of p-tau aggregates.
• scRNA-seq reveals enrichment of MHC-II microglia in mice with human APOE4 neuron transplants.

October 2023

Abnormal Temporal Slowing on EEG Findings in Preclinical Alzheimer’s Disease Patients With the ApoE4 Allele: A Pilot Study

https://www.cureus.com/articles/155550-abnormal-temporal-slowing-on-eeg-findings-in-preclinical-alzheimers-disease-patients-with-the-apoe4-allele-a-pilot-study?fbclid=IwAR0cl9FDTEGzHZ90t21RXZSeBZQCT8Oc8uVqNkhVLzPIbGI9OGfX_n_0EQ8#!/
Nathan N. Kim • Charissa Tan • Enze Ma • Selin Kutlu • Enrique Carrazana • Vajjhala Vimala • Jason Viereck • Kore Liow
Cureus 15(10): e47852
Published: October 28, 2023
DOI: 10.7759/cureus.47852
Abstract
Introduction:
Currently, there are limited accessible and cost-effective biomarkers for preclinical Alzheimer’s disease (AD) patients. However, the apolipoprotein E (ApoE) polymorphic alleles can predict if someone is at high (e4), neutral (e3), or low (e2) genetic risk for developing AD. This study analyzed electroencephalogram (EEG) reports from individuals with various ApoE genotypes, aiming to identify EEG changes and patterns that could potentially serve as predictive markers for preclinical AD progression.
Methods:
Participants aged 64-78 were selected from the patient database at an outpatient neurology clinic. Genotype studies were performed to determine ApoE status, followed by EEG analysis to identify any apparent trends. A case-control design was used, categorizing participants into cases (e2e3, e2e4, e3e4, e4e4) and controls (e3e3). EEG recordings were compared between the groups to identify potential differences in EEG characteristics, including abnormal temporal slowing, frequency, and ApoE genotype association.
Results:
Among 43 participants, 49% demonstrated evidence of abnormal temporal slowing on EEG. Of these, 48% displayed focal left temporal slowing, and 52% displayed bilateral temporal slowing. The right-sided temporal slowing was not observed. Among participants with abnormal slowing, 95% exhibited theta frequency (4-8 Hz) slowing, while only 4.8% displayed delta frequency (0-4 Hz) slowing. Among participants with the ApoE4 allele, 61.5% demonstrated evidence of abnormal slowing, compared to 43.3% without it. Furthermore, the presence of an ApoE4 allele was associated with a significantly higher proportion of males (54%) compared to those without it (13%) (p=0.009).
Conclusions:
Although we did not find a statistically significant difference in temporal EEG slowing among different ApoE genotypes, our findings suggest a potential association between temporal slowing on EEG and the presence of an ApoE4 allele in individuals with preclinical AD. These observations highlight the need for further exploration into the potential influence of the ApoE4 allele on EEG findings and the utility of EEG as a complementary diagnostic tool for AD. Longitudinal studies with large sample sizes are needed to establish the precise relationship between EEG patterns, ApoE genotypes, and AD progression.

APOE4-promoted gliosis and degeneration in tauopathy are ameliorated by pharmacological inhibition of HMGB1 release

https://www.cell.com/cell-reports/fulltext/S2211-1247(23)01264-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124723012640%3Fshowall%3Dtrue
Nicole Koutsodendris, Jessica Blumenfeld, Ayushi Agrawal, Michela Traglia, Oscar Yip, Antara Rao, Min Joo Kim, Maxine R. Nelson, Yung-Hua Wang, Brian Grone, Yanxia Hao, Reuben Thomas, Misha Zilberter, Seo Yeon Yoon, Patrick Arriola, Yadong Huang
Cell Reports VOLUME 42, ISSUE 10, 113252, OCTOBER 31, 2023
Published: October 19, 2023
DOI: https://doi.org/10.1016/j.celrep.2023.113252
Highlights
• APOE4 promotes neuronal HMGB1 translocation and release in tauopathy mice
• Neuronal APOE4 removal reduces HMGB1 translocation and release in tauopathy mice
• Treatment with HMGB1 inhibitors ameliorates APOE4-driven gliosis and AD pathologies
• The inhibitor treatment reduces disease-associated neuronal and glial subtypes
Summary
Apolipoprotein E4 (APOE4) is an important driver of Tau pathology, gliosis, and degeneration in Alzheimer’s disease (AD). Still, the mechanisms underlying these APOE4-driven pathological effects remain elusive. Here, we report in a tauopathy mouse model that APOE4 promoted the nucleocytoplasmic translocation and release of high-mobility group box 1 (HMGB1) from hippocampal neurons, which correlated with the severity of hippocampal microgliosis and degeneration. Injection of HMGB1 into the hippocampus of young APOE4-tauopathy mice induced considerable and persistent gliosis. Selective removal of neuronal APOE4 reduced HMGB1 translocation and release. Treatment of APOE4-tauopathy mice with HMGB1 inhibitors effectively blocked the intraneuronal translocation and release of HMGB1 and ameliorated the development of APOE4-driven gliosis, Tau pathology, neurodegeneration, and myelin deficits. Single-nucleus RNA sequencing revealed that treatment with HMGB1 inhibitors diminished disease-associated and enriched disease-protective subpopulations of neurons, microglia, and astrocytes in APOE4-tauopathy mice. Thus, HMGB1 inhibitors represent a promising approach for treating APOE4-related AD.

ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes

https://www.cell.com/cell-reports/fulltext/S2211-1247(23)01195-6?fbclid=IwAR24xWc95qO_j8P4ybH15tKycK6lT0RdwgkuZ0Lk6TgGPda1aquTphXGC7o
Hyein Lee, Sukhee Cho, Mi-Jin Kim, Yeo Jin Park, Eunji Cho, Yeon Suk Jo, Yong-Seok Kim, Jung Yi Lee, Themis Thoudam, Seung-Hwa Woo, Se-In Lee, Juyeong Jeon, Young-Sam Lee, Byung-Chang Suh, Jong Hyuk Yoon, Younghoon Go, In-Kyu Lee, Jinsoo Seo
Cell Reports VOLUME 42, ISSUE 10, 113183, OCTOBER 31, 2023
Published: October 02, 2023
Highlights
• Human ApoE4 astrocytes display increased glycolytic activity and reduced OXPHOS
• ApoE4 induces defective autophagy and mitochondrial dysfunction in human astrocytes
• Mitigating cholesterol burden restores mitochondrial respiration in ApoE4 astrocytes
Summary
Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer’s disease (AD). Among them, genetic variant ε4 of the APOE gene (APOE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. Ultrastructural and autophagy flux analyses show that ApoE4-induced cholesterol accumulation impairs lysosome-dependent removal of damaged mitochondria. Acute treatment with cholesterol-depleting agents restores autophagic activity, mitochondrial dynamics, and associated proteomes, and extended treatment rescues mitochondrial respiration in ApoE4 astrocytes. Taken together, our study provides a direct link between ApoE4-induced lysosomal cholesterol accumulation and abnormal oxidative phosphorylation.

September 2023

APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints

https://pubmed.ncbi.nlm.nih.gov/37749326/
Yin Z, Rosenzweig N, Kleemann KL, Zhang X, Brandão W, Margeta MA, Schroeder C, Sivanathan KN, Silveira S, Gauthier C, Mallah D, Pitts KM, Durao A, Herron S, Shorey H, Cheng Y, Barry JL, Krishnan RK, Wakelin S, Rhee J, Yung A, Aronchik M, Wang C, Jain N, Bao X, Gerrits E, Brouwer N, Deik A, Tenen DG, Ikezu T, Santander NG, McKinsey GL, Baufeld C, Sheppard D, Krasemann S, Nowarski R, Eggen BJL, Clish C, Tanzi RE, Madore C, Arnold TD, Holtzman DM, Butovsky O.
Nature Immunology 2023 Nov;24(11):1839-1853
Epub: 2023 Sep 25
DOI: 10.1038/s41590-023-01627-6
Abstract
The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD). Here, we show in mice and humans a negative role of microglial APOE4 in the induction of the MGnD response to neurodegeneration. Deletion of microglial APOE4 restores the MGnD phenotype associated with neuroprotection in P301S tau transgenic mice and decreases pathology in APP/PS1 mice. MGnD-astrocyte cross-talk associated with β-amyloid (Aβ) plaque encapsulation and clearance are mediated via LGALS3 signaling following microglial APOE4 deletion. In the brains of AD donors carrying the APOE4 allele, we found a sex-dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, compared to individuals homozygous for the APOE3 allele. Mechanistically, APOE4-mediated induction of ITGB8-transforming growth factor-β (TGFβ) signaling impairs the MGnD response via upregulation of microglial homeostatic checkpoints, including Inpp5d, in mice. Deletion of Inpp5d in microglia restores MGnD-astrocyte cross-talk and facilitates plaque clearance in APP/PS1 mice. We identify the microglial APOE4-ITGB8-TGFβ pathway as a negative regulator of microglial response to AD pathology, and restoring the MGnD phenotype via blocking ITGB8-TGFβ signaling provides a promising therapeutic intervention for AD.

Prebiotic inulin enhances gut microbial metabolism and anti-inflammation in apolipoprotein E4 mice with sex-specific implications

https://www.nature.com/articles/s41598-023-42381-x?fbclid=IwAR1JvG7vb2pEdt5nl7TYE-4rmxpKXSNVjm8hFIR1v4GpGM6abbK-hEF2QJw
Ya-Hsuan Chang, Lucille M. Yanckello, George E. Chlipala, Stefan J. Green, Chetan Aware, Amelia Runge, Xin Xing, Anna Chen, Kathryn Wenger, Abeoseh Flemister, Caixia Wan & Ai-Ling Lin
Scientific Reports 13, 15116 (2023)
Published 13 September 2023
DOI: https://doi.org/10.1038/s41598-023-42381-x
Abstract
Gut dysbiosis has been identified as a crucial factor of Alzheimer's disease (AD) development for apolipoprotein E4 (APOE4) carriers. Inulin has shown the potential to mitigate dysbiosis. However, it remains unclear whether the dietary response varies depending on sex. In the study, we fed 4-month-old APOE4 mice with inulin for 16 weeks and performed shotgun metagenomic sequencing to determine changes in microbiome diversity, taxonomy, and functional gene pathways. We also formed the same experiments with APOE3 mice to identify whether there are APOE-genotype dependent responses to inulin. We found that APOE4 female mice fed with inulin had restored alpha diversity, significantly reduced Escherichia coli and inflammation-associated pathway responses. However, compared with APOE4 male mice, they had less metabolic responses, including the levels of short-chain fatty acids-producing bacteria and the associated kinases, especially those related to acetate and Erysipelotrichaceae. These diet- and sex- effects were less pronounced in the APOE3 mice, indicating that different APOE variants also play a significant role. The findings provide insights into the higher susceptibility of APOE4 females to AD, potentially due to inefficient energy production, and imply the importance of considering precision nutrition for mitigating dysbiosis and AD risk in the future.

Lower mortality risk in APOE4 carriers with normal cognitive ageing

https://www.nature.com/articles/s41598-023-41078-5?fbclid=IwAR0h2sXze-JgpGWy5w2cgV7epkpusHlaUb09Ll-l_QKlvhon1TU15rrXHWs
Elizabeth Pirraglia, Lidia Glodzik & Yongzhao Shao
Scientific Reports 13, 15089 (2023)
Published 12 September 2023
DOI: https://doi.org/10.1038/s41598-023-41078-5
Abstract
Abnormal cognitive ageing, including dementia, poses serious challenges to health and social systems in ageing populations. As such, characterizing factors associated with abnormal cognitive ageing and developing needed preventive measures are of great importance. The ε4 allele of the Apolipoprotein E gene (APOE4) is a well-known genetic risk factor for late-onset Alzheimer’s disease. APOE4 carriers are also at elevated risk of cardiovascular diseases which are associated with increased risk of cognitive impairment. On the other hand, APOE4 is known to be associated with reduced risk of multiple common types of cancer—a major age-related disease and leading cause of mortality. We conducted the first-ever study of APOE4’s opposing effects on cognitive decline and mortality using competing risk models considering two types of death—death with high-amounts versus low-amounts of autopsy-assessed Alzheimer’s neuropathology. We observed that APOE4 was associated with decreased mortality risk in people who died with low amounts of Alzheimer’s-type neuropathology, but APOE4 was associated with increased mortality risk in people who died with high amounts of Alzheimer’s-type neuropathology, a major risk factor of cognitive impairment. Possible preventive measures of abnormal cognitive ageing are also discussed.

Lecanemab (Leqembi) is not the right drug for patients with Alzheimer's disease

https://advances.umw.edu.pl/pdf/2023/32/9/943.pdf
Markku Kurkinen
Advances in Clinical and Experimental Medicine 2023 Sep;32(9):943-947
Published online on September 7, 2023
DOI: 10.17219/acem/171379
Abstract
On July 6, 2023, the U.S. Food and Drug Administration (FDA) approved lecanemab (Leqembi) for the treatment of Alzheimer's dementia (AD) patients. In 2 clinical trials, lecanemab reduced amyloid in the brain and slowed cognitive decline. Here, I review in detail the clinical trial by van Dyck et al. (2023) entitled "Lecanemab in early Alzheimer's disease", published in The New England Journal of Medicine on January 5, 2023. In this 18-month trial, lecanemab did not slow cognitive decline in women. This is especially significant because women have a twofold increased risk of AD compared to men, that is, there are 2 times more women than men living with AD. Lecanemab did not slow cognitive decline in APOE4 carriers; rather, it enhanced the decline in study participants with 2 APOE4 genes. This is bad news for AD patients, 60-75% of whom carry at least 1 APOE4 gene. These negative results regarding lecanemab's therapeutic value make me wonder if the approval of lecanemab was the worst decision of the FDA up till now, after the approval of aducanumab on June 7, 2021.

August 2023

ApoE4 exacerbates the senescence of hippocampal neurons and spatial cognitive impairment by downregulating acetyl-CoA level

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13932?fbclid=IwAR0zzNG6oYhzpN2mx8rzs8wOG2qtwm2W99pB6AHwDcCzhXlie6o7BqVRHMs
Shuixin Lv, Yusi Zhang, Yingbin Lin, Wenting Fang, Yu Wang, Zihang Li, Anlan Lin, Xiaoman Dai, Qinyong Ye, Jing Zhang, Xiaochun Chen
Aging Cell, 22, e13932
First published: 18 August 2023
DOI: https://doi.org/10.1111/acel.13932
Abstract
Although aging and apolipoprotein E (APOE) ε4 allele have been documented as two major risk factors for late-onset Alzheimer's disease (LOAD), their interaction and potential underlying mechanisms remain unelucidated. Using humanized ApoE4- and ApoE3- target replacement mice, we found the accumulation of senescent neurons and the activation of mTOR and endosome-lysosome-autophagy (ELA) system in the hippocampus of aged ApoE4 mice. Further analyses revealed that ApoE4 aggravated the profile change of hippocampal transcription and metabolism in an age-dependent manner, accompanying with an disruption of metabolism, which is presented with the downregulating activity of citrate synthase, the level of ATP and, most importantly, the level of acetyl coenzyme A (Ac-CoA); GTA supplement, an Ac-CoA substrate, reversed the senescent characteristics, decreased the activation of mTOR and ELA system, and enhanced the synaptic structure and increasing level of pre-/post-synaptic plasticity-related protein, leading to cognitive improvement in aged ApoE4 mice. These data suggest that ApoE4 exacerbates neuronal senescence due to a deficiency of acetyl-CoA, which can be ameliorated by GTA supplement. The findings provide novel insights into the potential therapeutic value of GTA supplement for the cognitive improvement in aged APOE4 carriers.

Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-023-02870-2
Sarah R. Ocañas, Kevin D. Pham, Jillian E. J. Cox, Alex W. Keck, Sunghwan Ko, Felix A. Ampadu, Hunter L. Porter, Victor A. Ansere, Adam Kulpa, Collyn M. Kellogg, Adeline H. Machalinski, Manu A. Thomas, Zsabre Wright, Ana J. Chucair-Elliott & Willard M. Freeman
Journal of Neuroinflammation 20, 188 (2023)
Published 16 August 2023
DOI: https://doi.org/10.1186/s12974-023-02870-2
Abstract
Background
Microglia, the brain’s principal immune cells, have been implicated in the pathogenesis of Alzheimer’s disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment associated with late-onset AD. Here, we examined and compared transcriptomic and translatomic sex effects in young and old murine hippocampal microglia.
Methods
Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5–6 month-old [mo]) and old (22–25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome for RNA-sequencing and differential expression analyses. Flow cytometry, qPCR, and imaging approaches were used to confirm the transcriptomic and translatomic findings.
Results
There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally and autosomally encoded sex differences emerged with aging. These sex DEGs identified at old age were primarily female-biased and enriched in senescent and disease-associated microglial signatures. Normalized gene expression values can be accessed through a searchable web interface (https://neuroepigenomics.omrf.org/). Pathway analyses identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP.
Conclusions
These data suggest that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology and determine how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.
And from the discussion section of the text:
Recent AD clinical trials have shown that biological sex interacts with genomic risk factors to alter therapeutic efficacy, highlighting the need for precision medicine. For example, results of the Phase 3 lecanemab trial revealed that females and APOE4 homozygotes did not show improved cognition in response to lecanemab treatment, while males and APOE4 carriers showed significant improvement [84]. Additionally, hormone replacement therapy was shown to interact with APOE genotype to yield different efficacies in AD risk prevention in post-menopausal women [85]. Since APOE signals through TREM2 [61], the sex biases observed in TREM2 signaling pathways in aged microglia may be contributing to the differential response to AD treatment.

Common Alzheimer’s disease gene may have helped our ancestors have more kids

https://www.science.org/content/article/common-alzheimer-s-disease-gene-may-have-helped-our-ancestors-have-more-kids?fbclid=IwAR1XaEHHCMTpvi5sI7MZxc15az9tUZj60OV4dT_SPrIkTQrQR4G7PFcfCmo
JOCELYN KAISER, Science, 9 Aug 2023
9 Aug 2023
doi: 10.1126/science.adk2313
Roughly one in five people are born with at least one copy of a gene variant called APOE4 that makes them more prone to heart disease and Alzheimer’s disease in old age. That the variant is so common poses an evolutionary mystery: If it decreases our fitness, why hasn’t APOE4 been purged from the human population over time? Now, a study of nearly 800 women in a traditional society in the Amazon finds that those with the disease-promoting variant had slightly more children. Such a fertility benefit may have allowed the gene to persist during human evolution despite its harmful effects for older people today. “The study results are fascinating and illustrate that people living in rural, nonindustrial, and nonmechanized environments can provide perspective on the biology and health of those of us in industrialized areas of the world,” says biological anthropologist Cynthia Beall of Case Western Reserve University, who was not involved with the research. The APOE gene encodes apolipoprotein E, a molecule that helps the body transport cholesterol in the blood. There are three main variants and people can inherit a mix from their parents, with the one called APOE3 being much more common than APOE4. In populations of European ancestry, having one copy of APOE4 raises a person’s risk of cardiovascular disease and triples their odds of developing Alzheimer’s disease; those with two copies face a 12-fold or higher risk of the brain condition. Biological anthropologist Benjamin Trumble of Arizona State University has been among the researchers exploring why APOE4 persists if its effects are all bad. Previous work by his team and others has pointed to potential benefits that might counteract its negatives: Mice and children carrying APOE4 seem to be better than those without the variant at clearing intestinal worms and other parasites, which allows them to grow faster. If this helped women with APOE4 have more children, it could help explain why the gene persists. Researchers have tried to confirm this theory in industrialized and urban populations but have found no link between APOE4 and fertility. That’s not surprising because parasitic infections are rare in these settings and birth control is readily available, Trumble says. To probe the role of APOE4 among people who live a more traditional lifestyle, with more parasite exposure and less birth control, his team turned to a long-running health study led by U.S. and French researchers of the Tsimané people. This population of 17,000 hunts, forages, and practices horticulture in the Brazilian Amazon. The new study includes as co-authors a Bolivian researcher and a Tsimané research assistant who is now leader of the Tsimané governing council. The researchers got permission from individuals and the council and community leaders for the study. Trumble and his collaborators analyzed data collected over 20 years from interviewing 795 women ranging from ages 13 to 90 about their childbearing history, and also tested their DNA samples for APOE4. The women had nine children on average, but the 147 women who carried one copy of APOE4 averaged about 9.5 children. The 12 women with two copies had two additional children on average, the team reports today in Science Advances. The Tsimané data also allowed the team to home in on how APOE4 may boost fertility: Women carrying it were slightly heavier that those without it, started bearing children about 1 year earlier, and had their next child a few months sooner. That fits with being more resistant to parasites, Trumble says. “Being in a better immune state means that you can then devote more calories towards growing faster, and then you’re able to reproduce faster.” University of Copenhagen epidemiologist Rudolf Westendorp notes that his team, which saw a similar result in a Ghanaian population, has also observed such a trade-off in families with another cholesterol-related gene variant that raises heart disease risks: In the 19th century when many people died from infections, carriers actually lived longer. “In the past, carriers of that gene had a survival benefit, which explains why the variants are present nowadays,” he says. But although the new study’s “approach is quite interesting,” the fertility link poses a new puzzle, says geneticist Tábita Hünemeier at the University of São Paulo. The fertility boost is “so great” that natural selection should have led to a much higher frequency of APOE4 in the Tsimané, she suggests. Alzheimer’s and heart disease rates are low even among older Tsimané people, perhaps because of their active lifestyle, Trumble’s group has reported. But he says APOE4 could still have detrimental effects that balance the benefits—it may reduce fertility in men, for example, or decrease child survival. “Our next step is to figure out whether there are disadvantages at certain life stages,” he says.

Apolipoprotein-ε4 is associated with higher fecundity in a natural fertility population

https://www.science.org/doi/10.1126/sciadv.ade9797?adobe_mc=MCMID%3D75497593721852589891932825481923930098%7CMCORGID%3D242B6472541199F70A4C98A6%2540AdobeOrg%7CTS%3D1715724565
BENJAMIN C. TRUMBLE, MIA CHARIFSON, TOM KRAFT, ANGELA R. GARCIA, DANIEL K. CUMMINGS, PAUL HOOPER, AMANDA J. LEA, DANIEL EID RODRIGUEZ, STEPHANIE V. KOEBELE, KENNETH BUETOW, BRET BEHEIM, RIANA MINOCHER, MAGUIN GUTIERREZ, GREGORY S. THOMAS, MARGARET GATZ, JONATHAN STIEGLITZ, CALEB E. FINCH, HILLARD KAPLAN, AND MICHAEL GURVEN
SCIENCE ADVANCES VOL. 9, NO. 32
9 Aug 2023
DOI: 10.1126/sciadv.ade9797
Abstract
In many populations, the apolipoprotein-ε4 (APOE-ε4) allele increases the risk for several chronic diseases of aging, including dementia and cardiovascular disease; despite these harmful effects at later ages, the APOE-ε4 allele remains prevalent. We assess the impact of APOE-ε4 on fertility and its proximate determinants (age at first reproduction, interbirth interval) among the Tsimane, a natural fertility population of forager-horticulturalists. Among 795 women aged 13 to 90 (20% APOE-ε4 carriers), those with at least one APOE-ε4 allele had 0.3 to 0.5 more children than (ε3/ε3) homozygotes, while those with two APOE-ε4 alleles gave birth to 1.4 to 2.1 more children. APOE-ε4 carriers achieve higher fertility by beginning reproduction 0.8 years earlier and having a 0.23-year shorter interbirth interval. Our findings add to a growing body of literature suggesting a need for studies of populations living in ancestrally relevant environments to assess how alleles that are deleterious in sedentary urban environments may have been maintained by selection throughout human evolutionary history.

July 2023

Alzheimer’s polygenic risk scores, APOE, Alzheimer’s disease risk, and dementia-related blood biomarker levels in a population-based cohort study followed over 17 years

https://alzres.biomedcentral.com/articles/10.1186/s13195-023-01277-8?fbclid=IwAR08UHbDyiHLNEmgXIOVYIYrk2x2mQIrWEYhEnbLtLrheXdn_mw3po6meYs
Hannah Stocker, Kira Trares, Léon Beyer, Laura Perna, Dan Rujescu, Bernd Holleczek, Konrad Beyreuther, Klaus Gerwert, Ben Schöttker & Hermann Brenner
Alzheimer’s Research & Therapy 15, 129 (2023)
Published: 29 July 2023
DOI: https://doi.org/10.1186/s13195-023-01277-8
Abstract
Background
In order to utilize polygenic risk scores (PRSs) for Alzheimer’s disease (AD) in a meaningful way, influential factors (i.e. training set) and prediction across groups such as APOE e4 (APOE4) genotype as well as associations to dementia-related biomarkers should be explored. Therefore, we examined the association of APOE4 and various PRSs, based on training sets that utilized differing AD definitions, with incident AD and all-cause dementia (ACD) within 17 years, and with levels of phosphorylated tau181 (P-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) in blood. Secondarily, effect modification by APOE4 status and sex was examined.
Methods
In this prospective, population-based cohort study and nested case–control study, 9,940 participants in Germany were enrolled between 2000 and 2002 by their general practitioners and followed for up to 17 years. Participants were included in this study if dementia status and genetic data were available. A subsample of participants additionally had measurements of P-tau181, NfL, and GFAP obtained from blood samples. Cox and logistic regression analyses were used to assess the association of genetic risk (APOE genotype and PRSnoAPOE) with incident ACD/AD and log-transformed blood levels of P-tau181, NfL, and GFAP.
Results
Five thousand seven hundred sixty-five participants (54% female, aged 50-75years at baseline) were included in this study, of whom 464 received an all-cause dementia diagnosis within 17 years. The PRSs were not more predictive of dementia than APOE4. An APOE4 specific relationship was apparent with PRSs only exhibiting associations to dementia among APOE4 carriers. In the nested case–control study including biomarkers (n = 712), APOE4 status and polygenic risk were significantly associated to levels of GFAP in blood.
Conclusions
The use of PRSs may be beneficial for increased precision in risk estimates among APOE4 carriers. While APOE4 may play a crucial etiological role in initial disease processes such as Aβ deposition, the PRS may be an indicator of further disease drivers as well as astrocyte activation. Further research is necessary to confirm these findings, especially the association to GFAP.

High Prevalence of CAA-Related Lesions in APOE ε4/4 Homozygotes With Early Alzheimer disease

https://www.neurologylive.com/view/high-prevalence-caa-related-lesions-apoe-4-4-homozygotes-early-alzheimer-disease?fbclid=IwAR1BnUkRpbwtQeEMOYrJp13gKhrB9beY-2yvbXmbRlBIAoCSY7fd4woCJcI
Isabella Ciccone, MPH, Neurology Live July 26, 2023
Recent imaging results from the phase 3 APOLLOE4 trial (NCT04770220) investigating ALZ-801 (Alzheon), an investigational oral amyloid oligomer inhibitor, showed that patients with early-stage Alzheimer disease (AD) who are apolipoprotein ε4 allele (APOE4/4 homozygotes) carriers had a high prevalence of cerebral amyloid angiopathy (CAA)-related lesions at baseline.¹ These findings suggest that these patients would be more susceptible to treatment-induced brain edema and microhemorrhage (MH), known as amyloid related imaging abnormalities (ARIA).

Early Odor Detection Loss Linked to Alzheimer’s Gene Variant

https://neurosciencenews.com/olfaction-apoe4-alzheimers-23702/?fbclid=IwAR3aYzybMuDBc-0PtMGZlrYSU6T622CLrXUrqZ0PQujEXg4T9BHH-ZL1WK0
Neuroscience News, July 26, 2023
Summary:
Individuals carrying a gene variant associated with Alzheimer’s disease, APOE e4, may experience early loss in their ability to detect odors, hinting at future cognitive challenges. The study employed an at-home survey to test over 865 people’s sense of smell and cognitive skills at five-year intervals. Carriers of the gene variant were 37% less likely to detect odors well, with the reduction starting around ages 65 to 69. Although further research is needed, these findings hold promise in identifying early risks of dementia.
Key Facts:
• People carrying the APOE e4 gene variant associated with Alzheimer’s disease may lose their odor detection abilities earlier than those without the variant.
• This loss in odor detection could serve as an early indicator of potential cognitive problems in the future.
• The study discovered that the carriers of the gene variant started experiencing reduced smell detection around the age of 65 to 69.

APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer’s Disease pathology

https://www.medrxiv.org/content/10.1101/2023.07.20.23292771v1
Augustine Chemparathy, Yann Le Guen, Sunny Chen, Eun-Gyung Lee, Lesley Leong, John Gorzynski, Guangxue Xu, Michael Belloy, Nandita Kasireddy, Andrés Peña Tauber, Kennedy Williams, Ilaria Stewart, Thomas Wingo, James Lah, Suman Jayadev, Chad Hales, Elaine Peskind, Daniel D Child, C Dirk Keene, Le Cong, Euan Ashley, Chang-En Yu, Michael D. Greicius
medRxiv 2023.07.20.23292771
Posted July 24, 2023 (Preprint)
DOI: https://doi.org/10.1101/2023.07.20.23292771
Summary
The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer’s Disease (AD). Knockdown of this allele may provide a therapeutic strategy for AD, but the effect of APOE loss-of-function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of older controls and patients with AD and identified six heterozygote carriers of APOE LoF variants. Five carriers were controls (ages 71-90) and one was an AD case with an unremarkable age-at-onset between 75-79. Two APOE ε3/ε4 controls (Subjects 1 and 2) carried a stop-gain affecting the ε4 allele. Subject 1 was cognitively normal at 90+ and had no neuritic plaques at autopsy. Subject 2 was cognitively healthy within the age range 75-79 and underwent lumbar puncture at between ages 75-79 with normal levels of amyloid. The results provide the strongest human genetics evidence yet available suggesting that ε4 drives AD risk through a gain of abnormal function and support knockdown of APOE ε4 or its protein product as a viable therapeutic option.

Proteomic analysis reveals APOE isoform-specific regulation of ribosomes in neural precursor cells

https://www.biorxiv.org/content/10.1101/2023.07.15.549177v1?fbclid=IwAR0VMlexo7aJ_zE1ttJORiJwxHbA3Vij6yL4joS4ZIWA55tVP8zzHys6G2U
M Srividya, Pradip Paul, Sarayu Ramakrishna, Vivek Ghose, Gourav Dey, Ravi S Muddashetty, Sanjeev Jain, Meera Purushottam, Biju Viswanath, View ORCID ProfileReeteka Sud
bioRxiv 2023.07.15.549177
Posted July 18, 2023
doi: https://doi.org/10.1101/2023.07.15.549177
ABSTRACT
ApoE4 isoform contributes to increased risk for Alzheimer’s Disease (AD) over the life course of individuals. Much remains unknown about the biological pathways that connect APOE4 genotype with the development of pathology that eventually leads to AD, nor do we know how early in life these cellular alterations begin. To answer these questions, we derived neural precursor cells (NPCs) from induced pluripotent stem cells (IPSCs) that were CRISPR-edited at the APOE locus. We intended to characterize the protein expression landscape in the NPCs subsequent to targeted deletion of E4 from a parent IPSC line of APOE3/4 genotype. Differentially expressed proteins (DEPs) following mass spectrometric analysis were determined from the protein abundance fold change values obtained for each protein. Proteins which showed >1.5-fold difference with FDR adjusted P-value < 0.05 were considered differentially expressed. DEPs were mapped to the STRING database (v11.5) for retrieval of interacting proteins and functional enrichment. CRISPR-editing of E4 from the parent line revealed 98 differential expressed proteins. Of these, 54 were upregulated, and 44 were downregulated. Further analysis of the DEPs via STRING database showed that these changes primarily affect pathways linked to RNA processing, plasma membrane repair, and cytoskeleton organization. Indeed, we find the effects of E4 extend beyond proteins considered central to AD pathology. Knowing more about the protein interactions regulated by ApoE, in an isoform-specific manner, can reveal new mechanistic insights into development of AD.

Association between physical activity and episodic memory and the moderating effects of the apolipoprotein E ε4 allele and age

https://www.frontiersin.org/articles/10.3389/fnagi.2023.1184609/full
Boung Chul Lee, Young Min Choe, Guk-Hee Suh, Ihn-Geun Choi, Hyun Soo Kim, Jaeuk Hwang, Dahyun Yi, Jee Wook Kim
Frontiers in Aging Neuroscience, 11 July 2023, Sec. Neurocognitive Aging and Behavior, Volume 15 - 2023
11 July 2023
DOI: https://doi.org/10.3389/fnagi.2023.1184609
Background:
An abundance of evidence indicates that physical activity may protect against Alzheimer’s disease (AD) and related cognitive decline. However, little is known about the association between physical activity and AD-related cognitive decline according to age and the apolipoprotein E (APOE) ε4 allele (APOE4) as major risk factors. Therefore, we examined whether age and APOE4 status modulate the effects of physical activity on episodic memory as AD-related cognition in non-demented older adults.
Methods:
We enrolled 196 adults aged between 65 and 90 years, with no dementia. All participants underwent comprehensive clinical assessments including physical activity evaluation and APOE genotyping. The AD-related cognitive domain was assessed by the episodic memory, as the earliest cognitive change in AD, and non-memory cognition for comparative purposes. Overall cognition was assessed by the total score (TS) of the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery.
Results:
We found significant physical activity × age and physical activity × APOE4 interaction effects on episodic memory. Subgroup analyses indicated that an association between physical activity and increased episodic memory was apparent only in subjects aged > 70 years, and in APOE4-positive subjects.
Conclusion:
Our findings suggest that physical activity has beneficial effects on episodic memory, as an AD-related cognitive domain, in individuals aged > 70 years and in APOE4-positive individuals. Physicians should take age and APOE4 status account into when recommending physical activity to prevent AD-related cognitive decline.

June 2023

Can the APOE4 Gene Connect the Dots Between Cardiovascular and Periodontal Disease?

https://www.todaysrdh.com/can-the-apoe4-gene-connect-the-dots-between-cardiovascular-and-periodontal-disease/?fbclid=IwAR3dal4NQr8s9wHhnPLj_ipmZWWgPEpMGmoJW9U8RKUyzydVc0DVqc6Xipk
Spring Hatfield, Today’s RDH, June 29, 2023
According to the American Dental Association (ADA), no gene has been identified that has a large impact on periodontal disease.1 Nonetheless, we see this disease affects families, which would indicate there is some level of genetic factor associated with disease onset and progression. The ADA clearly states environmental influences are the biggest association with periodontal disease, and the connection may be due to gene-environmental interactions.¹

APOE4 expression confers a mild, persistent reduction in neurovascular function in the visual cortex and hippocampus of awake mice

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10676141/
Orla Bonnar, Kira Shaw, Silvia Anderle, Dori M Grijseels, Devin Clarke, Laura Bell, Sarah L King, and Catherine N Hall
Journal of Cerebral Blood Flow and Metabolism, 2023 Nov; 43(11): 1826–1841
Published online 2023 Jun 23
doi: 10.1177/0271678X231172842
Abstract
Vascular factors are known to be early and important players in Alzheimer’s disease (AD) development, however the role of the ε4 allele of the Apolipoprotein (APOE) gene (a risk factor for developing AD) remains unclear. APOE4 genotype is associated with early and severe neocortical vascular deficits in anaesthetised mice, but in humans, vascular and cognitive dysfunction are focused on the hippocampal formation and appear later. How APOE4 might interact with the vasculature to confer AD risk during the preclinical phase represents a gap in existing knowledge. To avoid potential confounds of anaesthesia and to explore regions most relevant for human disease, we studied the visual cortex and hippocampus of awake APOE3 and APOE4-TR mice using 2-photon microscopy of neurons and blood vessels. We found mild vascular deficits: vascular density and functional hyperaemia were unaffected in APOE4 mice, and neuronal or vascular function did not decrease up to late middle-age. Instead, vascular responsiveness was lower, arteriole vasomotion was reduced and neuronal calcium signals during visual stimulation were increased. This suggests that, alone, APOE4 expression is not catastrophic but stably alters neurovascular physiology. We suggest this state makes APOE4 carriers more sensitive to subsequent insults such as injury or beta amyloid accumulation.

Apolipoprotein E in lipid metabolism and neurodegenerative disease

https://www.cell.com/trends/endocrinology-metabolism/fulltext/S1043-2760(23)00092-9?fbclid=IwAR2AGZDZ5WM-St-J_cXQ6EB545nZv3RVocQ3iGXMhXz9hBWJqPjn_1XxUt0
Linda G. Yang , Zachary M. March, Roxan A. Stephenson, Priyanka S. Narayan
Trends in Endocrinology & Metabolism VOLUME 34, ISSUE 8, P430-445, AUGUST 2023
Published: June 23, 2023
DOI: https://doi.org/10.1016/j.tem.2023.05.002
Highlights
• Human APOE alleles modify lipid metabolism and the risk of multiple neurodegenerative diseases.
• APOE4 is associated with triglyceride and cholesterol accumulation in glia, and modulation of their immune reactivity.
• APOE4 is poorly lipidated compared with APOE3, and prevents efficient transport of lipids between glia and neurons. This impacts neuronal homeostasis and survival.
• APOE4 alters brain lipid metabolism in mouse models and human tissue.
• Targeting APOE-associated changes in lipid metabolism could form the basis of genotype-specific preventative strategies for a broad range of neurodegenerative diseases.
Abstract
Dysregulation of lipid metabolism has emerged as a central component of many neurodegenerative diseases. Variants of the lipid transport protein, apolipoprotein E (APOE), modulate risk and resilience in several neurodegenerative diseases including late-onset Alzheimer's disease (LOAD). Allelic variants of the gene, APOE, alter the lipid metabolism of cells and tissues and have been broadly associated with several other cellular and systemic phenotypes. Targeting APOE-associated metabolic pathways may offer opportunities to alter disease-related phenotypes and consequently, attenuate disease risk and impart resilience to multiple neurodegenerative diseases. We review the molecular, cellular, and tissue-level alterations to lipid metabolism that arise from different APOE isoforms. These changes in lipid metabolism could help to elucidate disease mechanisms and tune neurodegenerative disease risk and resilience.

Baseline Findings of PreventE4: A Double-Blind Placebo Controlled Clinical Trial Testing High Dose DHA in APOE4 Carriers before the Onset of Dementia

https://link.springer.com/article/10.14283/jpad.2023.77
Hussein Yassine, I. C. Arellanes, A. Mazmanian, L. De La Cruz, J. Martinez, L. Contreras, N. Kono, B. S. Liu, D. Badie, M. A. Bantugan, A. Grindon, T. Urich, L. D’Orazio, B. A. Emmanuel, H. C. Chui, W. J. Mack, M. G. Harrington, M. N. Braskie & L. S. Schneider
The Journal of Prevention of Alzheimer's Disease, Volume 10, pages 810–820, (2023)
Published: 19 June 2023
DOI: https://doi.org/10.14283/jpad.2023.77
Abstract
Introduction
Lower blood levels of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) are correlated with worse cognitive functions, particularly among APOE ε4 carriers. Whether DHA supplementation in APOE ε4 carriers with limited DHA consumption and dementia risk factors can delay or slow down disease progression when started before the onset of clinical dementia is not known.
Methods
PreventE4 is a double-blind, single site, randomized, placebo-controlled trial in cognitively unimpaired individuals with limited omega-3 consumption and dementia risk factors (n=368). Its objectives are to determine (1) whether carrying the APOE ε4 allele is associated with lower delivery of DHA to the brain; and (2) whether high dose DHA supplementation affects brain imaging biomarkers of AD and cognitive function.
Results
365 cognitively unimpaired individuals between 55 and 80 (mean age 66) were randomized to 2 grams of DHA per day or identically appearing placebo for a period of 2 years. Half the participants were asked to complete lumbar punctures at baseline and 6-month visits to obtain cerebrospinal fluid (CSF). The primary trial outcome measure is the change in CSF DHA to arachidonic acid ratio after 6 months of the intervention (n=181). Secondary trial outcomes include the change in functional and structural connectivity using resting state functional MRI at 24 months (n=365). Exploratory outcomes include the change in Repeatable Battery of the Assessment of Neuropsychological Status at 24 months (n=365).
Conclusions
Findings from PreventE4 will clarify the brain delivery of DHA in individuals carrying the APOE ε4 allele with implications for dementia prevention strategies. Trial was registered as NCT03613844.

Obstructive sleep apnea and cognitive functioning in the older general population: The moderating effect of age, sex, ApoE4, and obesity

https://onlinelibrary.wiley.com/doi/full/10.1111/jsr.13938
Nicola Andrea Marchi, Mathieu Berger, Geoffroy Solelhac, Virginie Bayon, José Haba-Rubio, Julie Legault, Cynthia Thompson, Nadia Gosselin, Peter Vollenweider, Pedro Marques-Vidal, Armin von Gunten, Marie-Pierre Françoise Strippoli, Martin Preisig, Bogdan Draganski, Raphael Heinzer
Journal of Sleep Research Volume33, Issue1 February 2024, e13938
First published: 13 June 2023
SUMMARY
Research on the relationship between obstructive sleep apnea and cognitive functioning has yielded conflicting results, particularly in the older population, and moderators of this association have rarely been studied. Here we investigated the cross-sectional association between obstructive sleep apnea and cognitive functioning as well as the moderating effect of age, sex, apolipoprotein E4, and obesity on this association among community-dwelling older people. We analysed data from 496 participants (71.4 ± 4.4 years; 45.6% men) of the HypnoLaus study who underwent polysomnography and a battery of neuropsychological tests. The sample was categorised as no-to-mild obstructive sleep apnea (apnea–hypopnea index 0–14.9/h; reference), moderate obstructive sleep apnea (apnea–hypopnea index 15.0–29.9/h), or severe obstructive sleep apnea (apnea–hypopnea index ≥30/h). Regression and moderation analyses were performed with adjustment for confounders. Apolipoprotein E4 and obesity moderated the association between severe obstructive sleep apnea and processing speed, whereas no moderating effects were found for age and sex. In apolipoprotein E4 carriers only, severe obstructive sleep apnea was associated with lower performance in Stroop condition 1 (B = 3.13, p = 0.024). In obese participants only, severe obstructive sleep apnea was associated with lower performance in Stroop condition 1 (B = 3.02, p = 0.025) and Stroop condition 2 (B = 3.30, p = 0.034). Severe obstructive sleep apnea was also associated with lower executive function in the whole sample according to Stroop condition 3 (B = 3.44, p = 0.020) and Stroop interference score (B = 0.24, p = 0.006). Our findings support associations of severe obstructive sleep apnea (but not moderate obstructive sleep apnea) with lower performance in processing speed and executive function in the older general population. Apolipoprotein E4 and obesity appear to be vulnerability factors that strengthen the association between severe obstructive sleep apnea and lower performance in processing speed.

Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer’s Disease drug candidate

https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-023-00620-9?fbclid=IwAR0cuG4-NK6YJbTvjq2yc77_z_jrm1no29llT1evpfr8uodXbvbQ_Dacwrk
Michal Nemergut, Sérgio M. Marques, Lukas Uhrik, Tereza Vanova, Marketa Nezvedova, Darshak Chandulal Gadara, Durga Jha, Jan Tulis, Veronika Novakova, Joan Planas-Iglesias, Antonin Kunka, Anthony Legrand, Hana Hribkova, Veronika Pospisilova, Jiri Sedmik, Jan Raska, Zbynek Prokop, Jiri Damborsky, Dasa Bohaciakova, Zdenek Spacil, Lenka Hernychova, David Bednar & Martin Marek
Molecular Neurodegeneration 18, 38 (2023)
Published 06 June 2023
DOI: https://doi.org/10.1186/s13024-023-00620-9
Abstract
Background
Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer’s Disease (AD). Although ApoE4 differs from its non-pathological ApoE3 isoform only by the C112R mutation, the molecular mechanism of its proteinopathy is unknown.
Methods
Here, we reveal the molecular mechanism of ApoE4 aggregation using a combination of experimental and computational techniques, including X-ray crystallography, site-directed mutagenesis, hydrogen-deuterium mass spectrometry (HDX-MS), static light scattering and molecular dynamics simulations. Treatment of ApoE ε3/ε3 and ε4/ε4 cerebral organoids with tramiprosate was used to compare the effect of tramiprosate on ApoE4 aggregation at the cellular level.
Results
We found that C112R substitution in ApoE4 induces long-distance (> 15 Å) conformational changes leading to the formation of a V-shaped dimeric unit that is geometrically different and more aggregation-prone than the ApoE3 structure. AD drug candidate tramiprosate and its metabolite 3-sulfopropanoic acid induce ApoE3-like conformational behavior in ApoE4 and reduce its aggregation propensity. Analysis of ApoE ε4/ε4 cerebral organoids treated with tramiprosate revealed its effect on cholesteryl esters, the storage products of excess cholesterol.
Conclusions
Our results connect the ApoE4 structure with its aggregation propensity, providing a new druggable target for neurodegeneration and ageing.

APOE4 carrier status determines association between white matter disease and grey matter atrophy in early-stage dementia

https://alzres.biomedcentral.com/articles/10.1186/s13195-023-01251-4?fbclid=IwAR1Q-a32gWj_6DtgczKSB5JpGIUu20qUsjGXkTjQX_xf-_JQf0E3qnKtAM4
Ashwati Vipin, Dilip Kumar, See Ann Soo, Fatin Zahra Zailan, Yi Jin Leow, Chen Ling Koh, Adeline Su Lyn Ng, Kok Pin Ng & Nagaendran Kandiah
Alzheimers Research & Therapy 15, 103 (2023)
Published 03 June 2023
DOI: https://doi.org/10.1186/s13195-023-01251-4
Abstract
Background
White matter hyperintensities, a neuroimaging marker of small-vessel cerebrovascular disease and apolipoprotein ε4 (APOE4) allele, are important dementia risk factors. However, APOE4 as a key effect modifier in the relationship between white matter hyperintensities and grey matter volume needs further exploration.
Methods
One hundred ninety-two early-stage dementia (including mild cognitive impairment and mild dementia) and 259 cognitively unimpaired participants from a neurocognitive research cohort with neuroimaging data, APOE genotyping, and neuropsychological assessments were studied. We investigated independent and interactive effects of white matter hyperintensities and APOE4 on whole-brain voxel-wise grey matter volume using voxel-based morphometry (uncorrected p < 0.001; minimum cluster size = 100 voxels). We further assessed interactive effects between APOE4 and white matter hyperintensities on global cognition, memory, and executive function in early-stage dementia and cognitively unimpaired participants.
Results
Independent of APOE4 status, higher white matter hyperintensity load was associated with greater grey matter atrophy across frontal, parietal, temporal, and occipital lobes in cognitively unimpaired and early-stage dementia subjects. However, interaction analyses and independent sample analyses revealed that APOE4 non-carriers demonstrated greater white matter hyperintensity-associated grey matter atrophy compared to APOE4 carriers in both cognitively unimpaired and early-stage dementia groups. Additional confirmatory analyses among APOE4 non-carriers demonstrated that white matter hyperintensities resulted in widespread grey matter loss. Analyses of cognitive function demonstrated that higher white matter hyperintensity load was associated with worse global (Mini-Mental State Examination, Montreal Cognitive Assessment) and executive function (Color Trails 2) in APOE4 non-carriers compared to APOE4 carriers in early-stage dementia but not cognitively unimpaired participants.
Conclusions
The association between white matter hyperintensities and grey matter loss is more pronounced in APOE4 non-carriers than APOE4 carriers in the cognitively unimpaired and early-stage dementia stages. Furthermore, white matter hyperintensity presence results in poorer executive function in APOE4 non-carriers compared to APOE4 carriers. This finding may have significant impact on the design of clinical trials with disease modifying therapies.

Single-nucleus multiregion transcriptomic analysis of brain vasculature in Alzheimer’s disease

https://www.nature.com/articles/s41593-023-01334-3#change-history
Na Sun, Leyla Anne Akay, Mitchell H. Murdock, Yongjin Park, Fabiola Galiana-Melendez, Adele Bubnys, Kyriaki Galani, Hansruedi Mathys, Xueqiao Jiang, Ayesha P. Ng, David A. Bennett, Li-Huei Tsai & Manolis Kellis
Nature Neuroscience 26, 970–982 (2023)
Published 01 June 2023
DOI: https://doi.org/10.1038/s41593-023-01334-3
Abstract
Cerebrovascular dysregulation is a hallmark of Alzheimer’s disease (AD), but the changes that occur in specific cell types have not been fully characterized. Here, we profile single-nucleus transcriptomes in the human cerebrovasculature in six brain regions from 220 individuals with AD and 208 age-matched controls. We annotate 22,514 cerebrovascular cells, including 11 subtypes of endothelial, pericyte, smooth muscle, perivascular fibroblast and ependymal cells. We identify 2,676 differentially expressed genes in AD, including downregulation of PDGFRB in pericytes, and of ABCB1 and ATP10A in endothelial cells, and validate the downregulation of SLC6A1 and upregulation of APOD, INSR and COL4A1 in postmortem AD brain tissues. We detect vasculature, glial and neuronal coexpressed gene modules, suggesting coordinated neurovascular unit dysregulation in AD. Integration with AD genetics reveals 125 AD differentially expressed genes directly linked to AD-associated genetic variants. Lastly, we show that APOE4 genotype-associated differences are significantly enriched among AD-associated genes in capillary and venule endothelial cells, as well as subsets of pericytes and fibroblasts.

Associations of ApoE4 status and DHA supplementation on plasma and CSF lipid profiles and entorhinal cortex thickness

https://www.jlr.org/article/S0022-2275(23)00027-5/fulltext
Mikaila Ann Bantugan, Haotian Xian, Victoria Solomon, Mitchell Lee, Zhiheng Cai, Shaowei Wang, Marlon V. Duro, Bilal E. Kerman, Alfred Fonteh, Cristiana Meuret, Meitong Li, Meredith N. Braskie, Laura Beth J. McIntire, Lucia Jurin, Sarah Oberlin, James Evans, Roderick Davis, Wendy J. Mack, Laila Abdullah, Hussein N. Yassine
Journal of Lipid Research, VOLUME 64, ISSUE 6, 100354, JUNE 2023
June 2023
DOI: https://doi.org/10.1016/j.jlr.2023.100354
Abstract
Apolipoprotein ε allele 4 (APOE4) influences the metabolism of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA). The entorhinal cortex (EC) in the brain is affected early in Alzheimer's disease and is rich in DHA. The purpose of this study is to identify the effect of APOE4 and DHA lipid species on the EC. Plasma and cerebrospinal fluid (CSF) lipidomic measurements were obtained from the DHA Brain Delivery Pilot, a randomized clinical trial of DHA supplementation (n = 10) versus placebo (n = 12) for six months in nondemented older adults stratified by APOE4 status. Wild-type C57B6/J mice were fed a high or low DHA diet for 6 months followed by plasma and brain lipidomic analysis. Levels of phosphatidylcholine DHA (PC 38:6) and cholesterol ester DHA (CE 22:6) had the largest increases in CSF following supplementation (P < 0.001). DHA within triglyceride (TG) lipids in CSF strongly correlated with corresponding plasma TG lipids, and differed by APOE4, with carriers having a lower increase than noncarriers. Changes in plasma PC DHA had the strongest association with changes in EC thickness in millimeters, independent of APOE4 status (P = 0.007). In mice, a high DHA diet increased PUFAs within brain lipids. Our findings demonstrate an exchange of DHA at the CSF-blood barrier and into the brain within all lipid species with APOE having the strongest effect on DHA-containing TGs. The correlation of PC DHA with EC suggests a functional consequence of DHA accretion in high density lipoprotein for the brain.

May 2023

An association of CSF apolipoprotein E glycosylation and amyloid-beta 42 in individuals who carry the APOE4 allele

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10204298/
Cristiana J. Meuret, Yueming Hu, Sabrina Smadi, Mikaila Ann Bantugan, Haotian Xian, Ashley E. Martinez, Ronald M. Krauss, Qiu-Lan Ma, Dobrin Nedelkov, and Hussein N. Yassine
Alzheimers Research & Therapy 2023 May 23;15(1):96
Published online 2023 May 23
DOI: 10.1186/s13195-023-01239-0
Abstract
Carrying the apolipoprotein E (ApoE) Ɛ4 allele is associated with an increased risk of cerebral amyloidosis and late-onset Alzheimer’s disease, but the degree to which apoE glycosylation affects its development is not clear. In a previous pilot study, we identified distinct total and secondary isoform-specific cerebral spinal fluid (CSF) apoE glycosylation profiles, with the E4 isoform having the lowest glycosylation percentage (E2 > E3 > E4). In this work, we extend the analysis to a larger cohort of individuals (n = 106), utilizing matched plasma and CSF samples with clinical measures of AD biomarkers. The results confirm the isoform-specific glycosylation of apoE in CSF, resulting from secondary CSF apoE glycosylation patterns. CSF apoE glycosylation percentages positively correlated with CSF Aβ42 levels (r = 0.53, p < 0.0001). These correlations were not observed for plasma apoE glycosylation. CSF total and secondary apoE glycosylation percentages also correlated with the concentration of CSF small high-density lipoprotein particles (s-HDL-P), which we have previously shown to be correlated with CSF Aβ42 levels and measures of cognitive function. Desialylation of apoE purified from CSF showed reduced Aβ42 degradation in microglia with E4 > E3 and increased binding affinity to heparin. These results indicate that apoE glycosylation has a new and important role in influencing brain Aβ metabolism and can be a potential target of treatment.

Association of APOE-ε4, Osteoarthritis, β-Amyloid, and Tau Accumulation in Primary Motor and Somatosensory Regions in Alzheimer Disease

https://www.neurology.org/doi/abs/10.1212/WNL.0000000000207369?fbclid=IwAR01NX530l3w8cP0YRoFqS9u4x41YWFwCIJxks1qPOdUEZnf-pHqguIhbHk
Jing Du, MSc, Anqi Li, MSc, Dai Shi, MD, Xuhui Chen, MD, Qingyong Wang, MD, Zhen Liu, PhD , Kun Sun, PhD, and Tengfei Guo, PhD Neurology July 4, 2023 issue 101 (1) e40-e49
May 15, 2023
Abstract
Background and Objectives
One of the most prevalent chronic diseases, osteoarthritis (OA), may work in conjunction with APOE-ε4 to accelerate Alzheimer disease (AD) alterations, particularly in the primary motor (precentral) and somatosensory (postcentral) cortices. To understand the reasoning behind this, we investigated how OA and APOE-ε4 influence the accumulation of β-amyloid (Aβ) and tau accumulation in primary motor and somatosensory regions in Aβ-positive (Aβ+) older individuals.
Methods
We selected Aβ+ Alzheimer Disease Neuroimaging Initiative participants, defined by baseline 18F-florbetapir (FBP) Aβ PET standardized uptake value ratio (SUVR) of AD summary cortical regions, who had longitudinal Aβ PET, the records of OA medical history, and APOE-ε4 genotyping. We examined how OA and APOE-ε4 relate to baseline and longitudinal Aβ accumulation and tau deposition measured at follow-up in precentral and postcentral cortical areas and how they modulate Aβ-associated future higher tau levels, adjusting for age, sex, and diagnosis and using multiple comparison corrections.
Results
A total of 374 individuals (mean age 75 years, 49.2% female, 62.8% APOE-ε4 carriers) who underwent longitudinal FBP PET with a median follow-up of 3.3 years (interquartile range [IQR] 3.4, range 1.6–9.4) were analyzed, and 96 people had 18F-flortaucipir (FTP) tau PET measured at a median of 5.4 (IQR 1.9, range 4.0–9.3) years postbaseline FBP PET. Neither OA nor APOE-ε4 was related to baseline FBP SUVR in precentral and postcentral regions. At follow-up, OA rather than APOE-ε4 was associated with faster Aβ accumulation in postcentral region (β = 0.005, 95% CI 0.001–0.008) over time. In addition, OA but not the APOE-ε4 allele was strongly linked to higher follow-up FTP tau levels in precentral (β = 0.098, 95% CI 0.034–0.162) and postcentral (β = 0.105, 95% CI 0.040–0.169) cortices. OA and APOE-ε4 were also interactively associated with higher follow-up FTP tau deposition in precentral (β = 0.128, 95% CI 0.030–0.226) and postcentral (β = 0.124, 95% CI 0.027–0.223) regions.
Discussion
This study suggests that OA was associated with faster Aβ accumulation and higher Aβ-dependent future tau deposition in primary motor and somatosensory regions, providing novel insights into how OA increases the risk of AD.

Upregulated NF-κB pathway proteins may underlie APOE44 associated astrocyte phenotypes in sporadic Alzheimer’s disease

https://www.biorxiv.org/content/10.1101/2023.04.19.537428v2
Adele Pryce Roberts, Karolina Dec, Branduff McAllister, Victoria Tyrrell, Valerie B O’Donnell, Adrian Harwood, Julie Williams
bioRxiv 2023.04.19.537428
Posted May 11, 2023
doi: https://doi.org/10.1101/2023.04.19.537428
Abstract
The Apolipoprotein-E4 allele (APOE) is the strongest genetic risk factor for sporadic Alzheimer’s disease but its role in disease pathogenesis is incompletely understood. The APOE gene encodes Apolipoprotein E (ApoE). Astrocytes are the main source of ApoE in the central nervous system (CNS) and are essential for homeostasis in health and disease. In response to CNS insult, a coordinated multicellular inflammatory response is triggered causing reactive astrogliosis with changes in astrocytic gene expression, cellular structure and function. Human embryonic stem-cells with the ‘neutral’ APOE33 genotype were edited using CRISPR Cas-9 gene-editing to create isogenic APOE lines with an APOE44 genotype. Quiescent astrocytes were differentiated then stimulated with TNF-α, IL1α and C1q inducing an astrogliotic A1 phenotype. Several potentially pathological APOE44-related phenotypes were identified in both quiescent cells and reactive A1 astrocytes including significantly decreased phagocytosis, impaired glutamate and a defective immunomodulatory response. In quiescent APOE44 astrocytes there was significantly decreased secretion of IL6, IL8 and several oxylipins. In A1 astrocytes there was a pro-inflammatory phenotype in APOE44 astrocytes with increases in GRO, ENA78, IL6 and IL8, a decrease in IL10 as well as significant differences in oxylipin expression. As TNF-α induced signaling in astrocytes is driven by Nuclear factor kappa B (NF-κB) proteins of this pathway were measured. Significantly higher levels of the p50, p65 and IκBα sub-units were found in both quiescent and A1 APOE44 astrocytes. This suggests that perturbation of NF-κB signaling may contribute to the damaging APOE44 cell phenotypes observed providing a new direction for targeted disease therapeutics.

Reduced binding of apoE4 to complement factor H promotes amyloid‐β oligomerization and neuroinflammation

https://www.embopress.org/doi/full/10.15252/embr.202256467
Larisa Chernyaeva, Giorgio Ratti, Laura Teirilä, Satoshi Fudo, Uni Rankka, Anssi Pelkonen, Paula Korhonen, Katarzyna Leskinen, Salla Keskitalo, Kari Salokas, Christina Gkolfinopoulou, Katrina E Crompton, Matti Javanainen, Lotta Happonen, Markku Varjosalo, Tarja Malm, Ville Leinonen, Angeliki Chroni, Päivi Saavalainen, Seppo Meri, Tommi Kajander, Adam JM Wollman, Eija Nissilä, and Karita Haapasalo
EMBO rep (2023) 24: e56467
8 May 2023 DOI: https://doi.org/10.15252/embr.202256467
Abstract
The APOE4 variant of apolipoprotein E (apoE) is the most prevalent genetic risk allele associated with late‐onset Alzheimer's disease (AD). ApoE interacts with complement regulator factor H (FH), but the role of this interaction in AD pathogenesis is unknown. Here we elucidate the mechanism by which isoform‐specific binding of apoE to FH alters Aβ1‐42‐mediated neurotoxicity and clearance. Flow cytometry and transcriptomic analysis reveal that apoE and FH reduce binding of Aβ1‐42 to complement receptor 3 (CR3) and subsequent phagocytosis by microglia which alters expression of genes involved in AD. Moreover, FH forms complement‐resistant oligomers with apoE/Aβ1‐42 complexes and the formation of these complexes is isoform specific with apoE2 and apoE3 showing higher affinity to FH than apoE4. These FH/apoE complexes reduce Aβ1‐42 oligomerization and toxicity, and colocalize with complement activator C1q deposited on Aβ plaques in the brain. These findings provide an important mechanistic insight into AD pathogenesis and explain how the strongest genetic risk factor for AD predisposes for neuroinflammation in the early stages of the disease pathology.

Differential association of cerebral blood flow and anisocytosis in APOE ε4 carriers at midlife

https://journals.sagepub.com/doi/full/10.1177/0271678X231173587?fbclid=IwAR3B2kpTaJdlsWY4AI8ni8UJf8h2dxQBmiyTKE326f_CAIN0qbK03TgF-hs
Maria-Eleni Dounavi, Elijah Mak, Peter Swann, Audrey Low, Graciela Muniz-Terrera, Anna McKeever, Marianna Pope, Guy B Williams, Katie Wells, Brian Lawlor, Lorina Naci, Paresh Malhotra, Clare Mackay, Ivan Koychev, Karen Ritchie, Li Su, Craig W Ritchie, John T O’Brien
Journal of Cerebral Blood Flow & Metabolism 2023;43(10):1672-1684
First published online May 3, 2023
doi:10.1177/0271678X231173587
Abstract
Cerebral hemodynamic alterations have been observed in apolipoprotein ε4 (APOE4) carriers at midlife, however the physiological underpinnings of this observation are poorly understood. Our goal was to investigate cerebral blood flow (CBF) and its spatial coefficient of variation (CoV) in relation to APOE4 and a measure of erythrocyte anisocytosis (red blood cell distribution width – RDW) in a middle-aged cohort. Data from 563 participants in the PREVENT-Dementia study scanned with 3 T MRI cross-sectionally were analysed. Voxel-wise and region-of-interest analyses within nine vascular regions were run to detect areas of altered perfusion. Within the vascular regions, interaction terms between APOE4 and RDW in predicting CBF were examined. Areas of hyperperfusion in APOE4 carriers were detected mainly in frontotemporal regions. The APOE4 allele differentially moderated the association between RDW and CBF, an association which was more prominent in the distal vascular territories (p – [0.01, 0.05]). The CoV was not different between the considered groups. We provide novel evidence that in midlife, RDW and CBF are differentially associated in APOE4 carriers and non-carriers. This association is consistent with a differential hemodynamic response to hematological alterations in APOE4 carriers.

Marauders of the Microbiome: Certain Gut Bacteria Found Thriving in People With Alzheimer’s, APOE4

https://www.beingpatient.com/microbiome-gut-bacteria-alzheimers-apoe4/?fbclid=IwAR2vE3JNzXIIvI_HK25RvN9_Tc7YxY0wcEvw1IabIeYEOrrXUyzbnvrgL9U
Simon Spichak, MSc, Being Patient
May 2nd, 2023
The new study published in the journal Scientific Reports analyzed the gut microbes of 2,077 people with Alzheimer’s and 2,081 healthy controls. People with Alzheimer’s had higher levels of certain types of gut bacteria. Some of these bacteria were also found in higher levels in the guts of people who had the Alzheimer’s gene, APOE4. This suggests a relationship between the Alzheimer’s gene and gut bacteria that could be contributing to Alzheimer’s.

April 2023

AAN 2023: ALZ-801 for Alzheimer’s found to improve cognition in trial

https://alzheimersnewstoday.com/news/aan-2023-alz-801-alzheimers-improves-cognition-phase-2-trial/?fbclid=IwAR2bJ18e2aKxsemQpw8JCb03mz8JZmWIg7ZRrif0jdBBM3XxwRA8z7mIdhw
Lindsey Shapiro, PhD , Alzheimer’s News Today, April 28, 2023
April 28, 2023
One year of treatment with ALZ-801 (valiltramiprosate) was found in a Phase 2 trial to improve cognition and lower the levels of disease biomarkers among people with early Alzheimer’s with one or two copies of the apolipoprotein E4 (APOE4) disease-associated genetic variant.Importantly, the investigational therapy from Alzheon did not cause certain side effects, such as brain swelling and bleeds, that have been sometimes linked to anti-amyloid antibody therapies — ones to which APOE4 carriers may be particularly susceptible. The new findings were detailed by John A. Hey, PhD, chief scientific officer of Alzheon, in an oral presentation at the American Academy of Neurology (AAN) Conference, held April 22-27 in Boston and virtually.

Dysregulated Lipid Metabolism Comes to the Fore at AD/PD

https://www.alzforum.org/news/conference-coverage/dysregulated-lipid-metabolism-comes-fore-adpd?fbclid=IwAR2jqKUPhu75aEbRTvaEIRmVlkCa08ixo_VqEq-3zFmx97zjWtQ0xT2k8tY
ALZForum 27 Apr 2023 coverage of International Conference on Alzheimer's and Parkinson's Diseases 2023
• Changes in phosphatidylcholine metabolism track with cognitive decline in AD.
• People with PD had more metabolites of this lipid in their blood.
• Lipids in the brain hit the skids prior to amyloid plaques.
• APOE4 oligodendrocytes and astrocytes contain excess cholesterol, other lipids.

APOE Genotyping Will Play a Major Role in Lecanemab Prescribing The Clinical, Ethical, and Financial Ramifications

https://journals.lww.com/neurotodayonline/Fulltext/2023/04200/APOE_Genotyping_Will_Play_a_Major_Role_in.1.aspx?fbclid=IwAR0bLz5W9EzRAwqK1t74CJ38MvAuaxnQsPDa5hQnbSDgOjXiQFVw6-M5DTA
By Gina Shaw, Neurology Today, April 20, 2023
April 20, 2023 Experts advise that patients who meet criteria for lecanemab should undergo genotyping for APO4E to assess their potential risk for adverse events. The importance of genotyping apolipoprotein E4 (APOE4) in clinical decision-making for physicians considering prescribing the newly approved Alzheimer's disease treatment lecanemab (Leqembi, Eisai) has been largely overlooked in the debate about the drug's benefits, experts argue in an editorial published March 13 in JAMA Neurology. …They noted that in the CLARITY AD trial that led to lecanemab's approval, patients who were homozygous for APOE4 were more than six times more likely than noncarriers to experience symptomatic amyloid-related imaging abnormalities (ARIA) with edema or effusions and more than three times more likely to experience ARIA with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis.

Interaction between KLOTHO-VS Heterozygosity and APOE ε4 Allele Predicts Rate of Cognitive Decline in Late-Onset Alzheimer’s Disease

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137709/
Xi Richard Chen, Yongzhao Shao, Martin J. Sadowski
Genes (Basel). 2023 Apr; 14(4): 917
Published online 2023 Apr 15
doi: 10.3390/genes14040917
Abstract
KLOTHO-VS heterozygosity (KL-VShet+) promotes longevity and protects against cognitive decline in aging. To determine whether KL-VShet+ mitigates Alzheimer’s disease (AD) progression, we used longitudinal linear-mixed models to compare the rate of change in multiple cognitive measures in AD patients stratified by APOE ε4 carrier status. We aggregated data on 665 participants (208 KL-VShet−/ε4−, 307 KL-VShet−/ε4+, 66 KL-VShet+/ε4−, and 84 KL-VShet+/ε4+) from two prospective cohorts, the National Alzheimer’s Coordinating Center and the Alzheimer’s Disease Neuroimaging Initiative. All participants were initially diagnosed with mild cognitive impairment, later developed AD dementia during the study, and had at least three subsequent visits. KL-VShet+ conferred slower cognitive decline in ε4 non-carriers (+0.287 MMSE points/year, p = 0.001; −0.104 CDR-SB points/year, p = 0.026; −0.042 ADCOMS points/year, p < 0.001) but not in ε4 carriers who generally had faster rates of decline than non-carriers. Stratified analyses showed that the protective effect of KL-VShet+ was particularly prominent in male participants, those who were older than the median baseline age of 76 years, or those who had an education level of at least 16 years. For the first time, our study provides evidence that KL-VShet+ status has a protective effect on AD progression and interacts with the ε4 allele.

How Microglia Contribute To Alzheimer’s Disease

https://currentsciencedaily.com/stories/641658646-how-microglia-contribute-to-alzheimer-s-disease?fbclid=IwAR0xaLM5HLWFsFjgeX_Mk8w-CgMw1gANo0oXfTb4haVGdYiiM8UZa7ynSjI
ANNE TRAFTON, MIT NEWS OFFICE, APR 15, 2023
APR 15, 2023
A new study from MIT shows how a type of cells called microglia contribute to this slowdown of neuron activity. The study found that microglia that express the APOE4 gene, one of the strongest genetic risk factors for Alzheimer’s disease, cannot metabolize lipids normally. This leads to a buildup of excess lipids that interferes with nearby neurons’ ability to communicate with each other.

Clinical trial participant’s autopsy and brain exam stoke Alzheimer’s drug fears

https://www.science.org/content/article/clinical-trial-participants-autopsy-brain-exam-stoke-alzheimers-drug-fears?fbclid=IwAR3-pKnTcEo4B461RgXQHzBxHERBKpunU4DWlwn8HQ_gvaYcX_Msn5VvoQs
Science, Apr 13, 2023
A full autopsy and detailed examination of the brain of a 79-year-old Florida woman who died after receiving lecanemab, an experimental Alzheimer’s therapy, in a pivotal clinical trial has deepened some researchers’ concerns that it poses serious risks for patients who share the woman’s hard-to-diagnose, preexisting condition. The woman was ApoEε4/4, and ApoE4s are more highly predisposed to CAA (Cerebral Amyloid Angiopathy). From this article, “The group wrote that Alzheimer’s patients with probable CAA and related brain inflammation, as indicated by brain imaging, should not receive lecanemab.” “The patient’s history and autopsy “strongly suggests that lecanemab infusions were a catalyst leading to the events resulting in her death,” says Vanderbilt University pathologist Hannah Harmsen, co-author of a recently completed case report, which Science has obtained. The authors say the woman’s fatal brain swelling and hemorrhaging likely resulted when the drug, a monoclonal antibody, attacked the abnormal protein deposits that had built up in her blood vessels.”

Macrophages Blamed for Vascular Trouble in ApoE4 Carriers

https://www.alzforum.org/news/conference-coverage/macrophages-blamed-vascular-trouble-apoe4-carriers?fbclid=IwAR1ZH3CDyn0pkUjyD2gn39tyeipLynwnKKqC5XrxLHuzmOig9azSd2LA8_k
AlzForum, 13 Apr 2023, reporting on International Conference on Alzheimer's and Parkinson's Diseases 2023
13 Apr 2023
• ApoE4 carriers face higher odds of cerebrovascular disease.
• In mice, ApoE4, but not E3, restricts cerebral blood flow.
• Perivascular macrophages release ApoE4, and respond to it.
• They spew damaging reactive oxygen species.

A haptoglobin (HP) structural variant alters the effect of APOE alleles on Alzheimer's disease

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13050
Haimeng Bai, Adam C. Naj, Penelope Benchek, Logan Dumitrescu, Timothy Hohman, Kara Hamilton-Nelson, Asha R. Kallianpur, Anthony J. Griswold, Badri Vardarajan, Eden R. Martin, Gary W. Beecham, Jennifer E. Below, Gerard Schellenberg, Richard Mayeux, Lindsay Farrer, Margaret A. Pericak-Vance, Jonathan L. Haines, William S. Bush Alzheimer's & Dementia Volume19, Issue11 November 2023 Pages 4886-4895
First published: 12 April 2023
Abstract
Background
Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid beta (Aβ) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2.
Methods
HP genotypes were imputed in 29 cohorts from the Alzheimer's Disease Genetics Consortium (N = 20,512). Associations between the HP polymorphism and Alzheimer's disease (AD) risk and age of onset through APOE interactions were investigated using regression models.
Results
The HP polymorphism significantly impacts AD risk in European-descent individuals (and in meta-analysis with African-descent individuals) by modifying both the protective effect of APOE ε2 and the detrimental effect of APOE ε4. The effect is particularly significant among APOE ε4 carriers.
Discussion
The effect modification of APOE by HP suggests adjustment and/or stratification by HP genotype is warranted when APOE risk is considered. Our findings also provided directions for further investigations on potential mechanisms behind this association.

Ancestry-related differences in chromatin accessibility and gene expression of APOE ε4 are associated with Alzheimer's disease risk

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13075
Katrina Celis, Maria D. M. Muniz Moreno, Farid Rajabli, Patrice Whitehead, Kara Hamilton-Nelson, Derek M. Dykxhoorn, Karen Nuytemans, Liyong Wang, Margaret Flanagan, Sandra Weintraub, Changiz Geula, Marla Gearing, Clifton L. Dalgard, Fulai Jin, David A. Bennett, Theresa Schuck, Margaret A. Pericak-Vance, Anthony J. Griswold, Juan I. Young, Jeffery M. Vance
Alzheimer’s & Dementia, Volume19, Issue9, September 2023, Pages 3902-3915
First published: 10 April 2023
DOI: https://doi.org/10.1002/alz.13075
Abstract
Introduction
European local ancestry (ELA) surrounding apolipoprotein E (APOE) ε4 confers higher risk for Alzheimer's disease (AD) compared to African local ancestry (ALA). We demonstrated significantly higher APOE ε4 expression in ELA versus ALA in AD brains from APOE ε4/ε4 carriers. Chromatin accessibility differences could contribute to these expression changes. Methods We performed single nuclei assays for transposase accessible chromatin sequencing from the frontal cortex of six ALA and six ELA AD brains, homozygous for local ancestry and APOE ε4. Results Our results showed an increased chromatin accessibility at the APOE ε4 promoter area in ELA versus ALA astrocytes. This increased accessibility in ELA astrocytes extended genome wide. Genes with increased accessibility in ELA in astrocytes were enriched for synapsis, cholesterol processing, and astrocyte reactivity. Discussion Our results suggest that increased chromatin accessibility of APOE ε4 in ELA astrocytes contributes to the observed elevated APOE ε4 expression, corresponding to the increased AD risk in ELA versus ALA APOE ε4/ε4 carriers.

Differential and substrate-specific inhibition of γ-secretase by the C-terminal region of ApoE2, ApoE3, and ApoE4

https://www.cell.com/neuron/abstract/S0896-6273(23)00220-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627323002209%3Fshowall%3Dtrue
Xianglong Hou, Xuexin Zhang, Huan Zou, Mingfeng Guan, Chaoying Fu, Wenyuan Wang, Zai-Rong Zhang, Yang Geng, Yelin Chen
Neuron VOLUME 111, ISSUE 12, P1898-1913.E5, JUNE 21, 2023
Published: April 10, 2023
Highlights
•ApoE isoforms differentially inhibit γ-cleavage of APP in cell-autonomous manners
•C-terminal region of ApoE inhibits γ-secretase with substrate specificity
•Neuronal expression of ApoE C-terminal region alleviates plaque burden in 5×FAD mice
•The C-terminal region orientates the migration of ApoE from neuron to amyloid plaque
Summary
Aberrant low γ-secretase activity is associated with most of the presenilin mutations that underlie familial Alzheimer’s disease (fAD). However, the role of γ-secretase in the more prevalent sporadic AD (sAD) remains unaddressed. Here, we report that human apolipoprotein E (ApoE), the most important genetic risk factor of sAD, interacts with γ-secretase and inhibits it with substrate specificity in cell-autonomous manners through its conserved C-terminal region (CT). This ApoE CT-mediated inhibitory activity is differentially compromised in different ApoE isoforms, resulting in an ApoE2 > ApoE3 > ApoE4 potency rank order inversely correlating to their associated AD risk. Interestingly, in an AD mouse model, neuronal ApoE CT migrates to amyloid plaques in the subiculum from other regions and alleviates the plaque burden. Together, our data reveal a hidden role of ApoE as a γ-secretase inhibitor with substrate specificity and suggest that this precision γ-inhibition by ApoE may protect against the risk of sAD.

Auburn University pharmacy team developing new Alzheimer’s therapy

https://www.wbrc.com/2023/04/02/auburn-university-pharmacy-team-developing-new-alzheimers-therapy/?fbclid=IwAR0zVXVzLIJAAVd0IAghcNJx2ULUIfbbX_J4wX5FtII56lAI_i2IgY_c5lc
By WSFA 12 News Staff
Published: Apr. 2, 2023
The Harrison College of Pharmacy’s Raj Amin has received $1.1 million in support from the National Institutes of Health to develop a compound that could help certain individuals who may be more susceptible to Alzheimer’s disease at an earlier age. The project, titled “Evaluation of a specific LXR/PPAR agonist for treatment of Alzheimer’s disease,” is funded by the National Institute of Neurological Disorders and Stroke Innovation Grants to Nurture Initial Translational Efforts program, or IGNITE. The Amin lab is developing a compound called AU403IS, which may help individuals with the APOe4 allele. Activating LXR beta may help in regulating APOe4 in the brain. The research this grant supports helps to understand further how AU403IS can potentially be therapeutic for patients with the APOe4 allele and Alzheimer’s disease.

Understanding Alzheimer’s disease in the context of aging: Findings from applications of stochastic process models to the Health and Retirement Study

https://www.sciencedirect.com/science/article/pii/S0047637423000179?via%3Dihub
Konstantin G. Arbeev, Olivia Bagley, Arseniy P. Yashkin, Hongzhe Duan, Igor Akushevich, Svetlana V. Ukraintseva, Anatoliy I. Yashin
Mechanisms of Ageing and Development, Volume 211, 2023, 111791
April 2023
DOI: https://doi.org/10.1016/j.mad.2023.111791
Abstract: There is growing literature on applications of biodemographic models, including stochastic process models (SPM), to studying regularities of age dynamics of biological variables in relation to aging and disease development. Alzheimer’s disease (AD) is especially good candidate for SPM applications because age is a major risk factor for this heterogeneous complex trait. However, such applications are largely lacking. This paper starts filling this gap and applies SPM to data on onset of AD and longitudinal trajectories of body mass index (BMI) constructed from the Health and Retirement Study surveys and Medicare-linked data. We found that APOE e4 carriers are less robust to deviations of trajectories of BMI from the optimal levels compared to non-carriers. We also observed age-related decline in adaptive response (resilience) related to deviations of BMI from optimal levels as well as APOE- and age-dependence in other components related to variability of BMI around the mean allostatic values and accumulation of allostatic load. SPM applications thus allow revealing novel connections between age, genetic factors and longitudinal trajectories of risk factors in the context of AD and aging creating new opportunities for understanding AD development, forecasting trends in AD incidence and prevalence in populations, and studying disparities in those.

March 2023

Genetic correlations between Alzheimer’s disease and gut microbiome genera

https://www.nature.com/articles/s41598-023-31730-5
Davis Cammann, Yimei Lu, Melika J. Cummings, Mark L. Zhang, Joan Manuel Cue, Jenifer Do, Jeffrey Ebersole, Xiangning Chen, Edwin C. Oh, Jeffrey L. Cummings & Jingchun Chen
Scientific Reports 13, 5258 (2023)
31 March 2023
DOI: https://doi.org/10.1038/s41598-023-31730-5
A growing body of evidence suggests that dysbiosis of the human gut microbiota is associated with neurodegenerative diseases like Alzheimer’s disease (AD) via neuroinflammatory processes across the microbiota-gut-brain axis. The gut microbiota affects brain health through the secretion of toxins and short-chain fatty acids, which modulates gut permeability and numerous immune functions. Observational studies indicate that AD patients have reduced microbiome diversity, which could contribute to the pathogenesis of the disease. Uncovering the genetic basis of microbial abundance and its effect on AD could suggest lifestyle changes that may reduce an individual’s risk for the disease. Using the largest genome-wide association study of gut microbiota genera from the MiBioGen consortium, we used polygenic risk score (PRS) analyses with the “best-fit” model implemented in PRSice-2 and determined the genetic correlation between 119 genera and AD in a discovery sample (ADc12 case/control: 1278/1293). To confirm the results from the discovery sample, we next repeated the PRS analysis in a replication sample (GenADA case/control: 799/778) and then performed a meta-analysis with the PRS results from both samples. Finally, we conducted a linear regression analysis to assess the correlation between the PRSs for the significant genera and the APOE genotypes. In the discovery sample, 20 gut microbiota genera were initially identified as genetically associated with AD case/control status. Of these 20, three genera (Eubacterium fissicatena as a protective factor, Collinsella, and Veillonella as a risk factor) were independently significant in the replication sample. Meta-analysis with discovery and replication samples confirmed that ten genera had a significant correlation with AD, four of which were significantly associated with the APOE rs429358 risk allele in a direction consistent with their protective/risk designation in AD association. Notably, the proinflammatory genus Collinsella, identified as a risk factor for AD, was positively correlated with the APOE rs429358 risk allele in both samples. Overall, the host genetic factors influencing the abundance of ten genera are significantly associated with AD, suggesting that these genera may serve as biomarkers and targets for AD treatment and intervention. Our results highlight that proinflammatory gut microbiota might promote AD development through interaction with APOE. Larger datasets and functional studies are required to understand their causal relationships.

In the whitewashed world of Alzheimer’s research, one scientist is on a quest to understand the diversity of brains

https://www.statnews.com/2023/03/30/alzheimers-research-lisa-barnes-brains/?fbclid=IwAR2PJ2tvUZ_QOhGKQYtbcykqbtbN_Z2YV7N2tde53rzFru6YPIS44GIpdgA
Usha Lee McFarling, STAT March 30, 2023 When she entered the field of Alzheimer’s research a quarter century ago, Lisa Barnes was deeply disappointed to find few Black people like her family members with dementia were being studied. Since 2004, Barnes has been running the Minority Aging Research Study, one of the nation’s largest studies of Alzheimer’s focused exclusively on Black people and has created a brain bank used by other researchers to understand the illness in this population.
Among the most cited of the nearly 300 research papers she’s written or co-authored is a genomics study showing that the APOE4 gene variant that’s tightly linked to Alzheimer’s in white populations does not have the same effect in Black populations.

Neurodegeneration—It’s Not the Tangles, It’s the T Cells

https://www.alzforum.org/news/research-news/neurodegeneration-its-not-tangles-its-t-cells?fbclid=IwAR31sq_4Cc9XbDdXxi96ZMfkYjTIgqXBgUGFA4nT3jRnfVTKMdG9Y6flThc
ALZForum 17 Mar 2023
• In an ApoE4/tau transgenic mouse model, T cells enter the brain.
• Some have clonally expanded in response to antigen.
• Removing these T cells averts neurodegeneration, brain atrophy.
• Does this mean Alzheimer’s is an autoimmune disease?

Effect of APOE4 Allele and Gender on the Rate of Atrophy in the Hippocampus, Entorhinal Cortex, and Fusiform Gyrus in Alzheimer's Disease

https://www.eurekaselect.com/article/130079
Eid Abo Hamza, Ahmed A. Moustafa, Richard Tindle, Rasu Karki, Shahed Nalla, Mohamed S. Hamid and Mohamad EL HAJ
Current Alzheimer Research, volume 19, issue 14, pages 943-953, year 2022
Published on: 15 March, 2023
DOI: 10.2174/1567205020666230309113749
Abstract
Background:
The hippocampus, entorhinal cortex, and fusiform gyrus are brain areas that deteriorate during early-stage Alzheimer’s disease (AD). The ApoE4 allele has been identified as a risk factor for AD development, is linked to an increase in the aggregation of amyloid β (Aβ) plaques in the brain, and is responsible for atrophy of the hippocampal area. However, to our knowledge, the rate of deterioration over time in individuals with AD, with or without the ApoE4 allele, has not been investigated.
Methods:
In this study, we, for the first time, analyze atrophy in these brain structures in AD patients with and without the ApoE4 using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset.
Results:
It was found that the rate of decrease in the volume of these brain areas over 12 months was related to the presence of ApoE4. Further, we found that neural atrophy was not different for female and male patients, unlike prior studies, suggesting that the presence of ApoE4 is not linked to the gender difference in AD.
Conclusion:
Our results confirm and extend previous findings, showing that the ApoE4 allele gradually impacts brain regions impacted by AD.

SOX9 Expression Is Increased in Alzheimer’s Disease (AD) and Is Associated With Disease Progression and APOE4 Genotype: A Computational Approach

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10100190/
Aliaa A. Alamoudi, March 14, 2023
Published online 2023 Mar 14
DOI: 10.7759/cureus.36129
Abstract
Introduction:
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by depositions of amyloid-β protein leading to neuronal loss. Despite our understanding of the disease several gaps remain, including the role of astrocytes and astrocytic genes in the disease development and progression. Recently, some reports have suggested that SOX9 transcription factor (TF), an important mediator of astrocyte differentiation and maturation, might be linked to AD. Using human AD publicly available dataset, we aimed to analyze SOX9 expression and its relation to disease.
Methodology:
The AD gene expression data set was obtained from National Center for Bioinformatics-Gene Expression Omnibus (NCBI-GEO). The GSE48350 consisted of mRNA microarray data from 55 normal controls (173 samples) and 26 AD cases (81 samples) obtained, from four brain regions. The SOX9 expression profile and correlations were analyzed using the R2 Genomics Analysis and Visualization platform.
Results:
The SOX9 was significantly upregulated (p<0.001) in AD tissue compared to control cases. The increased expression appeared to be more in the entorhinal cortex (EC) and hippocampus (HC) regions. The SOX9 expression positively correlated with BRAAK stages (p<0.05). Interestingly in AD patients the SOX9 expression was significantly less in APOE3/3 genotypes compared with genotypes containing APOE4 allele. The SOX9 expression negatively correlated with oxidative phosphorylation genes which could suggest a metabolic role for the TF. Conclusion:
From these data we hypothesize that SOX9 acts as a metabolic regulator responding to lipid metabolism disruption associated with APOE4 genotypes. In turn, SOX9 expression could be associated with astrocyte maturation and survival in the disease contributing thus to disease burden and disease progression.

Reimagining Alzheimer’s (Part 8): APOE4 Removal Reduces Symptoms Of Alzheimer’s Disease

https://www.forbes.com/sites/williamhaseltine/2023/03/11/reimagining-alzheimers-part-8-apoe4-removal-reduces-symptoms-of-alzheimers-disease/?sh=4059f482797e&fbclid=IwAR0kQiBcEZIOvHgQS8HKNpQseOVCdI7ozjQBajv4_z5oLoYvm2cNac0xSw8
William A Haseltine, Forbes, Mar 13, 2023
Now, Koutsodendris et al. have determined how APOE4 contributes to tau tangles, neuroinflammation, and gliosis among several other features of Alzheimer’s disease. To do so, the researchers used gene-edited mice. In mouse models, researchers can emulate the features of human disease by replacing genes found in mice with equivalent genes found in humans. To determine how the E4 variant of the APOE gene impacts Alzheimer’s disease, Koutsodendris et al. were tasked with creating a line of mice that contained the human APOE gene.
(To read Koutsodendris paper referred to by this article, see Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits published 20 February 2023)

APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10117631/
Sangderk Lee, Nicholas A. Devanney, Lesley R. Golden, Cathryn T. Smith, James L. Schwartz, Adeline E. Walsh, Harrison A. Clarke, Danielle S. Goulding, Elizabeth J. Allenger, Gabriella Morillo-Segovia, Cassi M. Friday,1Amy A. Gorman, Tara R. Hawkinson,Steven M. MacLean, Holden C. Williams, Ramon C. Sun, Josh M. Morganti, and Lance A. Johnson
Cell Reports 2023 Mar 28; 42(3): 112196.
Published online 2023 Mar 3
doi: 10.1016/j.celrep.2023.112196
SUMMARY
The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened proinflammatory response: two findings that may be intrinsically linked through the concept of immunometabolism. Here, we combined bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses in mice expressing human APOE to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNA sequencing (RNA-seq) highlighted immunometabolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct microglia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1α expression and a disrupted tricarboxylic acid (TCA) cycle and are inherently pro-glycolytic, while spatial transcriptomics and mass spectrometry imaging highlight an E4-specific response to amyloid that is characterized by widespread alterations in lipid metabolism. Taken together, our findings emphasize a central role for APOE in regulating microglial immunometabolism and provide valuable, interactive resources for discovery and validation research.

==== Apolipoprotein E ε4 modulates astrocyte neuronal support functions in the presence of amyloid-β
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903110/
==== Rebecca M. Fleeman, Madison K. Kuhn, Dennis C. Chan, and Elizabeth A. Proctor
Journal of Neurochemistry 2023 May; 165(4): 536–549
Published online 2023 Mar 1
doi: 10.1111/jnc.15781
Abstract
Apolipoprotein E (APOE) is a lipid transporter produced predominantly by astrocytes in the brain. The ε4 variant of APOE (APOE4) is the strongest and most common genetic risk factor for Alzheimer's disease (AD). Although the molecular mechanisms of this increased risk are unclear, APOE4 is known to alter immune signaling and lipid and glucose metabolism. Astrocytes provide various forms of support to neurons, including regulating neuronal metabolism and immune responses through cytokine signaling. Changes in astrocyte function because of APOE4 may therefore decrease neuronal support, leaving neurons more vulnerable to stress and disease insults. To determine whether APOE4 alters astrocyte neuronal support functions, we measured glycolytic and oxidative metabolism of neurons treated with conditioned media from APOE4 or APOE3 (the common, risk-neutral variant) primary astrocyte cultures. We found that APOE4 neurons treated with conditioned media from resting APOE4 astrocytes had similar metabolism to APOE3 neurons treated with media from resting APOE3 astrocytes, but treatment with astrocytic conditioned media from astrocytes challenged with amyloid-β (Aβ), a key pathological protein in AD, caused APOE4 neurons to increase their basal mitochondrial and glycolytic metabolic rates more than APOE3 neurons. These changes were not because of differences in astrocytic lactate production or glucose utilization, but instead correlated with increased glycolytic ATP production and a lack of cytokine secretion in response to Aβ. Additionally, we identified that astrocytic cytokine signatures could predict basal metabolism of neurons treated with the astrocytic conditioned media. Together, these findings suggest that in the presence of Aβ, APOE4 astrocytes alter immune and metabolic functions that result in a compensatory increase in neuronal metabolic stress.

Vitamin D supplementation and incident dementia: Effects of sex, APOE, and baseline cognitive status

https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/dad2.12404
Maryam Ghahremani, Eric E. Smith, Hung-Yu Chen, Byron Creese, Zahra Goodarzi, Zahinoor Ismail Alzheimer's Dement 2023; 15:e12404
First published: 01 March 2023
DOI: https://doi.org/10.1002/dad2.12404
Abstract
Introduction
Despite the association of vitamin D deficiency with incident dementia, the role of supplementation is unclear. We prospectively explored associations between vitamin D supplementation and incident dementia in 12,388 dementia-free persons from the National Alzheimer's Coordinating Center.
Methods
Baseline exposure to vitamin D was considered D+; no exposure prior to dementia onset was considered D−. Kaplan–Meier curves compared dementia-free survival between groups. Cox models assessed dementia incidence rates across groups, adjusted for age, sex, education, race, cognitive diagnosis, depression, and apolipoprotein E (APOE) ε4. Sensitivity analyses examined incidence rates for each vitamin D formulation. Potential interactions between exposure and model covariates were explored.
Results
Across all formulations, vitamin D exposure was associated with significantly longer dementia-free survival and lower dementia incidence rate than no exposure (hazard ratio = 0.60, 95% confidence interval: 0.55–0.65). The effect of vitamin D on incidence rate differed significantly across the strata of sex, cognitive status, and APOE ε4 status.
Discussion
Vitamin D may be a potential agent for dementia prevention.
Highlights
• In a prospective cohort study, we assessed effects of Vitamin D on dementia incidence in 12,388 participants from the National Alzheimer's Coordinating Center dataset.
• Vitamin D exposure was associated with 40% lower dementia incidence versus no exposure.
• Vitamin D effects were significantly greater in females versus males and in normal cognition versus mild cognitive impairment.
• Vitamin D effects were significantly greater in apolipoprotein E ε4 non-carriers versus carriers.
• Vitamin D has potential for dementia prevention, especially in the high-risk strata.

==== Apolipoprotein E ε4 modulates astrocyte neuronal support functions in the presence of amyloid-β
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903110/
==== Rebecca M. Fleeman, Madison K. Kuhn, Dennis C. Chan, and Elizabeth A. Proctor Journal of Neurochemistry 2023 May;165(4):536-549
Published online 2023 Mar 1
doi: 10.1111/jnc.15781
Abstract
Apolipoprotein E (APOE) is a lipid transporter produced predominantly by astrocytes in the brain. The ε4 variant of APOE (APOE4) is the strongest and most common genetic risk factor for Alzheimer's disease (AD). Although the molecular mechanisms of this increased risk are unclear, APOE4 is known to alter immune signaling and lipid and glucose metabolism. Astrocytes provide various forms of support to neurons, including regulating neuronal metabolism and immune responses through cytokine signaling. Changes in astrocyte function because of APOE4 may therefore decrease neuronal support, leaving neurons more vulnerable to stress and disease insults. To determine whether APOE4 alters astrocyte neuronal support functions, we measured glycolytic and oxidative metabolism of neurons treated with conditioned media from APOE4 or APOE3 (the common, risk-neutral variant) primary astrocyte cultures. We found that APOE4 neurons treated with conditioned media from resting APOE4 astrocytes had similar metabolism to APOE3 neurons treated with media from resting APOE3 astrocytes, but treatment with astrocytic conditioned media from astrocytes challenged with amyloid-β (Aβ), a key pathological protein in AD, caused APOE4 neurons to increase their basal mitochondrial and glycolytic metabolic rates more than APOE3 neurons. These changes were not because of differences in astrocytic lactate production or glucose utilization, but instead correlated with increased glycolytic ATP production and a lack of cytokine secretion in response to Aβ. Additionally, we identified that astrocytic cytokine signatures could predict basal metabolism of neurons treated with the astrocytic conditioned media. Together, these findings suggest that in the presence of Aβ, APOE4 astrocytes alter immune and metabolic functions that result in a compensatory increase in neuronal metabolic stress.

Could Alzheimer’s disease be a maladaptation of an evolutionary survival pathway mediated by intracerebral fructose and uric acid metabolism?

https://www.sciencedirect.com/science/article/pii/S0002916523000047?via%3Dihub
Richard J. Johnson, Dean R. Tolan, Dale Bredesen, Maria Nagel, Laura G. Sánchez-Lozada, Mehdi Fini, Scott Burtis, Miguel A. Lanaspa, David Perlmutter
The American Journal of Clinical Nutrition, Volume 117, Issue 3, 2023, Pages 455-466
March 2023
DOI: https://doi.org/10.1016/j.ajcnut.2023.01.002
Abstract:
An important aspect of survival is to assure enough food, water, and oxygen. Here, we describe a recently discovered response that favors survival in times of scarcity, and it is initiated by either ingestion or production of fructose. Unlike glucose, which is a source for immediate energy needs, fructose metabolism results in an orchestrated response to encourage food and water intake, reduce resting metabolism, stimulate fat and glycogen accumulation, and induce insulin resistance as a means to reduce metabolism and preserve glucose supply for the brain. How this survival mechanism affects brain metabolism, which in a resting human amounts to 20% of the overall energy demand, is only beginning to be understood. Here, we review and extend a previous hypothesis that this survival mechanism has a major role in the development of Alzheimer’s disease and may account for many of the early features, including cerebral glucose hypometabolism, mitochondrial dysfunction, and neuroinflammation. We propose that the pathway can be engaged in multiple ways, including diets high in sugar, high glycemic carbohydrates, and salt. In summary, we propose that Alzheimer’s disease may be the consequence of a maladaptation to an evolutionary-based survival pathway and what had served to enhance survival acutely becomes injurious when engaged for extensive periods. Although more studies are needed on the role of fructose metabolism and its metabolite, uric acid, in Alzheimer’s disease, we suggest that both dietary and pharmacologic trials to reduce fructose exposure or block fructose metabolism should be performed to determine whether there is potential benefit in the prevention, management, or treatment of this disease.
From the text
Apolipoprotein E4 polymorphism Apolipoprotein E4 (ApoE4) polymorphism is a major risk factor for AD, raising the question of how it relates to the fructose hypothesis. Notably, ApoE4 carriers show reduced cerebral glucose metabolism by positron emission testing and reduced uptake of glucose into astrocytes [143]. ApoE4-derived astrocytes also show enhanced glycolysis despite less mitochondrial OXPHOS and worse mitochondrial dysfunction compared with that with ApoE2 or ApoE3 astrocytes [143]. The relative similarities in the effects of fructose on the brain to that observed with the ApoE4 polymorphism suggest parallel pathogenic mechanisms.

February 2023

Axel Montagne, PhD, on Solving Alzheimer’s and Dementia with Blood-Brain Barrier Repair

https://www.youtube.com/watch?v=lChdNK0I8bw
Found my Fitness YouTube Channel (Dr Rhonda Patrick)
Premiered Feb 28, 2023
Dr. Axel Montagne is a chancellor's fellow and group leader at the UK Dementia Research Institute at the University of Edinburgh Centre for Clinical Brain Sciences. His group aims to understand how, when, and where critical components of the blood-brain barrier become dysfunctional preceding dementia and in the earliest stages of age-related cognitive decline. With this knowledge, they hope to develop precise treatments targeting brain vasculature to protect brain function. More importantly his work, and that of his colleagues, provide a critical lens through which to view the contributions of vascular dysfunction (or, conversely, vascular health – if we choose to preserve it) as a critical common thread in dementia and neurodegeneration.
CHAPTERS:
00:03:23 - What dementias have in common
00:04:22 - The importance of preserving small blood vessels (in the brain)
00:05:17 - Changes in the blood-brain barrier in aging that cause "leaking"
00:06:50 - Predicting cognitive decline early with biomarkers – an opportunity for intervention?
00:08:11 - Why targeting amyloid isn’t enough
00:10:34 - The impact of the APOE4 genotype on brain vasculature
00:15:58 - The cause of white matter damage in the brain
00:25:26 - Why the loss of omega-3 transport affects pericytes
00:27:04 - The role of exercise in prevention of blood-brain barrier dysfunction
00:27:25 - Why high heart rates during exercise preserve brain function
00:28:28 - The role of exercise in preserving vision health
00:31:56 - Why leaky vessels damage myelin and the brain
00:37:10 - Can you have more than one type of dementia?
00:39:34 - Does the breakdown of the blood-brain barrier cause “type 3 diabetes"?
00:45:43 - Why omega-3 may prevent detachment of pericytes
01:06:14 - Why a hepatitis drug restored cognition in APOE4 mice
01:11:19 - Why blood-brain barrier disruption results in the accumulation of amyloid-beta
01:16:54 - Why lifetime hypertension increases dementia risk
01:28:53 - Effects of obesity on blood-brain barrier leakage

Emerging Roles of Endothelial Nitric Oxide in Preservation of Cognitive Health

https://www.ahajournals.org/doi/full/10.1161/STROKEAHA.122.041444
Zvonimir S. Katusic, Livius V. d’Uscio and Tongrong He
Stroke 2023;54:686–696
Originally published 27 Feb 2023
https://doi.org/10.1161/STROKEAHA.122.041444
Abstract
eNOS (endothelial nitric oxide synthase) is critically important enzyme responsible for regulation of cardiovascular homeostasis. Under physiological conditions, constitutive eNOS activity and production of endothelial nitric oxide (NO) exert essential neurovascular protective functions. In this review, we first discuss the roles of endothelial NO in prevention of neuronal amyloid accumulation and formation of neurofibrillary tangles, hallmarks of Alzheimer disease pathology. Next, we review existing evidence suggesting that NO released from endothelium prevents activation of microglia, stimulates glycolysis in astrocytes, and increases biogenesis of mitochondria. We also address major risk factors for cognitive impairment including aging and ApoE4 (apolipoprotein 4) genotype with focus on their detrimental effects on eNOS/NO signaling. Relevant to this review, recent studies suggested that aged eNOS heterozygous mice are unique model of spontaneous cerebral small vessel disease. In this regard, we review contribution of dysfunctional eNOS to deposition of Aβ (amyloid-β) into blood vessel wall leading to development of cerebral amyloid angiopathy. We conclude that endothelial dysfunction manifested by the loss of neurovascular protective functions of NO may significantly contribute to development of cognitive impairment.

APOE genotype influences triglyceride and C-reactive protein responses to altered dietary fat intake in UK adults

https://www.sciencedirect.com/science/article/pii/S0002916523029349?via%3Dihub
Carvalho-Wells Andrew L, Jackson Kim G, Lockyer Stacey, Lovegrove Julie A, Minihane Anne M
American Journal of Clinical Nutrition Volume 96, Issue 6, 2012, Pages 1447-1453
Version of Record 24 February 2023
DOI: https://doi.org/10.3945/ajcn.112.043240
Background: The response of plasma lipids to dietary fat manipulation is highly heterogeneous, with some indications that APOE genotype may be important.
Objective: The objective was to use a prospective recruitment approach to determine the effect of dietary fat quantity and composition on both lipid and nonlipid cardiovascular disease biomarkers according to APOE genotype.
Design: Participants had a mean (±SD) age of 51 ± 9 y and a BMI (in kg/m2) of 26.0 ± 3.8 (n = 44 E3/E3,n = 44 E3/E4) and followed a sequential dietary intervention (the SATgenε study) in which they were assigned to a low-fat diet, a high-fat high-SFA (HSF) diet, and the HSF diet with 3.45 g DHA/d (HSF-DHA), each for 8 wk. Fasting blood samples were collected at the end of each intervention arm.
Results: An overall diet effect was evident for all cholesterol fractions (P < 0.01), with no significant genotype × diet interactions observed. A genotype × diet interaction (P = 0.033) was evident for plasma triglycerides, with 17% and 30% decreases in APOE3/E3 and APOE3/E4 individuals after the HSF-DHA diet relative to the low-fat diet. A significant genotype × diet interaction (P = 0.009) was also observed for C-reactive protein (CRP), with only significant increases in concentrations after the HSF and HSF-DHA diets relative to the low-fat diet in the APOE3/E4 group (P < 0.015).
Conclusions: Relative to the wild-type APOE3/E3 group, our results indicate a greater sensitivity of fasting triglycerides and CRP to dietary fat manipulation in those with an APOE3/E4 genotype (25% population), with no effect of this allelic profile on cholesterol concentrations. The SATgenε study was registered at clinicaltrials.gov as NCT01384032.

Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits

https://www.nature.com/articles/s43587-023-00368-3
Nicole Koutsodendris, Jessica Blumenfeld, Ayushi Agrawal, Michela Traglia, Brian Grone, Misha Zilberter, Oscar Yip, Antara Rao, Maxine R. Nelson, Yanxia Hao, Reuben Thomas, Seo Yeon Yoon, Patrick Arriola & Yadong Huang
Nature Aging volume 3, pages275–296 (2023)
Published: 20 February 2023
DOI: https://doi.org/10.1038/s43587-023-00368-3
Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the role of neuronal APOE4 in AD pathogenesis is still unclear. Here we report the characterization of neuronal APOE4 effects on AD-related pathologies in an APOE4-expressing tauopathy mouse model. The selective genetic removal of APOE4 from neurons led to a significant reduction in tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability and myelin deficits. Single-nucleus RNA-sequencing revealed that the removal of neuronal APOE4 greatly diminished neurodegenerative disease-associated subpopulations of neurons, oligodendrocytes, astrocytes and microglia whose accumulation correlated to the severity of tau pathology, neurodegeneration and myelin deficits. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies and its removal can mitigate the progressive cellular and tissue alterations occurring in this model of APOE4-driven tauopathy.

APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes

https://www.biorxiv.org/content/10.1101/2023.02.06.527204v1?fbclid=IwAR2sz33ob6dk7ZEl5Jhzang7wuokBl3EO2JVi56cfWE-Rs4U9DT-lCSkNyg
Sangderk Lee, Holden C. Williams, Amy A. Gorman, Nicholas A. Devanney, Douglas A. Harrison, Adeline E. Walsh, Danielle S. Goulding, Tony Tuck, James L. Schwartz, Diana J. Zajac, Shannon L. Macauley, Steven Estus, TCW Julia, Lance A. Johnson, Josh M. Morganti
bioRxiv 2023.02.06.527204
Posted February 06, 2023 (preprint)
doi: https://doi.org/10.1101/2023.02.06.527204
Summary
Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimer’s disease (AD). Across the CNS, astrocytes are the predominant expressor of APOE while also being critical mediators of neuroinflammation and cerebral metabolism. APOE4 has been consistently linked with dysfunctional inflammation and metabolic processes, yet insights into the molecular constituents driving these responses remain unclear. Utilizing complementary approaches across humanized APOE mice and isogenic human iPSC astrocytes, we demonstrate that ApoE4 alters the astrocyte immunometabolic response to pro-inflammatory stimuli. Our findings show that ApoE4-expressing astrocytes acquire distinct transcriptional repertoires at single-cell and spatially-resolved domains, which are driven in-part by preferential utilization of the cRel transcription factor. Further, inhibiting cRel translocation in ApoE4 astrocytes abrogates inflammatory-induced glycolytic shifts and in tandem mitigates production of multiple pro-inflammatory cytokines. Altogether, our findings elucidate novel cellular underpinnings by which ApoE4 drives maladaptive immunometabolic responses of astrocytes.

January 2023

Opposing Effects of ApoE2 and ApoE4 on Glycolytic Metabolism in Neuronal Aging Supports a Warburg Neuroprotective Cascade against Alzheimer’s Disease

https://www.mdpi.com/2073-4409/12/3/410?fbclid=IwAR3ZoJJYlaEQ3rLsve8_YV7UwPeo5yqWYAPrS2eM1fyL0Fd4ruWgSswQhBY
Xin Zhang, Long Wu, Russell H. Swerdlow and Liqin Zhao
Cells 2023, 12(3), 410
Published: 25 January 2023
DOI: https://doi.org/10.3390/cells12030410
Abstract
Apolipoprotein E4 (ApoE4) is the most recognized genetic risk factor for late-onset Alzheimer’s disease (LOAD), whereas ApoE2 reduces the risk for LOAD. The underlying mechanisms are unclear but may include effects on brain energy metabolism. Here, we used neuro-2a (N2a) cells that stably express human ApoE isoforms (N2a-hApoE), differentiated N2a-hApoE neuronal cells, and humanized ApoE knock-in mouse models to investigate relationships among ApoE isoforms, glycolytic metabolism, and neuronal health and aging. ApoE2-expressing cells retained robust hexokinase (HK) expression and glycolytic activity, whereas these endpoints progressively declined with aging in ApoE4-expressing cells. These divergent ApoE2 and ApoE4 effects on glycolysis directly correlated with markers of cellular wellness. Moreover, ApoE4-expressing cells upregulated phosphofructokinase and pyruvate kinase with the apparent intent of compensating for the HK-dependent glycolysis reduction. The introduction of ApoE2 increased HK levels and glycolysis flux in ApoE4 cells. PI3K/Akt signaling was distinctively regulated by ApoE isoforms but was only partially responsible for the ApoE-mediated effects on HK. Collectively, our findings indicate that human ApoE isoforms differentially modulate neuronal glycolysis through HK regulation, with ApoE2 upregulating and ApoE4 downregulating, which markedly impacts neuronal health during aging. These findings lend compelling support to the emerging inverse-Warburg theory of AD and highlight a therapeutic opportunity for bolstering brain glycolytic resilience to prevent and treat AD.

Association between healthy lifestyle and memory decline in older adults: 10 year, population based, prospective cohort study

https://www.bmj.com/content/380/bmj-2022-072691
Jianping Jia, Tan Zhao, Zhaojun Liu, Yumei Liang, Fangyu Li, Yan Li, Wenying Liu, Fang Li, Shengliang Shi, Chunkui Zhou, Heyun Yang, Zhengluan Liao, Yang Li, Huiying Zhao, Jintao Zhang, Kunnan Zhang, Minchen Kan, Shanshan Yang, Hao Li, Zhongling Liu, Rong Ma, Jihui Lv, Yue Wang, Xin Yan, Furu Liang, Xiaoling Yuan, Jinbiao Zhang, Serge Gauthier, Jeffrey Cummings
BMJ 2023; 380 :e072691
Published 25 January 2023
doi: https://doi.org/10.1136/bmj-2022-072691
Abstract
Objective
To identify an optimal lifestyle profile to protect against memory loss in older individuals. Design Population based, prospective cohort study.
Setting
Participants from areas representative of the north, south, and west of China. Participants Individuals aged 60 years or older who had normal cognition and underwent apolipoprotein E (APOE) genotyping at baseline in 2009.
Main outcome measures
Participants were followed up until death, discontinuation, or 26 December 2019. Six healthy lifestyle factors were assessed: a healthy diet (adherence to the recommended intake of at least 7 of 12 eligible food items), regular physical exercise (≥150 min of moderate intensity or ≥75 min of vigorous intensity, per week), active social contact (≥twice per week), active cognitive activity (≥twice per week), never or previously smoked, and never drinking alcohol. Participants were categorised into the favourable group if they had four to six healthy lifestyle factors, into the average group for two to three factors, and into the unfavourable group for zero to one factor. Memory function was assessed using the World Health Organization/University of California-Los Angeles Auditory Verbal Learning Test, and global cognition was assessed via the Mini-Mental State Examination. Linear mixed models were used to explore the impact of lifestyle factors on memory in the study sample.
Results
29 072 participants were included (mean age of 72.23 years; 48.54% (n=14 113) were women; and 20.43% (n=5939) were APOE ε4 carriers). Over the 10 year follow-up period (2009-19), participants in the favourable group had slower memory decline than those in the unfavourable group (by 0.028 points/year, 95% confidence interval 0.023 to 0.032, P<0.001). APOE ε4 carriers with favourable (0.027, 95% confidence interval 0.023 to 0.031) and average (0.014, 0.010 to 0.019) lifestyles exhibited a slower memory decline than those with unfavourable lifestyles. Among people who were not carriers of APOE ε4, similar results were observed among participants in the favourable (0.029 points/year, 95% confidence interval 0.019 to 0.039) and average (0.019, 0.011 to 0.027) groups compared with those in the unfavourable group. APOE ε4 status and lifestyle profiles did not show a significant interaction effect on memory decline (P=0.52).
Conclusion
A healthy lifestyle is associated with slower memory decline, even in the presence of the APOE ε4 allele. This study might offer important information to protect older adults against memory decline.

Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort

https://alzres.biomedcentral.com/articles/10.1186/s13195-022-01121-5?fbclid=IwAR31P41QimZuKgWZRARO_yQdyUmWb7BEbGy75M0TgHFP2wlDPFhsmRCLCdw
Rasha N. M. Saleh, Michael Hornberger, Craig W. Ritchie & Anne Marie Minihane
Alzheimer’s Research & Therapy 15, 10 (2023)
Published 09 January 2023
DOI: https://doi.org/10.1186/s13195-022-01121-5
Abstract
Background
The risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT initiation on the heterogeneity in cognitive response to HRT.
Methods
The analysis used baseline data from participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort (total n= 1906, women= 1178, 61.8%). Analysis of covariate (ANCOVA) models were employed to test the independent and interactive impact of APOE genotype and HRT on select cognitive tests, such as MMSE, RBANS, dot counting, Four Mountain Test (FMT), and the supermarket trolley test (SMT), together with volumes of the medial temporal lobe (MTL) regions by MRI. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes.
Results
APOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6–10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively). Earlier introduction of HRT was associated with larger right (standardized β= −0.555, p=0.035) and left hippocampal volumes (standardized β= −0.577, p=0.028) only in APOE4 carriers.
Conclusion
HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup. Confirmation of findings in a fit for purpose RCT with prospective recruitment based on APOE genotype is needed to establish causality.

Alzheimer’s drug lecanemab receives accelerated approval amid safety concerns

https://edition.cnn.com/2023/01/06/health/lecanemab-fda-approval/index.html?fbclid=IwAR21Fn4tnwhNd3ZcRl7GvKGKxnb1pds-6Kpk4kh3ZZhnbnyg-A-Kuiv6aHk
By Jacqueline Howard and Brenda Goodman, CNN
Updated 6:53 PM EST, Sat January 7, 2023
Some people who get ARIA may not have symptoms, but it can occasionally lead to hospitalization or lasting impairment. And the frequency of ARIA appeared to be higher in people who had a gene called APOE4, which can raise the risk of Alzheimer’s disease or other dementias. ARIA “were numerically less common” among APOE4 noncarriers, the study showed. … The FDA’s accelerated approval of lecanemab was expected, said Dr. Richard Isaacson, director of the Alzheimer’s Prevention Clinic in the Center for Brain Health at Florida Atlantic University’s Schmidt College of Medicine. Isaacson said lecanemab can be “another tool” in his toolbox to fight Alzheimer’s disease. “I will prescribe this drug in the right person, at the right dose and in a very carefully monitored way, but this drug is not for everyone,” he said. “I would do genetic testing for APOE4 first. I would have a frank discussion with my patients,” he said. “If someone is having side effects, if someone is on a blood-thinning medication, if someone has a problem, they need to discuss this with the treating physician, and they need to seek medical attention immediately.”

Identifying differential regulatory control of APOEɛ4 on African versus European haplotypes as potential therapeutic targets

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250552/
Karen Nuytemans, Marina Lipkin Vasquez, Liyong Wang, Derek Van Booven, Anthony J. Griswold, Farid Rajabli, Katrina Celis, Oded Oron, Natalia Hofmann, Sophie Rolati, Catherine Garcia-Serje, Shanshan Zhang, Fulai Jin, Mariana Argenziano, Struan F.A. Grant, Alessandra Chesi, Christopher D. Brown, Juan I. Young, Derek M. Dykxhoorn, Margaret A. Pericak-Vance, and Jeffery M. Vance
Alzheimers & Dementia 2022 Oct; 18(10): 1930–1942.
Published online 2022 Jan 3
doi: 10.1002/alz.12534
Abstract
We previously demonstrated that in Alzheimer’s disease (AD) patients, European apolipoprotein E (APOE) ε4 carriers express significantly more APOEε4 in their brains than African AD carriers. We examined single nucleotide polymorphisms near APOE with significant frequency differences between African and European/Japanese APOE ε4 haplotypes that could contribute to this difference in expression through regulation. Two enhancer massively parallel reporter assay (MPRA) approaches were performed, supplemented with single fragment reporter assays. We used Capture C analyses to support interactions with the APOE promoter. Introns within TOMM40 showed increased enhancer activity in the European/Japanese versus African haplotypes in astrocytes and microglia. This region overlaps with APOE promoter interactions as assessed by Capture C analysis. Single variant analyses pinpoints rs2075650/rs157581, and rs59007384 as functionally different on these haplotypes. Identification of the mechanisms for differential regulatory function for APOE expression between African and European/Japanese haplotypes could lead to therapeutic targets for APOE ε4 carriers.

#236 ‒ Neurodegenerative disease: pathology, screening, and prevention | Kellyann Niotis, M.D.

https://peterattiamd.com/kellyannniotis/?fbclid=IwAR0iy5Map8GHX_s5k-WDzaxKdfB-FEUeFBb-PWDQVzYwcgycpDZLhAmHAJw
Peter Attia, MD Podcast
January 2, 2023
This interview of Dr Niotis as conducted by Dr Attia addresses ApoE4 many times throughout the discussion. Kellyann Niotis is a neurologist specializing in risk reduction strategies for the prevention or slowing of neurodegenerative disorders. In this episode, Kellyann provides an overview of the various diseases associated with neurodegeneration, including, but not limited to, Alzheimer’s disease, Lewy body dementia, and Parkinson’s disease. She goes in-depth on Parkinson’s disease, explaining its pathology, role in movement capacity, very early warning signs, and the role of anxiety and sleep. Similarly, she provides an in-depth discussion of Alzheimer’s disease, including the latest in screening, genetics, and tools/strategies for prevention. She ties the discussion together by explaining the differences and commonalities among the various diseases of neurodegeneration and the potential causative triggers, and she highlights the importance of early screening, cognitive testing, and taking the proper steps to lowering the risk of disease.
We discuss:
• Kellyann’s background, training, and interest in the brain [2:30];
• A primer on neurodegeneration: different types, prevalences, interventions, and more [5:30];
• Overview of Parkinson’s disease and neuromuscular disorders including ALS [16:00];
• Parkinson’s disease: early signs, diagnosis, genetics, causative triggers, and more [17:30];
• Interventions to delay or avoid Parkinson’s disease, and the role of sleep and anxiety [31:15];
• The challenge of standardizing early interventions for Parkinson’s disease without a clear biomarker [39:45];
• Alzheimer’s disease: pathophysiology and the role of the amyloid and tau proteins [47:45];
• Can PET scans be informative for diagnosing Alzheimer’s disease? [51:15];
• Tau accumulation in the brain, tau scans, serum biomarkers, and possible early detection of Alzheimer’s disease pathology [57:00];
• Cognitive testing explained [1:03:30];
• The challenge of identifying the stage of the disease and why drugs have not shown efficacy [1:14:45];
• The association between hearing loss and dementia [1:17:45];
• The relationship between oral health and neurodegenerative diseases [1:21:30];
• Genetic risk for Alzheimer’s disease [1:24:45];
• What one’s mitochondrial haplotype can reveal about their risk of neurodegenerative disease [1:32:30];
• The positive impact of exercise on brain health [1:37:00];
• High blood pressure as a risk factor [1:40:00];
• Why women are disproportionately affected by Alzheimer’s disease [1:44:15];
• Final takeaways: the future of understanding neurodegenerative disease and further reducing risk [1:46:45];
• And More.

Effects of ApoE4 and ApoE2 genotypes on subcortical magnetic susceptibility and microstructure in 27,535 participants from the UK Biobank†

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9009383/
Talia M. Nir, Alyssa H. Zhu, Iyad Ba Gari, Daniel Dixon, Tasfiya Islam, and Julio E. Villalon-Reina
Pacific Symposium on Biocomputing 2022; 27: 121–132
2023 Jan 1
Abstract
Disrupted iron homeostasis is associated with several neurodegenerative diseases, including Alzheimer’s disease (AD), and may be partially modulated by genetic risk factors. Here we evaluated whether subcortical iron deposition is associated with ApoE genotype, which substantially affects risk for late-onset AD. We evaluated differences in subcortical quantitative susceptibility mapping (QSM), a type of MRI sensitive to cerebral iron deposition, between either ApoE4 (E3E4+E4E4) or ApoE2 (E2E3+E2E2) carriers and E3 homozygotes (E3E3) in 27,535 participants from the UK Biobank (age: 45–82 years). We found that ApoE4 carriers had higher hippocampal (d=0.036; p=0.012) and amygdalar (d=0.035; p=0.013) magnetic susceptibility, particularly individuals aged 65 years or older, while those carrying ApoE2 (which protects against AD) had higher QSM only in the hippocampus (d=0.05; p=0.006), particularly those under age 65. Secondary diffusion MRI microstructural associations in these regions revealed greater diffusivity and less diffusion restriction in E4 carriers, however no differences were detected in E2 carriers. Disease risk conferred by ApoE4 may be linked with higher subcortical iron burden in conjunction with inflammation or neuronal loss in aging individuals, while ApoE2 associations may not necessarily reflect unhealthy iron deposits earlier in life.

2022

December 2022

Effects of non-modifiable risk factors of Alzheimer’s disease on intracortical myelin content

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9805254/
Marina Fernandez-Alvarez, Mercedes Atienza, and Jose L. Cantero
Alzheimer’s Research & Therapy, 2022; 14: 202
Published online 2022 Dec 31
doi: 10.1186/s13195-022-01152-y
Abstract
Background
Non-modifiable risk factors of Alzheimer’s disease (AD) have lifelong effects on cortical integrity that could be mitigated if identified at early stages. However, it remains unknown whether cortical microstructure is affected in older individuals with non-modifiable AD risk factors and whether altered cortical tissue integrity produces abnormalities in brain functional networks in this AD-risk population.
Methods
Using relative T1w/T2w (rT1w/T2w) ratio maps, we have compared tissue integrity of normal-appearing cortical GM between controls and cognitively normal older adults with either APOE4 (N = 50), with a first-degree family history (FH) of AD (N = 52), or with the co-occurrence of both AD risk factors (APOE4+FH) (N = 35). Additionally, individuals with only one risk factor (APOE4 or FH) were combined into one group (N = 102) and compared with controls. The same number of controls matched in age, sex, and years of education was employed for each of these comparisons. Group differences in resting state functional connectivity (rs-FC) patterns were also investigated, using as FC seeds those cortical regions showing significant changes in rT1w/T2w ratios.
Results
Overall, individuals with non-modifiable AD risk factors exhibited significant variations in rT1w/T2w ratios compared to controls, being APOE4 and APOE4+FH at opposite ends of a continuum. The co-occurrence of APOE4 and FH was further accompanied by altered patterns of rs-FC.
Conclusions
These findings may have practical implications for early detection of cortical abnormalities in older populations with APOE4 and/or FH of AD and open new avenues to monitor changes in cortical tissue integrity associated with non-modifiable AD risk factors.

Revised clinical trial form for Alzheimer’s antibody warned of fatal brain bleeds

BYCHARLES PILLER, Science, 30 DEC 2022 11:30 AM ET
30 DEC 2022 Earlier this year, the developer of a promising antibody [Lecanemab] designed to slow Alzheimer’s disease strengthened a key warning given to participants in an ongoing trial of the experimental drug. Taking the antibody alongside blood clot medications, the Japanese biotech company Eisai cautioned, increases the risk of possibly fatal brain hemorrhages. That revision of its informed consent form, revealed in a 14 July version obtained by Science, appears to challenge the company’s contention that the antibody, known as lecanemab, played no role in the recently revealed deaths of two people who suffered dramatic brain bleeds while concurrently taking the drug and blood thinners. ...
The change to the form also raises questions about how effectively Eisai and its clinical trial partners communicated updated warnings to trial participants and how transparent the company has been about the risks of its product, which the U.S. Food and Drug Administration (FDA) has said it could approve for sale by 6 January 2023. ...
But neurologists disagree about whether such a difference would be perceptible to patients. And three key trial subgroups—people under age 65, women, and people who carry two copies of APOE4, a gene variant that raises one’s risk of developing Alzheimer’s—did not show any statistically significant benefit. ...
Gandy agrees the agency should assess the need for a black box warning that could include every class of drug—such as anticoagulants, tPA, and antiplatelet treatments—that can cause or increase the risk of brain bleeding. He also favors genetic testing of potential lecanemab recipients to ensure they know their APOE4 status. In the completed core phase of the lecanemab trial, participants who carry at least one copy of the gene variant suffered a much higher rate of brain swelling and bleeding.

Sulfatide Deficiency, an Early Alzheimer’s Lipidomic Signature, Causes Brain Ventricular Enlargement in the Absence of Classical Neuropathological Hallmarks

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820719/
Juan Pablo Palavicini, Lin Ding, Meixia Pan, Shulan Qiu, Hu Wang, Qiang Shen, Jeffrey L. Dupree, and Xianlin Han
International Journal of Molecular Sciences 2022 Dec 23;24(1):233
Published online 2022 Dec 23
doi: 10.3390/ijms24010233
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss and a decline in activities of daily life. Ventricular enlargement has been associated with worse performance on global cognitive tests and AD. Our previous studies demonstrated that brain sulfatides, myelin-enriched lipids, are dramatically reduced in subjects at the earliest clinically recognizable AD stages via an apolipoprotein E (APOE)-dependent and isoform-specific process. Herein, we provided pre-clinical evidence that sulfatide deficiency is causally associated with brain ventricular enlargement. Specifically, taking advantage of genetic mouse models of global and adult-onset sulfatide deficiency, we demonstrated that sulfatide losses cause ventricular enlargement without significantly affecting hippocampal or whole brain volumes using histological and magnetic resonance imaging approaches. Mild decreases in sulfatide content and mild increases in ventricular areas were also observed in human APOE4 compared to APOE2 knock-in mice. Finally, we provided Western blot and immunofluorescence evidence that aquaporin-4, the most prevalent aquaporin channel in the central nervous system (CNS) that provides fast water transportation and regulates cerebrospinal fluid in the ventricles, is significantly increased under sulfatide-deficient conditions, while other major brain aquaporins (e.g., aquaporin-1) are not altered. In short, we unraveled a novel and causal association between sulfatide deficiency and ventricular enlargement. Finally, we propose putative mechanisms by which sulfatide deficiency may induce ventricular enlargement.

Intertwined relationship among ROS, mitochondria and APOE4 during the onset of Alzheimer's disease

https://pubs.aip.org/aip/acp/article-abstract/2589/1/020024/2830327/Intertwined-relationship-among-ROS-mitochondria?redirectedFrom=fulltext
Sihan Wang
AIP Conference Proceedings 2589, 020024 (2022)
DECEMBER 19 2022
DOI: https://doi.org/10.1063/5.0111737
The Alzheimer's disease, a kind of dementia recognized by the National Institute of Neurological Disorders and Stroke as a "progressive, neurodegenerative disease", is destroying the life of around 50 million people worldwide. Multiple biomarkers have been detected in relation to AD, with a current emphasis in figuring out how the accumulation of Aβ can be affected by the interplay of ROS, mitochondria, and APOE4. While ROS arises from highly chemicals formed by oxygen and mitochondria being the energy center of human body, APOE4 is a newly-targeted gene connected with AD. This review tries to go through the mechanisms mediated by the three potential factors mentioned above. As the mechanisms count considerably in the cause of AD, the related drugs and therapeutic methods aimed to mitigate the influence brought by the three factors will also be summarized.

Reimagining Alzheimer’s (Part 7): Cholesterol Abnormalities May Contribute To Alzheimer’s Disease

https://www.forbes.com/sites/williamhaseltine/2022/12/17/reimagining-alzheimers-part-7-cholesterol-abnormalities-may-contribute-to-alzheimers-disease/?sh=6536fb655679
William A Haseltine, Forbes, Dec 12, 2022
Dec 12, 2022
The E4 variant of the APOE gene is accepted as the predominant genetic risk factor for Alzheimer’s. Those who contain one copy of the E4 variant are three times more likely to develop Alzheimer’s, while those who contain two copies of the E4 variant are nearly ten times more likely to develop the disease. Unfortunately, while the E4 variant has been associated with Alzheimer’s for decades, it is still unclear exactly how it contributes to the debilitating biological and cognitive symptoms of Alzheimer’s. Now, a study conducted by Tsai et al. at the Massachusetts Institute of Technology shows that those who contain the E4 variant display abnormalities in cholesterol metabolism. The MIT team suggests that the disruption of cholesterol metabolism could be a fundamental reason why those with the E4 variant are more likely to develop Alzheimer’s disease symptoms.

Nutritional metabolism and cerebral bioenergetics in Alzheimer's disease and related dementias

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12845
Hussein N. Yassine, Wade Self, Bilal E. Kerman, Giulia Santoni, Nanda Kumar Navalpur Shanmugam, Laila Abdullah, Lesley R. Golden, Alfred N. Fonteh, Michael G. Harrington, Johannes Gräff, Gary E. Gibson, Raj Kalaria, Jose A. Luchsinger, Howard H. Feldman, Russell H. Swerdlow, Lance A. Johnson, Benedict C. Albensi, Berislav V. Zlokovic, Rudolph Tanzi, Stephen Cunnane, Cécilia Samieri, Nikolaos Scarmeas, Gene L. Bowman
Alzheimer's & Dementia, Volume19, Issue3, March 2023, Pages 1041-1066
First published: 08 December 2022
DOI: https://doi.org/10.1002/alz.12845
Abstract
Disturbances in the brain's capacity to meet its energy demand increase the risk of synaptic loss, neurodegeneration, and cognitive decline. Nutritional and metabolic interventions that target metabolic pathways combined with diagnostics to identify deficits in cerebral bioenergetics may therefore offer novel therapeutic potential for Alzheimer's disease (AD) prevention and management. Many diet-derived natural bioactive components can govern cellular energy metabolism but their effects on brain aging are not clear. This review examines how nutritional metabolism can regulate brain bioenergetics and mitigate AD risk. We focus on leading mechanisms of cerebral bioenergetic breakdown in the aging brain at the cellular level, as well as the putative causes and consequences of disturbed bioenergetics, particularly at the blood-brain barrier with implications for nutrient brain delivery and nutritional interventions. Novel therapeutic nutrition approaches including diet patterns are provided, integrating studies of the gut microbiome, neuroimaging, and other biomarkers to guide future personalized nutritional interventions.
Section 2.3 specifically addresses APOE4 and cerebral bioenergetics

Association of Red Blood Cell Omega-3 Fatty Acids With MRI Markers and Cognitive Function in Midlife The Framingham Heart Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9754651/
Claudia L. Satizabal, PhD, Jayandra Jung Himali, PhD, Alexa S. Beiser, PhD, Vasan Ramachandran, MD, Debora Melo van Lent, PhD, Dibya Himali, MS, Hugo J. Aparicio, MD, MPH, Pauline Maillard, PhD, Charles S. DeCarli, MD, William S. Harris, PhD, and Sudha Seshadri, MD
Neurology 2022 Dec 6; 99(23): e2572–e2582
2022 Dec 6
doi: 10.1212/WNL.0000000000201296
Abstract
Background and Objectives
Diet may be a key contributor to brain health in midlife. In particular, omega-3 fatty acids have been related to better neurologic outcomes in older adults. However, studies focusing on midlife are lacking. We investigated the cross-sectional association of red blood cell (RBC) omega-3 fatty acid concentrations with MRI and cognitive markers of brain aging in a community-based sample of predominantly middle-aged adults and further explore effect modification by APOE genotype.
Methods
We included participants from the Third-Generation and Omni 2 cohorts of the Framingham Heart Study attending their second examination. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) concentrations were measured from RBC using gas chromatography, and the Omega-3 index was calculated as EPA + DHA. We used linear regression models to relate omega-3 fatty acid concentrations to brain MRI measures (i.e., total brain, total gray matter, hippocampal, and white matter hyperintensity volumes) and cognitive function (i.e., episodic memory, processing speed, executive function, and abstract reasoning) adjusting for potential confounders. We further tested for interactions between omega-3 fatty acid levels and APOE genotype (e4 carrier vs noncarrier) on MRI and cognitive outcomes.
Results
We included 2,183 dementia-free and stroke-free participants (mean age of 46 years, 53% women, 22% APOE-e4 carriers). In multivariable models, higher Omega-3 index was associated with larger hippocampal volumes (standard deviation unit beta ±standard error; 0.003 ± 0.001, p = 0.013) and better abstract reasoning (0.17 ± 0.07, p = 0.013). Similar results were obtained for DHA or EPA concentrations individually. Stratification by APOE-e4 status showed associations between higher DHA concentrations or Omega-3 index and larger hippocampal volumes in APOE-e4 noncarriers, whereas higher EPA concentrations were related to better abstract reasoning in APOE-e4 carriers. Finally, higher levels of all omega-3 predictors were related to lower white matter hyperintensity burden but only in APOE-e4 carriers.
Discussion
Our results, albeit exploratory, suggest that higher omega-3 fatty acid concentrations are related to better brain structure and cognitive function in a predominantly middle-aged cohort free of clinical dementia. These associations differed by APOE genotype, suggesting potentially different metabolic patterns by APOE status. Additional studies in middle-aged populations are warranted to confirm these findings.

Predictive link between systemic metabolism and cytokine signatures in the brain of apolipoprotein E ε4 mice

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9892258/
Rebecca M Fleeman, Amanda M Snyder, Madison K Kuhn, Dennis C Chan, Grace C Smith, Nicole A Crowley, Amy C Arnold, and Elizabeth A Proctor
Neurobiology Aging 2023 Mar; 123: 154–169
Published online 2022 Dec 5
doi: 10.1016/j.neurobiolaging.2022.11.015
Abstract
The ε4 variant of apolipoprotein E (APOE) is the strongest and most common genetic risk factor for Alzheimer’s disease (AD). While the mechanism of conveyed risk is incompletely understood, promotion of inflammation, dysregulated metabolism, and protein misfolding and aggregation are contributors to accelerating disease. Here we determined the concurrent effects of systemic metabolic changes and brain inflammation in young (3-month-old) and aged (18-month-old) male and female mice carrying the APOE4 gene. Using functional metabolic assays alongside multivariate modeling of hippocampal cytokine levels, we found that brain cytokine signatures are predictive of systemic metabolic outcomes, independent of AD proteinopathies. Male and female mice each produce different cytokine signatures as they age and as their systemic metabolic phenotype declines, and these signatures are APOE genotype dependent. Ours is the first study to identify a quantitative and predictive link between systemic metabolism and specific pathological cytokine signatures in the brain. Our results highlight the effects of APOE4 beyond the brain and suggest the potential for bi-directional influence of risk factors in the brain and periphery.

Reimagining Alzheimer’s (Part 6): The Many Effects Of The APOE4 Variant

https://www.forbes.com/sites/williamhaseltine/2022/12/05/reimagining-alzheimers-part-6-the-many-effects-of-the-apoe4-variant/?sh=59e7467f6584
William A Haseltine, Forbes, Dec 5, 2022
Dec 5, 2022
A recent paper [APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes https://www.nature.com/articles/s41586-022-05439-w] published in the journal Nature has revealed a new mechanism by which the genetic risk factor, APOE4, may contribute to Alzheimer’s disease pathology. The E4 variant of the APOE gene is the predominant genetic risk factor for Alzheimer’s disease. Those who contain one copy of the E4 variant are three times more likely to develop Alzheimer’s, while those who contain two copies of the E4 variant are nearly ten times more likely to develop the disease. The E4 variant has been associated with Alzheimer’s disease for years. However, it is still not understood exactly why or how this genetic variant contributes to the debilitating biological and cognitive symptoms of Alzheimer’s. Now, studies conducted by a team at the Massachusetts Institute of Technology suggest that the E4 variant of the APOE gene disrupts how fat molecules are processed in the brain. It appears that the disruption of these fat molecules could be the fundamental reason why those that contain the E4 variant are more likely to develop Alzheimer’s symptoms including brain cell death, memory issues, and cognitive decline.

Apolipoprotein E4 Influences Amyloid Deposition But Not Cell Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

https://www.jneurosci.org/content/22/23/10083
Richard E. Hartman, Helmut Laurer, Luca Longhi, Kelly R. Bales, Steven M. Paul, Tracy K. McIntosh and David M. Holtzman
Journal of Neuroscience 1 December 2002, 22 (23) 10083-10087
1 December2022
DOI: https://doi.org/10.1523/JNEUROSCI.22-23-10083.2002
Abstract
The ε4 allele of apolipoprotein E (APOE) and traumatic brain injury (TBI) are both risk factors for the development of Alzheimer's disease (AD). These factors may act synergistically, in that APOE4+ individuals are more likely to develop dementia after TBI. Because the mechanism underlying these effects is unclear, we questioned whetherAPOE4 and TBI interact either through effects on amyloid-β (Aβ) or by enhancing cell death/tissue injury. We assessed the effects of TBI in PDAPP mice (transgenic mice that develop AD-like pathology) expressing human APOE3(PDAPP:E3), human APOE4 (PDAPP:E4), or noAPOE (PDAPP:E−/−). Mice were subjected to a unilateral cortical impact injury at 9–10 months of age and allowed to survive for 3 months. Aβ load, hippocampal/cortical volumes, and hippocampal CA3 cell loss were quantified using stereological methods. All of the groups contained mice with Aβ-immunoreactive deposits (56% PDAPP:E4, 20% PDAPP:E3, 75% PDAPP:E−/−), but thioflavine-S-positive Aβ (amyloid) was present only in the molecular layer of the dentate gyrus in the PDAPP:E4 mice (44%). In contrast, our previous studies showed that in the absence of TBI, PDAPP:E3 and PDAPP:E4 mice have little to no Aβ deposition at this age. After TBI, all of the Aβ deposits present in PDAPP:E3 and PDAPP:E−/− mice were diffuse plaques. In contrast to the effect of APOE4 on amyloid, PDAPP:E3, PDAPP:E4, and PDAPP:E−/− mice did not differ in the amount of brain tissue or cell loss. These data support the hypothesis thatAPOE4 influences the neurodegenerative cascade after TBI via an effect on Aβ.

High-clearance anti-amyloid immunotherapies in Alzheimer's disease. Part 1: Meta-analysis and review of efficacy and safety data, and medico-economical aspects

https://www.sciencedirect.com/science/article/pii/S003537872200738X?via%3Dihub
N. Villain, V. Planche, R. Levy
Revue Neurologique Volume 178, Issue 10, December 2022, Pages 1011-1030
Dec 2022
DOI: https://doi.org/10.1016/j.neurol.2022.06.012
Abstract
In 2021, aducanumab, an immunotherapy targeting amyloid-β, was approved for Alzheimer's disease (AD) by the US Food and Drug Administration thanks to positive results on a putative biological surrogate marker. This approval has raised an unprecedented controversy. It was followed by a refusal of the European Medicine Agency, which does not allow the marketing of drugs solely on biological arguments and raised safety issues, and important US coverage limitations by the Centers for Medicare & Medicaid Services. Two other anti-amyloid immunotherapies showed significant results regarding a clinical outcome in phase 2 trials, and five drugs are being studied in phase 3 trials. Compared to those tested in previous trials of the 2010s, the common feature and novelty of these anti-amyloid immunotherapies is their ability to induce a high clearance of amyloid load, as measured with positron emission tomography, in the brain of early-stage biomarker-proven AD patients. Here, we review the available evidence regarding efficacy and safety data and medico-economical aspects for high-clearance anti-amyloid immunotherapies. We also perform frequentist and Bayesian meta-analyses of the clinical efficacy and safety of the highest dose groups from the two aducanumab phase 3 trials and the donanemab and lecanemab phase 2 trials. When pooled together, the data from high-clearance anti-amyloid immunotherapies trials confirm a statistically significant clinical effect of these drugs on cognitive decline after 18 months (difference in cognitive decline measured with CDR-SB after 18 months between the high dose immunotherapy groups vs. placebo = −0.24 points; P = 0.04, frequentist random-effect model), with results on ADAS-Cog being the most statistically robust. However, this effect remains below the previously established minimal clinically relevant values. In parallel, the drugs significantly increased the occurrence of amyloid-related imaging abnormalities-edema (ARIA-E: risk ratio = 13.39; P < 0.0001), ARIA-hemorrhage (risk ratio = 2.78; P = 0.0002), and symptomatic and serious ARIA (7/1321 = 0.53% in the high dose groups versus 0/1446 in the placebo groups; risk ratio = 6.44; P = 0.04). The risk/benefit ratio of high-clearance immunotherapies in early AD is so far questionable after 18 months. Identifying subgroups of better responders, the perspective of combination therapies, and a longer follow-up may help improve their clinical relevance. Finally, the preliminary evidence from medico-economical analyses seems to indicate that the current cost of aducanumab in the US is not in reasonable alignment with its clinical benefits.
AND FROM TEXT
Fig. 3. Illustration of serious symptomatic ARIA under lecanemab (Clarity AD ongoing phase 3 trial). A. FLAIR brain MRI of a 69-year-old woman, biologically-proven amnesic AD, APOE ɛ4 carrier, massive ARIA-E responsible for a partial status epilepticus occurring after four months of treatment. The status epilepticus was then complicated by a post-ictal Tako-Tsubo responsible for acute heart failure, confusion responsible for a fall, an unstable T12 vertebral fracture, and an L5 vertebral fracture. MMSE one month before ARIA: 25/30, MMSE eleven months after ARIA: 16/30. B. FLAIR and SWI brain MRIs of a 70-year-old woman, biologically-proven amnesic AD, APOE ɛ4 carrier, massive ARIA-H (7 cm hematoma) revealed by an acute headache occurring after two months of treatment and at one month of suspension of infusions for ARIA-E discovered incidentally on follow-up MRI. The patient was on an effective dose of apixaban. MMSE three months before the first infusion: 25/30, MMSE seven months after ARIA: 13/30, sequela hemianopia (Dr. Nicolas Villain, personal communication).
ALSO FROM TEXT
Currently identified risk factors for ARIA in the aducanumab trials are the APOE status (with ɛ4 carriers being more prone to ARIA, and following an allele-dose effect; HR 2.5: 95% CI, 1.90–3.20) and the baseline microbleed count (HR 1.7; 95%CI, 1.31–2.27) [[12], [68], [69]]. These trials were performed with strict exclusion criteria regarding comorbid cerebrovascular conditions, vascular risk factors, and concomitant antithrombotic medications (Table 2). Other ARIA risk factors identified from the low-clearance immunotherapies trials were: the effect of antibody (with the notable example of solanezumab that does not induce an increased risk of ARIA) and a dose-effect [9], [10], [68], [69].

November 2022

Eisai, Biogen Alzheimer's drug slows cognitive decline, safety for some becomes focus

https://finance.yahoo.com/news/eisai-biogen-alzheimers-drug-slows-005000270.html?guce_referrer=aHR0cHM6Ly9sLmZhY2Vib29rLmNvbS8&guce_referrer_sig=AQAAAAG5F32Nbo4zJJz-gFr7t6-1n91bzbGT7crkXWK1XOrqojUCiDch_Zzn4EkSVK03G7dZs_vczuSDua_oBud5QVRcWuzH79CGfoVl6pG2Twq3q2QGNAjrojXtWCJ0bA45An6PP5qnHANoiU-E57bCqGiVnzSu5GoZp5KWtiykNIsQ
Deena Beasley Reuters Nov 29, 2022
Nov 29, 2022
Lecanemab, a drug that depends on the validity of the amyloid hypothesis (which has been under fire of late), does not improve cognition, it simply slows decline. So these results with concerning side effects are not exactly something to cheer about, plus there are still many unanswered questions.
According to detailed data presented on Tuesday, the drug, lecanemab, was associated with a dangerous type of brain swelling in nearly 13% of patients in the trial that spanned 18 months and enrolled nearly 1,800 participants with early-stage Alzheimer's. Some patients also experienced bleeding in the brain, with five suffering macrohemorrhages and 14% suffering microhemorrhages - a symptom linked to two deaths of people receiving the drug in a follow-on study.
"For that small group of (ApoE4) homozygous patients, when it comes to CDR-SB (rate of decline on a clinical dementia scale) we don't see a signal favoring lecanemab," Ivan Cheung, Eisai's U.S. chairman, said in an interview. He suggested that could be because homozygous study patients who were given a placebo fared better than expected.

Lecanemab in Early Alzheimer’s Disease

https://www.nejm.org/doi/10.1056/NEJMoa2212948?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
Christopher H. van Dyck, M.D., Chad J. Swanson, Ph.D., Paul Aisen, M.D., Randall J. Bateman, M.D., Christopher Chen, B.M., B.Ch., Michelle Gee, Ph.D., Michio Kanekiyo, M.S., David Li, Ph.D., Larisa Reyderman, Ph.D., Sharon Cohen, M.D., Lutz Froelich, M.D., Ph.D., Sadao Katayama, M.D., Marwan Sabbagh,M.D., Bruno Vellas, M.D., David Watson, Psy.D., Shobha Dhadda, Ph.D., Michael Irizarry, M.D., Lynn D. Kramer, M.D., and Takeshi Iwatsubo, M.D.
New England Journal of Medicine, 2023;388(1):9–21
Published November 29, 2022
DOI: 10.1056/NEJMoa2212948
Abstract
BACKGROUND
The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer’s disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer’s disease.
METHODS
We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer’s disease (mild cognitive impairment or mild dementia due to Alzheimer’s disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating–Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer’s Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment).
RESULTS
A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, −0.45; 95% confidence interval [CI], −0.67 to −0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, −59.1 centiloids; 95% CI, −62.6 to −55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, −1.44 (95% CI, −2.27 to −0.61; P<0.001); for the ADCOMS, −0.050 (95% CI, −0.074 to −0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%.
CONCLUSIONS
Lecanemab reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455
From Results section
ARIA-E and ARIA-H were numerically less common among ApoE ε4 noncarriers than among carriers, with higher frequency among ApoE ε4 homozygotes than among ApoE ε4 heterozygotes (Table 3).
and
The incidences of both overall and symptomatic ARIA-E were highest among ApoE ε4 homozygotes.

APOE variants affect COVID-19 outcome

https://www.nature.com/articles/s42255-022-00675-w
Joseph Willson
Nature Metabolism 4, 1430 (2022)
Published: 18 November 2022
DOI: https://doi.org/10.1038/s42255-022-00675-w
The course of SARS-CoV-2 infection varies greatly and ranges from asymptomatic infections to lethal cases. Now, Ostendorf et al. find that common variants of APOE — a gene involved in lipid metabolism that is also linked to Alzheimer disease, atherosclerosis and cancer metastasis — could partially explain the variation in SARS-CoV-2 outcome. In a murine model of SARS-CoV-2 infection, infected mice that were homozygous for the human APOE alleles APOE2 or APOE4 — which are collectively present in approximately 3% of the human population — showed elevated viral loads and markedly poorer survival outcomes relative to those with the APOE3 variant. Mechanistic data suggested that the detrimental effects of APOE2 and APOE4 are caused by impaired adaptive immune responses and enhanced viral entry, as early in the course of infection, APOE2 and APOE4 mice showed depletion of major lymphoid populations and the downregulation of genes involved in T cell and B cell activation in the lungs.
Analysis of human data in the UK Biobank supported a role for APOE in modulating SARS-CoV-2 risk, as individuals homozygous for the APOE4 variant showed a more than two-fold greater mortality rate over those homozygous for APOE3, and individuals homozygous for APOE2 also experienced worse survival outcomes — mirroring the mouse experimental findings. Further studies are needed to determine whether the APOE genotype could be used for risk stratification and to inform therapeutic approaches for individual patients.

Alzheimer's risk gene undermines insulation of brain's 'wiring'

https://medicalxpress.com/news/2022-11-alzheimer-gene-undermines-insulation-brain.html?fbclid=IwAR0lApNaIzDcVMOYbAnFRPYnOSf3IGcKCyDWUqRPUx1fF2awPujC6IrFXEQ
Massachusetts Institute of Technology, MedicalXpress, NOVEMBER 16, 2022
NOVEMBER 16, 2022
It's well known that carrying one copy of the APOE4 gene variant increases one's risk for Alzheimer's disease threefold and two copies about tenfold, but the fundamental reasons why and what can be done to help patients remain largely unknown. A study published by an MIT-based team Nov. 16 in Nature provides some new answers as part of a broader line of research that has demonstrated APOE4's consequences cell type by cell type in the brain.

APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes

https://www.nature.com/articles/s41586-022-05439-w
Joel W. Blanchard, Leyla Anne Akay, Jose Davila-Velderrain, Djuna von Maydell, Hansruedi Mathys, Shawn M. Davidson, Audrey Effenberger, Chih-Yu Chen, Kristal Maner-Smith, Ihab Hajjar, Eric A. Ortlund, Michael Bula, Emre Agbas, Ayesha Ng, Xueqiao Jiang, Martin Kahn, Cristina Blanco-Duque, Nicolas Lavoie, Liwang Liu, Ricardo Reyes, Yuan-Ta Lin, Tak Ko, Lea R’Bibo, William T. Ralvenius, David A. Bennett, Hugh P. Cam, Manolis Kellis, Li-Huei Tsai
Nature 611, 769–779 (2022)
Published 16 November 2022
DOI: https://doi.org/10.1038/s41586-022-05439-w
APOE4 is the strongest genetic risk factor for Alzheimer’s disease1,2,3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer’s disease4,5,6,7,8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2,3,4,5,6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes—myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer’s disease.

Lipid Dys-Homeostasis Contributes to APOE4-Associated AD Pathology

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9688773/
Adina-Nicoleta Lazar, Linda Hanbouch, Lydie Boussicaut, Baptiste Fourmaux, Patricia Daira, Mark J. Millan, Nathalie Bernoud-Hubac, Marie-Claude Potier
Cells 2022 Nov 15;11(22):3616
Published online 2022 Nov 15
doi: 10.3390/cells11223616
Abstract
The association of the APOE4 (vs. APOE3) isoform with an increased risk of Alzheimer’s disease (AD) is unequivocal, but the underlying mechanisms remain incompletely elucidated. A prevailing hypothesis incriminates the impaired ability of APOE4 to clear neurotoxic amyloid-β peptides (Aβ) from the brain as the main mechanism linking the apolipoprotein isoform to disease etiology. The APOE protein mediates lipid transport both within the brain and from the brain to the periphery, suggesting that lipids may be potential co-factors in APOE4-associated physiopathology. The present study reveals several changes in the pathways of lipid homeostasis in the brains of mice expressing the human APOE4 vs. APOE3 isoform. Carriers of APOE4 had altered cholesterol turnover, an imbalance in the ratio of specific classes of phospholipids, lower levels of phosphatidylethanolamines bearing polyunsaturated fatty acids and an overall elevation in levels of monounsaturated fatty acids. These modifications in lipid homeostasis were related to increased production of Aβ peptides as well as augmented levels of tau and phosphorylated tau in primary neuronal cultures. This suite of APOE4-associated anomalies in lipid homeostasis and neurotoxic protein levels may be related to the accrued risk for AD in APOE4 carriers and provides novel insights into potential strategies for therapeutic intervention.

ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9686673/
Erica Staurenghi, Valerio Leoni, Marco Lo Iacono, Barbara Sottero, Gabriella Testa, Serena Giannelli, Gabriella Leonarduzzi, and Paola Gamba
Antioxidants (Basel) 2022 Nov; 11(11): 2168
Published online 2022 Nov 1
doi: 10.3390/antiox11112168
Abstract
The strongest genetic risk factor for sporadic Alzheimer’s disease (AD) is the presence of the ε4 allele of the apolipoprotein E (ApoE) gene, the major apolipoprotein involved in brain cholesterol homeostasis. Being astrocytes the main producers of cholesterol and ApoE in the brain, we investigated the impact of the ApoE genotype on astrocyte cholesterol homeostasis. Two mouse astrocytic cell lines expressing the human ApoE3 or ApoE4 isoform were employed. Gas chromatography–mass spectrometry (GC-MS) analysis pointed out that the levels of total cholesterol, cholesterol precursors, and various oxysterols are altered in ApoE4 astrocytes. Moreover, the gene expression analysis of more than 40 lipid-related genes by qRT-PCR showed that certain genes are up-regulated (e.g., CYP27A1) and others down-regulated (e.g., PPARγ, LXRα) in ApoE4, compared to ApoE3 astrocytes. Beyond confirming the significant reduction in the levels of PPARγ, a key transcription factor involved in the maintenance of lipid homeostasis, Western blotting showed that both intracellular and secreted ApoE levels are altered in ApoE4 astrocytes, as well as the levels of receptors and transporters involved in lipid uptake/efflux (ABCA1, LDLR, LRP1, and ApoER2). Data showed that the ApoE genotype clearly affects astrocytic cholesterol homeostasis; however, further investigation is needed to clarify the mechanisms underlying these differences and the consequences on neighboring cells. Indeed, drug development aimed at restoring cholesterol homeostasis could be a potential strategy to counteract AD.

October 2022

APOE alleles modulate associations of plasma metabolites with variants from multiple genes on chromosome 19q13.3

https://www.frontiersin.org/articles/10.3389/fnagi.2022.1023493/full
Alireza Nazarian, Elena Loiko,, Hussein N. Yassine,, Caleb E. Finch, Alexander M. Kulminski1
Frontiers in Aging Neuroscience, 2022 Oct 28;14:1023493
28 October 2022
DOI: 10.3389/fnagi.2022.1023493
Abstract
The APOE ε2, ε3, and ε4 alleles differentially impact various complex diseases and traits. We examined whether these alleles modulated associations of 94 single-nucleotide polymorphisms (SNPs) harbored by 26 genes in 19q13.3 region with 217 plasma metabolites using Framingham Heart Study data. The analyses were performed in the E2 (ε2ε2 or ε2ε3 genotype), E3 (ε3ε3 genotype), and E4 (ε3ε4 or ε4ε4 genotype) groups separately. We identified 31, 17, and 22 polymorphism-metabolite associations in the E2, E3, and E4 groups, respectively, at a false discovery rate P FDR < 0.05. These entailed 51 and 19 associations with 20 lipid and 12 polar analytes. Contrasting the effect sizes between the analyzed groups showed 20 associations with group-specific effects at Bonferroni-adjusted P < 7.14E-04. Three associations with glutamic acid or dimethylglycine had significantly larger effects in the E2 than E3 group and 12 associations with triacylglycerol 56:5, lysophosphatidylethanolamines 16:0, 18:0, 20:4, or phosphatidylcholine 38:6 had significantly larger effects in the E2 than E4 group. Two associations with isocitrate or propionate and three associations with phosphatidylcholines 32:0, 32:1, or 34:0 had significantly larger effects in the E4 than E3 group. Nine of 70 SNP-metabolite associations identified in either E2, E3, or E4 groups attained P FDR < 0.05 in the pooled sample of these groups. However, none of them were among the 20 group-specific associations. Consistent with the evolutionary history of the APOE alleles, plasma metabolites showed higher APOE-cluster-related variations in the E4 than E2 and E3 groups. Pathway enrichment mainly highlighted lipids and amino acids metabolism and citrate cycle, which can be differentially impacted by the APOE alleles. These novel findings expand insights into the genetic heterogeneity of plasma metabolites and highlight the importance of the APOE-allele-stratified genetic analyses of the APOE-related diseases and traits.

The Ancestral ApoE4 Gene: Friend or Foe?

https://www.apollohealthco.com/the-ancestral-apoe4-gene-friend-or-foe/?fbclid=IwAR0MbKHfp7Yqp5mNm6XXqtedmRzKGeX8GBzyAeY-dQ60D8TsHyFiZRmjYQ0
By Ram Rao, Ph.D., Principal Research Scientist for Apollo Health
ApolloHealth, October 20, 2022
October 20, 2022
Apolipoprotein E (ApoE) is a protein that helps carry cholesterol around the body. ApoE comes in mainly three forms-ε2, ε3 and ε4. We all inherit a copy of some form of ApoE from each parent. The ApoE3 variant is thought to have occurred through a mutation around 220,000 years ago and is the dominant version. The ApoE2 variant is thought to have appeared around 70,000 years ago. The ApoE4 variant is the oldest, evolutionarily speaking, and having one or two copies of the ApoE4 variant increases the risk of developing Alzheimer’s disease (AD). About 25 percent of people carry one copy of ApoE4 and develop the disease by age 85. The risk for AD rises to 55 percent for the 2 to 3% of people that carry two copies of ApoE4. In addition to raising risk, the ApoE4 variant may tend to make symptoms appear at a younger age than usual.
Interestingly, there appears to be a close connection between the ancestral ApoE4, inflammation, and walking upright on two legs which is the trait that defines the hominid lineage. When our ancestors-the hominids-descended from the trees and started walking on the savanna, they had to survive injuries to the feet and serious wounds during long hunts. Furthermore, they had to overcome infections from bodily injuries, poor hygiene, or eating raw meat. They very likely went long periods without eating and physically labored as hunter-gatherers to find food. They would have been awakened by the sunrise and slept with the sunset and would have been least exposed to modern aspects of living (stress, pollution, processed and/or fast foods or food on demand, autos, electronic devices, poor sleeping habits, etc.). In these situations and more, they would have survived thanks to a robust and protective inflammatory response triggered by ApoE4 together with other inflammatory genes.
However, in a process called antagonistic pleiotrophy, in which a gene promotes wellness and fitness early in life at the expense of longevity, the same ApoE4 now turns out to be the adversary of modern man, whose lifespan increased from 25+ to 65+ years. Increased lifespan, together with better comforts and a modern lifestyle, brought with it the negative aspect of ApoE4 in the form of ApoE4-triggered inflammation, which is now linked to AD. Thus, in today’s world, it is more likely that people who inherit one or two copies of ApoE4 will develop the inflammatory subtype of AD. In people that carry two copies of ApoE4, AD symptoms may begin very early (40+ years of age). Inflammatory AD is accompanied by increased levels of several inflammatory molecules like C-reactive protein, tumor necrosis factor, and IL6. In addition to promoting inflammation, ApoE4 increases the amounts of misfolded Aβ and Tau in the brain. ApoE4 slows the degradation and elimination of misfolded Aβ aggregates and exacerbates the cellular damage caused by misfolded Tau tangles. Research studies also point to ApoE4’s role in blocking the microglial response to Aβ accumulation, suppressing autophagy, and inhibiting the disposal of damaged mitochondria, thereby perturbing cellular energy metabolism. Furthermore, ApoE4 damages blood vessels in the brain and makes them leaky, slowing down cerebral blood flow.
Thus, in the present modern and industrialized world, ApoE4 is considered a purely deleterious allele, increasing inflammation and lipid levels and escalating the risk of inflammatory-associated diseases. However, inheriting one or both copies of the ApoE4 allele does not mean that a person will definitely develop AD. Some people with the ApoE4 allele never get the disease, and others who develop AD do not have the ApoE4 allele. Thus, it appears that not all of ApoE4 is Mr. Hyde, as it also has a friendlier Dr. Jekyll’s face. It appears that in a high-pathogen, insufficient food, and an energy-limited environment, carrying an ApoE4 allele may actually be beneficial. Most of the benefits associated with ApoE4 come from studies on indigenous tribes that live in remote, tropical rainforests. One such tribe is the Tsimane of lowland Bolivia. This is an indigenous forager-farmer population living in small, mobile, hunter-gathering groups without access to sanitation or clean water, with high infectious morbidity, inflammation, and shortened life expectancy. A preliminary study of genetic markers in the Tsimane suggests some notable differences in ApoE allele frequencies relative to other populations. For example, ApoE4 and not ApoE2 is the predominant gene in this relatively large sample of Tsimane subjects, which is consistent with studies of other Amazonian tribes, Mayans of Mexico, and Australian aborigines. Contrary to observations in industrial populations, E4 carriers with a high parasite burden either maintained or showed improvements in cognitive performance, whereas non-E4 carriers with a high parasite burden showed reduced cognitive performance. Similarly, adults with high eosinophil counts (indicative of parasitic infection or a severe allergic reaction) and who carried at least one copy of the E4 allele showed better cognitive performance than did non-carriers indicating a protective effect of ApoE4 on cognition when exposed to environmental insults. Other studies have found evidence of protective interactions between ApoE4 alleles, testosterone, and estrogen. In all these cases, free testosterone, estrogen, and physical exercise enhanced memory performance in ApoE4 carriers. Considered together, the evidence suggests that the impact of the ApoE4 allele is not always deleterious and may be adaptive and beneficial in some populations with a high infectious burden. In a subgroup analysis of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) study, ApoE4 carriers had a better and faster improvement in terms of cognitive benefits from a multipronged intervention compared to non-ApoE4 carriers. This is good news for people who worry that having an ApoE4 gene may hinder healthy lifestyle changes’ potential benefits. While ApoE4 carriers have higher lipid levels, these may be beneficial for immune response and survival and unlikely to increase cardiovascular risk without other cardio-metabolic risk factors. Thus, despite being present in an industrialized, hyper-competitive, and stressful environment, ApoE4 carriers could still reap the benefits associated with their forest-dwelling ancestors. At Apollo health, we have the ReCODE Program™ which is based largely on diet, physical and mental exercise, sleep, detox, stress management, and supplementation. The program is very congruent with the ancestral lifestyle, including an emphasis on whole, low-glycemic index foods, lots of vegetables (preferably organic), clean protein, and a minimum of a 12-hour fast and physical exercise. Honoring the still primitive gene and following ancestral patterns to a greater extent will hopefully continue to reveal more of the friendlier face of the ApoE4 gene.

Radiosynthesis of 20-[18F]fluoroarachidonic acid for PET-MR imaging: Biological evaluation in ApoE4-TR mice

https://www.plefa.com/article/S0952-3278(22)00122-3/abstract
Juno Van Valkenburgh, Marlon Vincent V. Duro, Erica Burnham, Quan Chen, Shaowei Wang, Jenny Tran, Bilal E. Kerman, Sung Hee Hwang, Xiaodan Liu, Naomi S. Sta. Maria, Francesca Zanderigo, Etienne Croteau, Stanley I. Rapoport, Stephen C. Cunnane, Russell E. Jacobs, Hussein N. Yassine, Kai Chen
Prostaglandins, Leukotrienes & Essential Fatty Acids, 2022 Nov;186:102510
Epub 2022 Oct 20
DOI: 10.1016/j.plefa.2022.102510
Abstract
Dysreglulated brain arachidonic acid (AA) metabolism is involved in chronic inflammation and is influenced by apolipoprotein E4 (APOE4) genotype, the strongest genetic risk factor of late-onset Alzheimer's disease (AD). Visualization of AA uptake and distribution in the brain can offer insight into neuroinflammation and AD pathogenesis. Here we present a novel synthesis and radiosynthesis of 20-[18F]fluoroarachidonic acid ([18F]-FAA) for PET imaging using a convergent route and a one-pot, single-purification radiolabeling procedure, and demonstrate its brain uptake in human ApoE4 targeted replacement (ApoE4-TR) mice. By examining p38 phosphorylation in astrocytes, we found that fluorination of AA at the ω-position did not significantly alter its biochemical role in cells. The brain incorporation coefficient (K*) of [18F]-FAA was estimated via multiple methods by using an image-derived input function from the right ventricle of the heart as a proxy of the arterial input function and brain tracer concentrations assessed by dynamic PET-MR imaging. This new synthetic approach should facilitate the practical [18F]-FAA production and allow its translation into clinical use, making investigations of dysregulation of lipid metabolism more feasible in the study of neurodegenerative diseases.

Reimagining Alzheimer’s (Part 3): The APOE Story In Alzheimer’s And Other Diseases

https://www.forbes.com/sites/williamhaseltine/2022/10/17/reimagining-alzheimers-part-3-the-apoe-story-in-alzheimers-and-other-diseases/?sh=440a28527bb5&fbclid=IwAR1iMRB_lEmqeXPnIPSwxkNv3HlN5bPPi5A7cSAUcLqUWPN60HwQfS8OFVo
William A Haseltine, Forbes, Oct 17, 2022
Alzheimer’s is a serious disease that affects nearly 6 million people in the United States. Interestingly, some people have a much higher chance of developing Alzheimer’s than others, especially as they age. A principal risk factor of Alzheimer’s disease depends on a single gene called Apolipoprotein E (APOE). By having two copies of a particular APOE variant called APOE4, you become twenty times more likely to develop the disease. Although APOE4 is not the only inherited cause of Alzheimer’s, it is by far the most predominant. For this reason, APOE demands some special attention as to what it is and how it works.

Eicosanoid lipidome activation in post-mortem brain tissues of individuals with APOE4 and Alzheimer’s dementia

https://alzres.biomedcentral.com/articles/10.1186/s13195-022-01084-7
Brandon Ebright, Isaac Assante, Roy A. Poblete, Shaowei Wang, Marlon V. Duro, David A. Bennett, Zoe Arvanitakis, Stan G. Louie & Hussein N. Yassine
Alzheimer’s Research & Therapy 14, 152 (2022)
Published: 11 October 2022
Abstract
Background
Chronic neuroinflammation is one of the hallmarks of late-onset Alzheimer’s disease (AD) dementia pathogenesis. Carrying the apolipoprotein ε4 (APOE4) allele has been associated with an accentuated response to brain inflammation and increases the risk of AD dementia progression. Among inflammation signaling pathways, aberrant eicosanoid activation plays a prominent role in neurodegeneration.
Methods
Using brains from the Religious Order Study (ROS), this study compared measures of brain eicosanoid lipidome in older persons with AD dementia to age-matched controls with no cognitive impairment (NCI), stratified by APOE genotype.
Results
Lipidomic analysis of the dorsolateral prefrontal cortex demonstrated lower levels of omega-3 fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and DHA-derived neuroprotectin D1 (NPD-1) in persons with AD dementia, all of which associated with lower measures of cognitive function. A significant interaction was observed between carrying the APOE4 allele and higher levels of both pro-inflammatory lipids and pro-resolving eicosanoid lipids on measures of cognitive performance and on neuritic plaque burden. Furthermore, analysis of lipid metabolism pathways implicated activation of calcium-dependent phospholipase A2 (cPLA2), 5-lipoxygenase (5-LOX), and soluble epoxide hydrolase (sEH) enzymes.
Conclusion
These findings implicate activation of the eicosanoid lipidome in the chronic unresolved state of inflammation in AD dementia, which is increased in carriers of the APOE4 allele, and identify potential therapeutic targets for resolving this chronic inflammatory state.

Uncovering mechanisms of brain inflammation in Alzheimer's disease with APOE4: Application of single cell-type lipidomics

https://nyaspubs.onlinelibrary.wiley.com/doi/10.1111/nyas.14907
Isaac Asante, Stan Louie, Hussein N. Yassine
Annals of the New York Academy of Sciences 2022 Dec;1518(1):84-105
First published: 06 October 2022
DOI: https://doi.org/10.1111/nyas.14907
Abstract
A chronic state of unresolved inflammation in Alzheimer's disease (AD) is intrinsically involved with the remodeling of brain lipids. This review highlights the effect of carrying the apolipoprotein E ε4 allele (APOE4) on various brain cell types in promoting an unresolved inflammatory state. Among its pleotropic effects on brain lipids, we focus on APOE4’s activation of Ca2+-dependent phospholipase A2 (cPLA2) and its effects on arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid signaling cascades in the brain. During the process of neurodegeneration, various brain cell types, such as astrocytes, microglia, and neurons, together with the neurovascular unit, develop distinct inflammatory phenotypes that impact their functions and have characteristic lipidomic fingerprints. We propose that lipidomic phenotyping of single cell-types harvested from brains differing by age, sex, disease severity stage, and dietary and genetic backgrounds can be employed to probe mechanisms of neurodegeneration. A better understanding of the brain cellular inflammatory/lipidomic response promises to guide the development of nutritional and drug interventions for AD dementia.

Liver-ing in your head rent free: peripheral ApoE4 drives CNS pathology

https://link.springer.com/article/10.1186/s13024-022-00569-1?fbclid=IwAR3eAAIXljiDqSQ7HE-FjfMe03_HUyVWPqdv4GGLbTFLt5EnIV82RIKuhDo
Lesley R. Golden & Lance A. Johnson
Molecular Neurodegeneration, Volume 17, article number 65, (2022)
Published: 04 October 2022 No abstract, 1st paragraph:
The ε4 allele of Apolipoprotein E (APOE), which is carried by approximately one out of six individuals, remains the strongest known genetic risk factor for late-onset Alzheimer’s Disease (AD). Despite established roles in numerous peripheral disorders [1], the AD field has almost exclusively focused its APOE attention above the neck. This makes sense taken at face value, as the two major pools of ApoE protein – peripheral (hepatocyte-derived) and CNS (primarily astrocyte-derived) – appear to remain separated by the blood–brain barrier (BBB) [2, 3]. However, mounting evidence suggests that regardless of any physical separation between these two pools, peripheral ApoE may still notably impact CNS function [4, 5]. In the latest issue of Nature Neuroscience, Liu et al. further explore the effects of peripheral to CNS ApoE cross-talk, reporting detrimental outcomes on brain function and AD-associated pathologies following peripheral-only expression of ApoE4 [6].

Reimagining Alzheimer’s (Part 2): Breaking The Barrier

https://www.forbes.com/sites/williamhaseltine/2022/10/03/reimagining-alzheimers-part-2-breaking-the-barrier/?sh=4638671628bc
William A Haseltine, Forbes, 03 Oct 2022
03 Oct 2022
Here, we take a deeper dive into the disease by focusing on a recent paper that explores the primary genetic risk factor of Alzheimer’s. This risk factor is APOE4. Now, researchers believe that APOE4 may induce Alzheimer’s disease by damaging the brain’s main defense system—the blood-brain barrier.

September 2022

Implications of Microorganisms in Alzheimer’s Disease

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9600878/
Pardeep Yadav,Yeon-Hee Lee, Hrithika Panday, Shubham Kant, Neha Bajwa, Ritika Parashar, Saurabh Kumar Jha, Niraj Kumar Jha, Parma Nand, Sang-Soo Lee, and Abhimanyu Kumar Jha
Current Issues in Molecular Biology 2022 Sep 30;44(10):4584-4615
Published online 2022 Sep 30
doi: 10.3390/cimb44100314
Abstract
Alzheimer’s disease (AD) is a deadly brain degenerative disorder that leads to brain shrinkage and dementia. AD is manifested with hyperphosphorylated tau protein levels and amyloid beta (Aβ) peptide buildup in the hippocampus and cortex regions of the brain. The nervous tissue of AD patients also contains fungal proteins and DNA which are linked to bacterial infections, suggesting that polymicrobial infections also occur in the brains of those with AD. Both immunohistochemistry and next-generation sequencing (NGS) techniques were employed to assess fungal and bacterial infections in the brain tissue of AD patients and non-AD controls, with the most prevalent fungus genera detected in AD patients being Alternaria, Botrytis, Candida, and Malassezia. Interestingly, Fusarium was the most common genus detected in the control group. Both AD patients and controls were also detectable for Proteobacteria, followed by Firmicutes, Actinobacteria, and Bacteroides for bacterial infection. At the family level, Burkholderiaceae and Staphylococcaceae exhibited higher levels in the brains of those with AD than the brains of the control group. Accordingly, there is thought to be a viscous cycle of uncontrolled neuroinflammation and neurodegeneration in the brain, caused by agents such as the herpes simplex virus type 1 (HSV1), Chlamydophila pneumonia, and Spirochetes, and the presence of apolipoprotein E4 (APOE4), which is associated with an increased proinflammatory response in the immune system. Systemic proinflammatory cytokines are produced by microorganisms such as Cytomegalovirus, Helicobacter pylori, and those related to periodontal infections. These can then cross the blood–brain barrier (BBB) and lead to the onset of dementia. Here, we reviewed the relationship between the etiology of AD and microorganisms (such as bacterial pathogens, Herpesviridae viruses, and periodontal pathogens) according to the evidence available to understand the pathogenesis of AD. These findings might guide a targeted anti-inflammatory therapeutic approach to AD.

Common human genetic variants of APOE impact murine COVID-19 mortality

https://www.nature.com/articles/s41586-022-05344-2
Benjamin N. Ostendorf, Mira A. Patel, Jana Bilanovic, H.-Heinrich Hoffmann, Sebastian E. Carrasco, Charles M. Rice & Sohail F. Tavazo
Nature 611, 346–351 (2022)
Published 21 September 2022
DOI: https://doi.org/10.1038/s41586-022-05344-2
Abstract
Clinical outcomes of severe acute respiratory syndrome 2 (SARS-CoV-2) infection are highly heterogeneous, ranging from asymptomatic infection to lethal coronavirus disease 2019 (COVID-19). The factors underlying this heterogeneity remain insufficiently understood. Genetic association studies have suggested that genetic variants contribute to the heterogeneity of COVID-19 outcomes, but the underlying potential causal mechanisms are insufficiently understood. Here we show that common variants of the apolipoprotein E (APOE) gene, homozygous in approximately 3% of the world’s population1 and associated with Alzheimer’s disease, atherosclerosis and anti-tumour immunity2,3,4,5, affect COVID-19 outcome in a mouse model that recapitulates increased susceptibility conferred by male sex and advanced age. Mice bearing the APOE2 or APOE4 variant exhibited rapid disease progression and poor survival outcomes relative to mice bearing the most prevalent APOE3 allele. APOE2 and APOE4 mice exhibited increased viral loads as well as suppressed adaptive immune responses early after infection. In vitro assays demonstrated increased infection in the presence of APOE2 and APOE4 relative to APOE3, indicating that differential outcomes are mediated by differential effects of APOE variants on both viral infection and antiviral immunity. Consistent with these in vivo findings in mice, our results also show that APOE genotype is associated with survival in patients infected with SARS-CoV-2 in the UK Biobank (candidate variant analysis, P = 2.6 × 10−7). Our findings suggest APOE genotype to partially explain the heterogeneity of COVID-19 outcomes and warrant prospective studies to assess APOE genotyping as a means of identifying patients at high risk for adverse outcomes.

Alzheon Reports Industry-Leading Biomarker, Brain Preservation and Clinical Effects Following 12 Months of Treatment in Phase 2 Trial of Oral ALZ-801 (Valiltramiprosate) in Patients with Early Alzheimer’s Disease

https://www.businesswire.com/news/home/20220920005110/en/Alzheon-Reports-Industry-Leading-Biomarker-Brain-Preservation-and-Clinical-Effects-Following-12-Months-of-Treatment-in-Phase-2-Trial-of-Oral-ALZ-8
Business Wire September 20, 2022
• 41% Reduction in Plasma P-tau181 from Baseline to 12 Months, Suggests Robust Disease Modification in Carriers of One or Two Copies of APOE4 Gene who Represent Two Thirds of Alzheimer’s Patients
• Unprecedented Preservation of Hippocampal Volume Compared to Matched Group from AD Neuroimaging Initiative Indicates Neuroprotective Effects on Brain Structures: First & Only Treatment Showing Reduction of Brain Atrophy
• Improvement from Baseline on Memory Tests at 3 and 6 Months, and Maintained Above Baseline at 1-Year Timepoint, Consistent with Biomarker & Brain Imaging Effects on Core Alzheimer’s Pathologies
• Safety profile in ALZ-801 Studies Remains Favorable & Consistent with Prior Data in Over 2,000 AD Patients, with no Evidence of Vasogenic Brain Edema

Shooting Themselves in the Foot? Microglia Block “Good” State with ApoE4

https://www.alzforum.org/news/conference-coverage/shooting-themselves-foot-microglia-block-good-state-apoe4
Alzheimer's Association International Conference (AAIC) - 2022 coverage, ALZForum 09 Sep 2022
• ApoE4 made in microglia stymies these cells' protective responses to Aβ and tau pathology.
• In meninges, myeloid cells produce ApoE4, and lymphatic vessels expand in E4 mice.
• At the blood-brain barrier, ApoE4 triggers profound gene expression changes.

Regular proton pump inhibitor use and incident dementia: population-based cohort study

https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-022-02478-y?fbclid=IwAR0AfyKHk10HernO6Eb8QKWGA-BbGvM0stPhsT619S3MRX2IE9gAy-Vd_pQ
Peidong Zhang, Zhihao Li, Peiliang Chen, Ao Zhang, Yu Zeng, Xiru Zhang, Qingmei Huang, Dan Liu, Songtao Qi & Chen Mao
BMC Medicine volume 20, Article number: 271 (2022)
Published: 01 September 2022
DOI: https://doi.org/10.1186/s12916-022-02478-y
Abstract
Background
To examine the association between regular use of proton pump inhibitors and the risk of incident dementia, including dementia subtypes, and whether the association differs between APOE genotypes.
Methods
Based on a prospective analysis of data from the UK Biobank, 501,002 individuals (female, 54.4%) aged between 40 and 70 years, who had no prevalent dementia at baseline, were enrolled between 2006 and 2010 and followed up to 2018. We compared all-cause dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) incidence rates between proton pump inhibitor users and non-users by the Cox proportional hazard model.
Results
During 4,438,839 person-years of follow-up (median length of follow-up, 9.0 years), there were 2505 incident cases of all-cause dementia, including 932 cases of AD and 524 cases of VaD. The incident rate of all-cause dementia among proton pump inhibitor users was 1.06 events per 1000 person-years, compared with 0.51 events per 1000 person-years among non-users. After adjustment for multiple confounders and indications, the hazard ratios (HRs) of the proton pump inhibitor users were 1.20 (95% CI, 1.07–1.35) for incident all-cause dementia, 1.23 (95% CI, 1.02–1.49) for incident AD, and 1.32 (95% CI, 1.05–1.67) for incident VaD. In addition, the association between proton pump inhibitor use and all-cause dementia differed by APOE genotype (P for interaction = 0.048). Among APOE ε4 heterozygotes, the fully adjusted HR of proton pump inhibitor use was 1.46 (95% CI, 1.22–1.75) and 1.68 (95% CI, 1.36–2.07), especially for individuals aged 65 years and older.
Conclusions
The finding of this large population-based cohort study indicates that the use of proton pump inhibitors is associated with an increased risk of incident dementia, particularly among APOE ε4 heterozygotes.

August 2022

Apolipoprotein E in Cardiometabolic and Neurological Health and Diseases

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9456500/
Jeyashree Alagarsamy, Anja Jaeschke, and David Y. Hui
International Journal of Molecular Sciences, 2022 Sep; 23(17): 9892
Published online 2022 Aug 31
doi: 10.3390/ijms23179892
Abstract
A preponderance of evidence obtained from genetically modified mice and human population studies reveals the association of apolipoprotein E (apoE) deficiency and polymorphisms with pathogenesis of numerous chronic diseases, including atherosclerosis, obesity/diabetes, and Alzheimer’s disease. The human APOE gene is polymorphic with three major alleles, ε2, ε3 and ε4, encoding apoE2, apoE3, and apoE4, respectively. The APOE gene is expressed in many cell types, including hepatocytes, adipocytes, immune cells of the myeloid lineage, vascular smooth muscle cells, and in the brain. ApoE is present in subclasses of plasma lipoproteins, and it mediates the clearance of atherogenic lipoproteins from plasma circulation via its interaction with LDL receptor family proteins and heparan sulfate proteoglycans. Extracellular apoE also interacts with cell surface receptors and confers signaling events for cell regulation, while apoE expressed endogenously in various cell types regulates cell functions via autocrine and paracrine mechanisms. This review article focuses on lipoprotein transport-dependent and -independent mechanisms by which apoE deficiency or polymorphisms contribute to cardiovascular disease, metabolic disease, and neurological disorders.

A “multi-omics” analysis of blood–brain barrier and synaptic dysfunction in APOE4 mice

https://rupress.org/jem/article/219/11/e20221137/213428/A-multi-omics-analysis-of-blood-brain-barrier-and
Giuseppe Barisano, Kassandra Kisler, Brent Wilkinson, Angeliki Maria Nikolakopoulou, Abhay P. Sagare, Yaoming Wang, William Gilliam, Mikko T. Huuskonen, Shu-Ting Hung, Justin K. Ichida, Fan Gao, Marcelo P. Cobak, Berislav V. Zlokovic
Journal of Experimental Medicine (JEM) (2022) 219 (11): e20221137
August 30 2022
DOI: https://doi.org/10.1084/jem.20221137
Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer’s disease, leads to blood–brain barrier (BBB) breakdown in humans and mice. Remarkably, BBB dysfunction predicts cognitive decline and precedes synaptic deficits in APOE4 human carriers. How APOE4 affects BBB and synaptic function at a molecular level, however, remains elusive. Using single-nucleus RNA-sequencing and phosphoproteome and proteome analysis, we show that APOE4 compared with APOE3 leads to an early disruption of the BBB transcriptome in 2–3-mo-old APOE4 knock-in mice, followed by dysregulation in protein signaling networks controlling cell junctions, cytoskeleton, clathrin-mediated transport, and translation in brain endothelium, as well as transcription and RNA splicing suggestive of DNA damage in pericytes. Changes in BBB signaling mechanisms paralleled an early, progressive BBB breakdown and loss of pericytes, which preceded postsynaptic interactome disruption and behavioral deficits that developed 2–5 mo later. Thus, dysregulated signaling mechanisms in endothelium and pericytes in APOE4 mice reflect a molecular signature of a progressive BBB failure preceding changes in synaptic function and behavior.

The inter-relationship between delirium and dementia: the importance of delirium prevention

https://www.nature.com/articles/s41582-022-00698-7?fbclid=IwAR3uVdHU-7SEKCxKAx6ov2zX8jd2cmvrx9Qeyio0lS7DDncspTcJLUtNuL8
Tamara G. Fong & Sharon K. Inouye
Nature Reviews Neurology volume 18, pages579–596 (2022)
Published: 26 August 2022
DOI: https://doi.org/10.1038/s41582-022-00698-7
Abstract
Delirium and dementia are two frequent causes of cognitive impairment among older adults and have a distinct, complex and interconnected relationship. Delirium is an acute confusional state characterized by inattention, cognitive dysfunction and an altered level of consciousness, whereas dementia is an insidious, chronic and progressive loss of a previously acquired cognitive ability. People with dementia have a higher risk of developing delirium than the general population, and the occurrence of delirium is an independent risk factor for subsequent development of dementia. Furthermore, delirium in individuals with dementia can accelerate the trajectory of the underlying cognitive decline. Delirium prevention strategies can reduce the incidence of delirium and associated adverse outcomes, including falls and functional decline. Therefore, delirium might represent a modifiable risk factor for dementia, and interventions that prevent or minimize delirium might also reduce or prevent long-term cognitive impairment. Additionally, understanding the pathophysiology of delirium and the connection between delirium and dementia might ultimately lead to additional treatments for both conditions. In this Review, we explore mechanisms that might be common to both delirium and dementia by reviewing evidence on shared biomarkers, and we discuss the importance of delirium recognition and prevention in people with dementia.
Key points
• Delirium and dementia are frequent causes of cognitive impairment among older adults and have a distinct, complex and interconnected relationship.
• Delirium prevention strategies have been shown to reduce not only the incidence of delirium but also the incidence of adverse outcomes associated with delirium such as falls and functional decline.
• Adverse outcomes associated with delirium, such as the onset of dementia symptoms in individuals with preclinical dementia, and/or the acceleration of cognitive decline in individuals with dementia might also be delayed by the implementation of delirium prevention strategies.
• Evidence regarding the association of systemic inflammatory and neuroinflammatory biomarkers with delirium is variable, possibly as a result of co-occurring dementia pathology or disruption of the blood–brain barrier.
• Alzheimer disease pathology, even prior to the onset of symptoms, might have an effect on delirium risk, with potential mechanisms including neuroinflammation and gene–protein interactions with the APOE ε4 allele.
• Novel strategies, including proteomics, multi-omics, neuroimaging, transcranial magnetic stimulation and EEG, are beginning to reveal how changes in cerebral blood flow, spectral power and connectivity can be associated with delirium; further work is needed to expand these findings to patients with delirium superimposed upon dementia.

Correlations between APOE4 allele and regional amyloid and tau burdens in cognitively normal older individuals

https://www.nature.com/articles/s41598-022-18325-2?fbclid=IwAR2cAPOqdPX_XBVRsN9bgOgorCL-wImdwB9-2YWqbeCSKkZaq-l7HRZ4XCk
Yun Jeong Hong, Chan-Mi Kim, Jae Hong Lee & Jorge Sepulcre
Scientific Reports volume 12, Article number: 14307 (2022)
Published: 22 August 2022
DOI: https://doi.org/10.1038/s41598-022-18325-2
Abstract
The correlations between apolipoprotein epsilon 4 (APOE4) status and regional amyloid, tau, and cortical thickness in cognitively normal elderly are not fully understood. Our cross-sectional study aimed to compare regional amyloid/tau burden, and cortical thickness according to APOE4 carrier status and assess correlations between APOE4 and Alzheimer’s disease (AD)-related biomarker burdens. We analyzed 185 cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Participants aged 55–90 with normal cognitive function were divided into amyloid ß-positive (Aß+) APOE4 carriers (group 1, n = 27), Aß+ APOE4 non-carriers (group 2, n = 29), and Aß− normal controls (group 0, n = 129). We compared amyloid depositions, tau depositions, and cortical thickness among the three groups and assessed correlations between APOE4 existence and imaging biomarkers adjusted for age and sex. The participants in group 2 were older than those in the other groups. The regional amyloid/tau standardized uptake value ratios (SUVRs) did not differ between groups 1 and 2, but the amyloid/tau SUVRs in most regions were numerically higher after adjusting for age difference. APOE4 allele had robust correlations with increased amyloid burden in the fronto-temporo-parietal cortical areas after adjustment for age and sex, but it had weaker and mixed correlations with the regional tau burden and did not have significant correlation with cortical thickness. We identified that the presence of APOE4 allele might be more highly associated with amyloid deposition than with other AD-related biomarkers such as tau or cortical thickness in cognitively normal elderly.

APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-κB activation

https://www.cell.com/cell-reports/fulltext/S2211-1247(22)01017-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124722010178%3Fshowall%3Dtrue
Laurie Arnaud, Philippe Benech, Louise Greetham, Delphine Stephan, Angélique Jimenez, Nicolas Jullien, Laura García-González, Philipp O. Tsvetkov, François Devred, Ignacio Sancho-Martinez, Juan Carlos Izpisua Belmonte, Kévin Baranger, Santiago Rivera, Emmanuel Nivet
Cell Reports VOLUME 40, ISSUE 7, 111200, AUGUST 16, 2022
AUGUST 16, 2022
DOI: https://doi.org/10.1016/j.celrep.2022.111200
Highlights
• hiPSC astrocytes carrying the APOEε4 allele feature a pro-inflammatory phenotype
• APOE4 associates with TAGLN3 downregulation and NF-κB activation in astrocytes
• TAGLN3 supplementation in APOE4 astrocytes reduces inflammatory responses
• TAGLN3 downregulation is a common trait in brains from patients with Alzheimer’s disease
Summary
Apolipoprotein E4 (APOEε4) is the major allelic risk factor for late-onset sporadic Alzheimer’s disease (sAD). Inflammation is increasingly considered as critical in sAD initiation and progression. Identifying brain molecular mechanisms that could bridge these two risk factors remain unelucidated. Leveraging induced pluripotent stem cell (iPSC)-based strategies, we demonstrate that APOE controls inflammation in human astrocytes by regulating Transgelin 3 (TAGLN3) expression and, ultimately, nuclear factor κB (NF-κB) activation. We uncover that APOE4 specifically downregulates TAGLN3, involving histone deacetylases activity, which results in low-grade chronic inflammation and hyperactivated inflammatory responses. We show that APOE4 exerts a dominant negative effect to prime astrocytes toward a pro-inflammatory state that is pharmacologically reversible by TAGLN3 supplementation. We further confirm that TAGLN3 is downregulated in the brain of patients with sAD. Our findings highlight the APOE-TAGLN3-NF-κB axis regulating neuroinflammation in human astrocytes and reveal TAGLN3 as a molecular target to modulate neuroinflammation, as well as a potential biomarker for AD

Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma

https://www.cell.com/immunity/fulltext/S1074-7613(22)00349-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1074761322003491%3Fshowall%3Dtrue
Milica A. Margeta, Zhuoran Yin, Charlotte Madore, Kristen M. Pitts, Sophia M. Letcher, Jing Tang, Shuhong Jiang, Christian D. Gauthier, Sebastian R. Silveira, Caitlin M. Schroeder, Eleonora M. Lad, Alan D. Proia, Rudolph E. Tanzi, David M. Holtzman, Susanne Krasemann, Dong Feng Chen, Oleg Butovsky
Immunity VOLUME 55, ISSUE 9, P1627-1644.E7, SEPTEMBER 13, 2022
Published:August 16, 2022
DOI: https://doi.org/10.1016/j.immuni.2022.07.014
Highlights
• Microglia switch from a homeostatic to a neurodegenerative phenotype in glaucoma
• Apoe and APOE3 induce Galectin-3, a key effector of neurodegenerative microglia
• Apoe−/− and APOE4 retinal microglia have a decreased response to neurodegeneration
•APOE4 allele protects against retinal ganglion cell (RGC) loss in glaucoma
Summary
The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here, we found that in two mouse glaucoma models, microglia transitioned to a neurodegenerative phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3), which were also upregulated in human glaucomatous retinas. Mice with targeted deletion of Apoe in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss, despite elevated intraocular pressure (IOP). Similarly to Apoe−/− retinal microglia, APOE4-expressing microglia did not upregulate neurodegeneration-associated genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma and that the APOE-Galectin-3 signaling can be targeted to treat this blinding disease.

APOE ε4 and Alzheimer's disease diagnosis associated differences in L-carnitine, GBB, TMAO, and acylcarnitines in blood and brain

https://www.sciencedirect.com/science/article/abs/pii/S2452318622000307?via%3Dihub
Claire J.C. Huguenard, Adam Cseresznye, James E. Evans, Teresa Darcey, Aurore Nkiliza, Andrew P. Keegan, Cheryl Luis, David A. Bennett, Zoe Arvanitakis, Hussein N. Yassine, Michael Mullan, Fiona Crawford, Laila Abdullah
Current Research in Translational Medicine Volume 71, Issue 1, January–March 2023, 103362
Available online 11 August 2022
DOI: https://doi.org/10.1016/j.retram.2022.103362
Summary
Background
The apolipoprotein E (APOE) ε4 allele, involved in fatty acid (FA) metabolism, is a major genetic risk factor for Alzheimer's disease (AD). This study examined the influence of APOE genotypes on blood and brain markers of the L-carnitine system, necessary for fatty acid oxidation (FAO), and their collective influence on the clinical and pathological outcomes of AD.
Methods
L-carnitine, its metabolites γ-butyrobetaine (GBB) and trimethylamine-n-oxide (TMAO), and its esters (acylcarnitines) were analyzed in blood from predominantly White community/clinic-based individuals (n = 372) and in plasma and brain from the Religious Order Study (ROS) (n = 79) using liquid chromatography tandem mass spectrometry (LC-MS/MS).
Findings
Relative to total blood acylcarnitines, levels of short chain acylcarnitines (SCAs) were higher whereas long chain acylcarnitines (LCAs) were lower in AD, which was observed pre-clinically in APOE ε4s. Plasma medium chain acylcarnitines (MCAs) were higher amongst cognitively healthy APOE ε2 carriers relative to other genotypes. Compared to their respective controls, elevated TMAO and lower L-carnitine and GBB were associated with AD clinical diagnosis and these differences were detected preclinically among APOE ε4 carriers. Plasma and brain GBB, TMAO, and acylcarnitines were also associated with post-mortem brain amyloid, tau, and cerebrovascular pathologies.
Interpretation
Alterations in blood L-carnitine, GBB, TMAO, and acylcarnitines occur early in clinical AD progression and are influenced by APOE genotype. These changes correlate with post-mortem brain AD and cerebrovascular pathologies. Additional studies are required to better understand the role of the FAO disturbances in AD.

Lipid Accumulation Induced by APOE4 Impairs Microglial Surveillance of Neuronal-Network Activity

https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00300-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1934590922003009%3Fshowall%3Dtrue
Matheus B. Victor, Noelle Leary, Xochitl Luna, Hiruy S. Meharena, Aine Ni Scannaill, P. Lorenzo Bozzelli, George Samaan, Mitchell H. Murdock, Djuna von Maydell, Audrey H. Effenberger, Oyku Cerit, Hsin-Lan Wen, Liwang Liu, Gwyneth Welch, Maeve Bonner, Li-Huei Tsai
Cell Stem Cell VOLUME 29, ISSUE 8, P1197-1212.E8, AUGUST 04, 2022
AUGUST 04, 2022
DOI:https://doi.org/10.1016/j.stem.2022.07.005
Highlights
• Microglia-like cells (iMGLs) respond to soluble factors secreted by neurons
• APOE4 renders iMGLs weakly responsive to neuronal activity
• APOE4 iMGLs disrupts the coordinated activity of neuronal ensembles
• Microglial lipid homeostasis is critical to sustain surveillance states
Summary
Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for developing sporadic Alzheimer’s disease. How the interaction of APOE4 microglia with neurons differs from microglia expressing the disease-neutral APOE3 allele remains unknown. Here, we employ CRISPR-edited induced pluripotent stem cells (iPSCs) to dissect the impact of APOE4 in neuron-microglia communication. Our results reveal that APOE4 induces a lipid-accumulated state that renders microglia weakly responsive to neuronal activity. By examining the transcriptional signatures of APOE3 versus APOE4 microglia in response to neuronal conditioned media, we established that neuronal cues differentially induce a lipogenic program in APOE4 microglia that exacerbates pro-inflammatory signals. Through decreased uptake of extracellular fatty acids and lipoproteins, we identified that APOE4 microglia disrupts the coordinated activity of neuronal ensembles. These findings suggest that abnormal neuronal network-level disturbances observed in Alzheimer’s disease patients harboring APOE4 may in part be triggered by impairment in lipid homeostasis in non-neuronal cells.

How Microglia Contribute to Alzheimer’s Disease

https://neurosciencenews.com/microglia-alzhiemers-21181/?fbclid=IwAR1TYOY45f4K918csxLAQFnocQqBz7FVMP65JT4MrnPXD7EC8eUEhC536tc
Source: MIT, Neuroscience News, August 4, 2022
Summary: Microglia that express the Alzheimer’s associated APOE4 genetic variant are unable to effectively metabolize lipids. This causes lipids to build up, promoting inflammation and preventing effective neurotransmission.

Peripheral apoE4 enhances Alzheimer’s pathology and impairs cognition by compromising cerebrovascular function

https://www.nature.com/articles/s41593-022-01127-0
Chia-Chen Liu, Jing Zhao, Yuan Fu, Yasuteru Inoue, Yingxue Ren, Yuanxin Chen, Sydney V. Doss, Francis Shue, Suren Jeevaratnam, Ligia Bastea, Na Wang, Yuka A. Martens, Wenhui Qiao, Minghui Wang, Na Zhao, Lin Jia, Yu Yamazaki, Akari Yamazaki, Cassandra L. Rosenberg, Zhen Wang, Dehui Kong, Zonghua Li, Lindsey A. Kuchenbecker, Zachary A. Trottier, Lindsey Felton, Justin Rogers, Zachary S. Quicksall, Cynthia Linares, Joshua Knight, Yixing Chen, Aishe Kurti, Takahisa Kanekiyo, John D. Fryer, Yan W. Asmann, Peter Storz, Xusheng Wang, Junmin Peng, Bin Zhang, Betty Y. S. Kim & Guojun Bu
Nature Neuroscience, 25, pages 1020–1033 (2022)
Published: 01 August 2022
DOI: https://doi.org/10.1038/s41593-022-01127-0
Abstract
The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer’s disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood–brain barrier, differentially impact Alzheimer’s disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young mice improved cognition and reduced vessel-associated gliosis when transfused into aged mice, whereas apoE4 compromised the beneficial effects of young plasma. A human induced pluripotent stem cell-derived endothelial cell model recapitulated the plasma apoE isoform-specific effect on endothelial integrity, further supporting a vascular-related mechanism. Upon breeding with amyloid model mice, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate pathogenic effects of peripheral apoE4, providing a strong rationale for targeting peripheral apoE to treat Alzheimer’s disease.

July 2022

Effects of Sex, APOE4, and Lifestyle Activities on Cognitive Reserve in Older Adults

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9484731/
Judy Pa, PhD, Vahan Aslanyan, BS, Kaitlin B. Casaletto, PhD, Miguel Arce Rentería, PhD, Amal Harrati, PhD, Sarah E. Tom, PhD, Nicole Armstrong, PhD, Kumar Rajan, PhD, Justina Avila-Rieger, PhD, Yian Gu, PhD, Nicole Schupf, PhD, Jennifer J. Manly, PhD, Adam Brickman, PhD, and Laura Zahodne, PhD
Neurology 2022 Aug 23; 99(8): e789–e798
Epub 2022 Jul 20
doi: 10.1212/WNL.0000000000200675
Abstract
Background and Objectives
Lifestyle activities, such as physical activity and cognitive stimulation, may mitigate age-associated cognitive decline, delay dementia onset, and increase cognitive reserve. Whether the association between lifestyle activities and cognitive reserve differs by sex and APOE4 status is an understudied yet critical component for informing targeted prevention strategies. The current study examined interactions between sex and physical or cognitive activities on cognitive reserve for speed and memory in older adults.
Methods
Research participants with unimpaired cognition, mild cognitive impairment, or dementia from the Washington Heights-Inwood Columbia Aging Cohort were included in this study. Cognitive reserve scores for speed and memory were calculated by regressing out hippocampal volume, total gray matter volume, and white matter hyperintensity volume from composite cognitive scores for speed and memory, respectively. Self-reported physical activity was assessed using the Godin Leisure Time Exercise Questionnaire, converted to metabolic equivalents (METS). Self-reported cognitive activity (COGACT) was calculated as the sum of 3 yes/no questions. Sex by activity interactions and sex-stratified analyses were conducted using multivariable linear regression models, including a secondary analysis with APOE4 as a moderating factor.
Results
Seven hundred fifty-eight participants (mean age = 76.11 ± 6.31 years, 62% women) were included in this study. Higher METS was associated with greater speed reserve in women (β = 0.04, CI 0.0–08) but not in men (β = 0.004, CI −0.04 to 0.05). METS was not associated with memory reserve in women or men. More COGACT was associated with greater speed reserve in the cohort (β = 0.13, CI 0.05–0.21). More COGACT had a trend for greater memory reserve in women (β = 0.06, CI −0.02 to 0.14) but not in men (β = −0.04, CI −0.16 to 0.08). Only among women, APOE4 carrier status attenuated relationships between METS and speed reserve (β = −0.09, CI −0.22 to 0.04) and between COGACT and both speed (β = −0.26, CI −0.63 to 0.11) and memory reserves (β = −0.20, CI −0.50.0 to 093).
Discussion
The associations of self-reported physical and cognitive activities with cognitive reserve are more pronounced in women, although APOE4 attenuates these associations. Future studies are needed to understand the causal relationship among sex, lifestyle activities, and genetic factors on cognitive reserve in older adults to best understand which lifestyle activities may be most beneficial and for whom.

Precision Medicine Approach to Alzheimer’s Disease: Successful Pilot Project

https://content.iospress.com/articles/journal-of-alzheimers-disease/jad215707
Toups, Kat, Hathaway, Ann, Gordon, Deborah, Chung, Henrianna, Raji, Cyrus Boyd, Alan, Hill, Benjamin D. Hausman-Cohen, Sharon, Attarha, Mouna, Chwa, Won Jong,, Jarrett, Michael,, Bredesen, Dale E.
Journal of Alzheimer’s Disease 88 (2022) 1411–1421
DOI: 10.3233/JAD-215707
Pre-press 4 July 2022
Abstract
Background:
Effective therapeutics for Alzheimer’s disease are needed. However, previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of the neurodegenerative process. Therefore, increasing data set size to include the potential contributors to cognitive decline for each patient, and addressing the identified potential contributors, may represent a more effective strategy. Objective: To determine whether a precision medicine approach to Alzheimer’s disease and mild cognitive impairment is effective enough in a proof-of-concept trial to warrant a larger, randomized, controlled clinical trial. Methods: Twenty-five patients with dementia or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Patients were treated for nine months with a personalized, precision medicine protocol, and cognition was assessed at t = 0, 3, 6, and 9 months. Results: All outcome measures revealed improvement: statistically significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and Alzheimer’s Questionnaire Change score were documented. No serious adverse events were recorded. MRI volumetrics also improved. Conclusion: Based on the cognitive improvements observed in this study, a larger, randomized, controlled trial of the precision medicine therapeutic approach described herein is warranted.
And from Methods section Four were homozygous for APOE4, 8 were heterozygous for APOE4,

June 2022

Vascular Dysfunction Is Central to Alzheimer’s Disease Pathogenesis in APOE e4 Carriers

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9266739/
Andrew N. McCorkindale, Hamish D. Mundell, Boris Guennewig, and Greg T. Sutherland
International Journal of Molecular Sciences 2022 Jul; 23(13): 7106
Published online 2022 Jun 26
doi: 10.3390/ijms23137106
Abstract
Alzheimer’s disease (AD) is the most common form of dementia and the leading risk factor, after age, is possession of the apolipoprotein E epsilon 4 allele (APOE4). Approximately 50% of AD patients carry one or two copies of APOE4 but the mechanisms by which it confers risk are still unknown. APOE4 carriers are reported to demonstrate changes in brain structure, cognition, and neuropathology, but findings have been inconsistent across studies. In the present study, we used multi-modal data to characterise the effects of APOE4 on the brain, to investigate whether AD pathology manifests differently in APOE4 carriers, and to determine if AD pathomechanisms are different between carriers and non-carriers. Brain structural differences in APOE4 carriers were characterised by applying machine learning to over 2000 brain MRI measurements from 33,384 non-demented UK biobank study participants. APOE4 carriers showed brain changes consistent with vascular dysfunction, such as reduced white matter integrity in posterior brain regions. The relationship between APOE4 and AD pathology was explored among the 1260 individuals from the Religious Orders Study and Memory and Aging Project (ROSMAP). APOE4 status had a greater effect on amyloid than tau load, particularly amyloid in the posterior cortical regions. APOE status was also highly correlated with cerebral amyloid angiopathy (CAA). Bulk tissue brain transcriptomic data from ROSMAP and a similar dataset from the Mount Sinai Brain Bank showed that differentially expressed genes between the dementia and non-dementia groups were enriched for vascular-related processes (e.g., “angiogenesis”) in APOE4 carriers only. Immune-related transcripts were more strongly correlated with AD pathology in APOE4 carriers with some transcripts such as TREM2 and positively correlated with pathology severity in APOE4 carriers, but negatively in non-carriers. Overall, cumulative evidence from the largest neuroimaging, pathology, and transcriptomic studies available suggests that vascular dysfunction is key to the development of AD in APOE4 carriers. However, further studies are required to tease out non-APOE4-specific mechanisms.

Untangling the APOE4 Gene, the Most Significant Genetic Risk Factor for Alzheimer’s Disease

https://neurosciencenews.com/apoe4-genetics-alzheimers-20897/?fbclid=IwAR2AD9QkGLWP8EiLkujvTx4t2ZXK09vJo7xqJA3xOI__IjC920V2Y_-s4G4
Source: Boston University, Neuroscience News, June 23, 2022
Summary: The genetic background around APOE region can modify the Alzheimer’s disease-associated APOE4 risk effects.

Early and lifelong effects of APOE4 on neuronal gene expression networks relevant to Alzheimer’s disease

https://www.biorxiv.org/content/10.1101/2022.06.16.496371v1?fbclid=IwAR1NLJ_h8wnfjo62bMZh6-draRfTU1F1cCjncv0Fq8J8iYCVinMFaQwXlLE
Brian P. Grone, Kelly A. Zalocusky, Yanxia Hao, Seo Yeon Yoon, Patrick Arriola, Yadong Huang
bioRxiv 2022.06.16.496371
Posted June 17, 2022 (preprint)
doi: https://doi.org/10.1101/2022.06.16.496371
Abstract
Apolipoprotein E4 (APOE4) genotype and aging are critical risk factors for Alzheimer’s disease (AD). Aged APOE4 knock-in (APOE4-KI) mice have phenotypes reflecting features of AD. We conducted a large-scale single nucleus RNA-sequencing study to identify cell-type-specific effects of APOE4 on hippocampal gene expression during aging. APOE4-KI mice showed prominent alterations, relative to APOE3-KI mice, in neuronal transcriptome related to synaptic function, calcium signaling, and MAPK/Rap1/Pld signal transduction, starting by 5 months and persisting during aging. Mice with the APOE4 gene removed specifically from neurons failed to show most of these neuronal transcriptomic changes, suggesting a specific effect of neuron-derived APOE4 on the transcriptome. APOE4 affects similar cellular pathways in induced pluripotent stem cell-derived human neurons transplanted into APOE4-KI mouse hippocampus and in cortical neurons from aged human brains. Thus, neuronal APOE4 has early and persistent effects on neuronal transcriptomes, suggesting the requirement of early interventions for successfully treating APOE4-related AD.

Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4

https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-022-00549-5?fbclid=IwAR2aDBx2pOBVHoaW4K9abshsvv1wlSXMbYfQSJB8DGhdizUlTbE7I8aRn6I
Shaowei Wang, Boyang Li, Victoria Solomon, Alfred Fonteh, Stanley I. Rapoport, David A. Bennett, Zoe Arvanitakis, Helena C. Chui, Patrick M. Sullivan & Hussein N. Yassine
Molecular Neurodegeneration volume 17, Article number: 42 (2022)
Published: 15 June 2022
DOI: https://doi.org/10.1186/s13024-022-00549-5
Abstract
Background
Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer’s disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. The relation between APOE4 genotype and cPLA2 activity is not known.
Methods
Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress.
Results
Greater cPLA2 phosphorylation, cPLA2 activity and leukotriene B4 (LTB4) levels were identified in ApoE4 compared to ApoE3 in primary astrocytes, brains of ApoE-targeted replacement (ApoE-TR) mice, and in human brain homogenates from the inferior frontal cortex of persons with AD dementia carrying APOE3/4 compared to APOE3/3. Higher phosphorylated p38 MAPK but not ERK1/2 was found in ApoE4 primary astrocytes and mouse brains than that in ApoE3. Greater cPLA2 translocation to cytosol was observed in human postmortem frontal cortical synaptosomes with recombinant ApoE4 than ApoE3 ex vivo. In ApoE4 astrocytes, the greater levels of LTB4, reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) were reduced after cPLA2 inhibition.
Conclusions
Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.

May 2022

DHA-Enriched Fish Oil Ameliorates Deficits in Cognition Associated with Menopause and the APOE4 Genotype in Rodents

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103304/
Matthew G. Pontifex, Anneloes Martinsen, Rasha N. M. Saleh, Glenn Harden, Chris Fox, Michael Muller, David Vauzour, and Anne-Marie Minihane1 Nutrients 2022 May; 14(9): 1698
Published online 2022 Apr 19
doi: 10.3390/nu14091698
Abstract
Female APOE4 carriers have a greater predisposition to developing Alzheimer’s disease (AD) compared to their male counterparts, which may partly be attributed to menopause. We previously reported that a combination of menopause and APOE4 led to an exacerbation of cognitive and neurological deficits, which were associated with reduced brain DHA and DHA:AA ratio. Here, we explored whether DHA-enriched fish oil (FO) supplementation mitigated the detrimental impact of these risk factors. Whilst DHA-enriched fish oil improved recognition memory (NOR) in APOE4 VCD (4-vinylcyclohexene diepoxide)-treated mice (p < 0.05), no change in spatial working memory (Y-maze) was observed. FO supplementation increased brain DHA and nervonic acid and the DHA:AA ratio. The response of key bioenergetic and blood–brain barrier related genes and proteins provided mechanistic insights into these behavioural findings, with increased BDNF protein concentration as well as mitigation of aberrant Erβ, Cldn1 and Glut-5 expression in APOE4 mice receiving fish oil supplementation (p < 0.05). In conclusion, supplementation with a physiologically relevant dose of DHA-enriched fish oil appears to offer protection against the detrimental effects of menopause, particularly in “at-risk” APOE4 female carriers.

A rare mutation protects against Alzheimer's disease, Stanford-led research finds

https://med.stanford.edu/news/all-news/2022/05/gene-mutation-alzheimers.html?fbclid=IwAR16VAQALfUnvVkioVDFhZjuIllt4DMyeJ5zT8ZNMxN6QeSwhcsea1fc1iE

By Hadley Leggett Stanford Medicine, May 31, 2022 Researchers have discovered that a rare mutation inherited with the APOE4 gene variant protects against Alzheimer's, shedding new light on ways to counteract high-risk genes for the disease.

A Review of ApoE4 Interference Targeting Mitophagy Molecular Pathways for Alzheimer's Disease

https://www.frontiersin.org/articles/10.3389/fnagi.2022.881239/full?fbclid=IwAR04XYRiXutM9z3swmMPlVce1r73xXF9NbQHlDx1aGWTZxvkDf1OTwKQzlw
Huiyi Chen, Feng Chen, Ying Jiang, Lu Zhang, Guizhen Hu, Furong Sun, Miaoping Zhang, Yao Ji Yanting Chen, Gang Che, Xu Zhou, Yu Zhang Frontiers in Aging Neuroscience, 20 May 2022 Sec. Neuroinflammation and Neuropathy Volume 14 - 2022
20 May 2022
DOI: https://doi.org/10.3389/fnagi.2022.881239
Alzheimer's disease (AD) is one of the major worldwide causes of dementia that is characterized by irreversible decline in learning, memory loss, and behavioral impairments. Mitophagy is selective autophagy through the clearance of aberrant mitochondria, specifically for degradation to maintain energy generation and neuronal and synaptic function in the brain. Accumulating evidence shows that defective mitophagy is believed to be as one of the early and prominent features in AD pathogenesis and has drawn attention in the recent few years. APOE ε4 allele is the greatest genetic determinant for AD and is widely reported to mediate detrimental effects on mitochondria function and mitophagic process. Given the continuity of the physiological process, this review takes the mitochondrial dynamic and mitophagic core events into consideration, which highlights the current knowledge about the molecular alterations from an APOE-genotype perspective, synthesizes ApoE4-associated regulations, and the cross-talk between these signaling, along with the focuses on general autophagic process and several pivotal processes of mitophagy, including mitochondrial dynamic (DRP1, MFN-1), mitophagic induction (PINK1, Parkin). These may shed new light on the link between ApoE4 and AD and provide novel insights for promising mitophagy-targeted therapeutic strategies for AD.

April 2022

#74 Dr. Dominic D'Agostino on Developing a Well-Designed Ketogenic Diet and Harnessing its Benefits

https://www.foundmyfitness.com/episodes/dominic-dagostino-2?fbclid=IwAR0V-37_3sqClhxDmF6UJJDsX82DZcXaYVTPapChq7jip-ZLsyYT2czaeuQ
Found My Fitness (Dr Rhonda Patrick)
Posted on April 28, 2022
In this 2.5-hour episode you will learn:
• 00:11:44 - Benefits of slowly titrating down carbs in the early days of a ketogenic diet.
• 00:12:29 - Whether the ketogenic diet has side effects and how they can be circumvented.
• 00:13:16 - The Dom D'Agostino diet and protocol for optimal ketosis.
• 00:13:28 - How dietary fiber can be beneficial when following a ketogenic diet.
• 00:22:54 - How to start a ketogenic diet, which biomarkers to measure to assess suitability, and ideas on how to adjust the diet for APOE4 genotype.
• 00:43:24 - Why glucose can drop into hypoglycemic ranges with high-dose ketones.
• 00:46:35 - How ketone salts can be used to augment the diet
• 00:47:25 - How ketones have a satiating effect on the brain, staving off hunger.
• 01:17:01 - How ketones affect human performance.
• 01:11:40 - How the ketones produced during fasting perform an anti-catabolic function, preventing some muscle loss.

Ageing related thyroid deficiency increases brain-targeted transport of liver-derived ApoE4-laden exosomes leading to cognitive impairment

https://www.nature.com/articles/s41419-022-04858-x?fbclid=IwAR30eCS-5aDnL2hbYqPvxXTjItfsLUk4a2J6ZZ09uF9bFIIqL2z7NyA1zVo
Manman Zhang, Wenliang Gong, Dianjun Zhang, Ming Ji, Binjie Chen, Beina Chen, Xinyu Li, Yuefei Zhou, Chengyi Dong, Gehua Wen, Xiaoni Zhan, Xiafang Wu, Lulu Cui, Yuliang Feng, Siman Wang, Huiya Yuan, Enyu Xu, Maosheng Xia, Alexei Verkhratsky & Baoman Li
Cell Death & Disease volume 13, Article number: 406 (2022)
Published: 25 April 2022
DOI: https://doi.org/10.1038/s41419-022-04858-x
Abstract
Alzheimer’s disease (AD) is the prevalent cause of dementia in the ageing world population. Apolipoprotein E4 (ApoE4) allele is the key genetic risk factor for AD, although the mechanisms linking ApoE4 with neurocognitive impairments and aberrant metabolism remains to be fully characterised. We discovered a significant increase in the ApoE4 content of serum exosomes in old healthy subjects and AD patients carrying ApoE4 allele as compared with healthy adults. Elevated exosomal ApoE4 demonstrated significant inverse correlation with serum level of thyroid hormones and cognitive function. We analysed effects of ApoE4-containing peripheral exosomes on neural cells and neurological outputs in aged or thyroidectomised young mice. Ageing-associated hypothyroidism as well as acute thyroidectomy augmented transport of liver-derived ApoE4 reach exosomes into the brain, where ApoE4 activated nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome by increasing cholesterol level in neural cells. This, in turn, affected cognition, locomotion and mood. Our study reveals pathological potential of exosomes-mediated relocation of ApoE4 from the periphery to the brain, this process can represent potential therapeutic target.

DHA-Enriched Fish Oil Ameliorates Deficits in Cognition Associated with Menopause and the APOE4 Genotype in Rodents

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103304/

Matthew G. Pontifex, Anneloes Martinsen, Rasha N. M. Saleh, Glenn Harden, Chris Fox, Michael Muller, David Vauzour, and Anne-Marie Minihane1

Nutrients 2022 May; 14(9): 1698

Published online 2022 Apr 19

doi: 10.3390/nu14091698

Abstract

Female APOE4 carriers have a greater predisposition to developing Alzheimer’s disease (AD) compared to their male counterparts, which may partly be attributed to menopause. We previously reported that a combination of menopause and APOE4 led to an exacerbation of cognitive and neurological deficits, which were associated with reduced brain DHA and DHA:AA ratio. Here, we explored whether DHA-enriched fish oil (FO) supplementation mitigated the detrimental impact of these risk factors. Whilst DHA-enriched fish oil improved recognition memory (NOR) in APOE4 VCD (4-vinylcyclohexene diepoxide)-treated mice (p < 0.05), no change in spatial working memory (Y-maze) was observed. FO supplementation increased brain DHA and nervonic acid and the DHA:AA ratio. The response of key bioenergetic and blood–brain barrier related genes and proteins provided mechanistic insights into these behavioural findings, with increased BDNF protein concentration as well as mitigation of aberrant Erβ, Cldn1 and Glut-5 expression in APOE4 mice receiving fish oil supplementation (p < 0.05). In conclusion, supplementation with a physiologically relevant dose of DHA-enriched fish oil appears to offer protection against the detrimental effects of menopause, particularly in “at-risk” APOE4 female carriers.

Association of APOE ε4 with cerebral gray matter volumes in non-demented older adults: The MEMENTO cohort study

https://www.sciencedirect.com/science/article/pii/S1053811922000957?via%3Dihub&fbclid=IwAR0PkDP_NyXrYHytqln579T0JFxZOh-L5y6n_UjBQfgbuPnkb1rm2B-jD80
Mélina Régy, Aline Dugravot, Séverine Sabia, Aurore Fayosse, Jean-Francois Mangin, Marie Chupin, Clara Fischer, Vincent Bouteloup, Carole Dufouil, Geneviève Chêne Claire Paquet, Bernard Hanseeuw, Archana Singh-Manoux, Julien Dumurgier
NeuroImage Volume 250, 15 April 2022, 118966
15 April 2022
DOI: https://doi.org/10.1016/j.neuroimage.2022.118966
Abstract
Data on 2,045 non-demented individuals with memory complaints were drawn from the Memento cohort study to examine the association between Apolipoprotein E ε4 allele (APOE4) and regional brain gray matter volumes. Linear regression was used to examine the association of APOE4 and measures of regional gray matter volumes in cross-sectional analysis and change therein using longitudinal analyses based on two brain MRI performed at baseline and at two-year follow-up. Overall, in analyses adjusted for age, sex, and intracranial volume, the presence of APOE4 was associated with lower total gray matter volume at baseline and with a higher atrophy rate over the follow-up. The hippocampus and entorhinal cortex were the two gray matter regions most associated with APOE4. Further adjustment for cardiovascular risk factors had little impact on these associations. There was an interaction between age, APOE4 status and total brain volume atrophy rate, with evidence of an earlier age at onset of atrophy in hippocampal volume in APOE4 carriers compared to non-carriers. Those results are in accordance with the role of medial temporal structures in the greater risk of dementia observed in people carrying the APOE4 allele.

Peter on Alzheimer’s disease prevention and the latest on APOE4

https://peterattiamd.com/peter-on-alzheimers-disease-prevention-and-the-latest-on-apoe4/?fbclid=IwAR1WCHb-lkn3FgFoRiSpYrQrymZ13jf5-C__WgwsCTyuR0AThD9tNLNFAm8
Peter Attia, April 11, 2022
SHOW NOTES
Alzheimer’s disease: genes that modify risk associated with the APOE4 variant [40:15] Changes in thought related to Alzheimer’s disease: When it comes to Alzheimer’s disease, Peter’s focus on genes outside of APOE is now pretty significant
• It turns out that there are a lot of genes that seem to modify the risk of APOE
• APOE has three subtypes, e2, e3, and e4
• Everyone has a pair meaning there are six possible combinations
• The fourth isoform (e4) is the high risk one
• If you’re a e2/e4 it seems to, more or less, be a wash with maybe slight increase in risk
• The e3/e4 seems to be associated with about a 2x-3x increase in risk in Alzheimer’s disease
• The e4/e4 probably has about an 8x-12x increase in risk
• But even though everything above is true at the population level, it doesn’t explain what happens at the individual level
• There are some individuals who walk around with e4/e4 who don’t seem to get Alzheimer’s disease or if they do, they get it very late in life
Genes that modify the risk of the e4 variant
• It turns out that there are a bunch of other genes that we’re now starting to understand, modify the risk of e4 (some genes make it more significant, some genes make it less)
• So there are certain haplotypes of the TOMM40 gene that amplify risk
• There are certain mitochondrial haplotypes that amplify risk
• One of the most exciting genes is the Klotho modifier
• KL-VS is the modified snip of klotho that actually seems to erase all of the downside of APOE4 • So APOE4 people who have this klotho subtype have baseline risk
Prospects of identifying these genes in individuals
• Unfortunately the ways to measure these other genes, it’s very challenging and we have to do it by brute force today

o it takes a lot of time and costs a lot of money to take a whole genome sequence and do the search for all of these other subtypes

o A big step in the right direction here is going to be getting more data and getting those data for less than $20,000 per person.

When might this be practical to do for people?
• Probably sooner than 10 years from now
• This is a solvable problem technically speaking, it’s just about throwing enough dollars at it

Effects of genetic liability to Alzheimer’s disease on circulating metabolites across the life course

https://www.medrxiv.org/content/10.1101/2022.03.24.22272867v3
Hannah Compton, Madeleine L Smith, Caroline Bull, Roxanna Korologou-Linden, Yoav Ben-Shlomo, Joshua A. Bell, Emma L Anderson
MedRxiv April 5, 2022 (preprint)
doi: https://doi.org/10.1101/2022.03.24.22272867
ABSTRACT
Objective
Alzheimer’s disease (AD) has several known genetic determinants, yet the mechanisms through which they lead to disease onset remain poorly understood. This study aims to estimate the effects of genetic liability to AD on plasma metabolites measured at seven different stages across the life course. Methods
Genetic and metabolomic data from 5,648 offspring from the Avon Longitudinal Study of Parents and Children birth cohort were used. Linear regression models examined the association between higher AD liability, as measured by a genetic risk score (GRS), and plasma metabolites measured at 8, 16, 18 and 25 years of age. Two hundred twenty-nine metabolites were studied, most relating to lipid/lipoprotein traits. Two-sample Mendelian randomization was performed using summary statistics from age-stratified genome-wide association studies (GWAS) of the same metabolites for 118,466 participants from the UK Biobank, to examine the persistence of any AD liability effects into late adulthood.
Results
The GRS including the APOE4 isoform demonstrated the strongest positive associations for cholesterol-related traits per doubling of genetic liability to AD, e.g., for low-density lipoprotein cholesterol (LDL-C) at age 25yrs (0.12 SD; 95% CI 0.09, 0.14), with similar magnitudes of association across age groups in ALSPAC. In the UK Biobank, the effect of AD liability decreased with age tertile for several lipid traits (e.g., LDL-C, youngest: 0.15 SD; 95% CI 0.07, 0.23, intermediate: 0.13 SD; 95% CI 0.07, 0.20, oldest: 0.10 SD; 95% CI 0.05, 0.16). Across both cohorts, the effect of AD liability on high-density lipoprotein cholesterol (HDL-C) attenuated as age increased. Fatty acid metabolites also demonstrated positive associations in both cohorts, though smaller in magnitude compared with lipid traits. Sensitivity analyses indicated that these effects were driven by the APOE4 isoform. Conclusions
These results support a profound influence of the APOE4 isoform on circulating lipids and fatty acids from early life to later adulthood. Such lipid and fatty acid traits may be implicated in early AD pathogenesis and warrant further investigation as potential targets for preventing the onset of AD.

How Circulating Metabolites Can Predict Alzheimer's Pathogenesis

https://www.medscape.com/viewarticle/971525?fbclid=IwAR3kfWotkgKGs9kybPTq6Qi-afzWQEmH7pZpFd-MjQk_8I-UY0ayixijJ3U&form=fpf
Susan Kreimer, for Medscape April 04, 2022
Key Takeaways
• The investigators attempted to estimate the metabolic features of genetic liability to Alzheimer's disease (AD) at seven different stages across the life span, with the aim of identifying early features of AD pathogenesis that may be potential targets to prevent the clinical onset of AD.
• They designed a genetic instrument for AD liability and explored its association with circulating metabolites measured in two studies: the Avon Longitudinal Study of Parents and Children (ALSPAC) and the UK Biobank.
• The results bolster a deep-seated influence of the APOE4 isoform on circulating lipids and fatty acids from early life to later adulthood. These lipid and fatty acid traits may be involved in early AD pathogenesis.
• AD-associated metabolic disorders take root in childhood, multiple decades before the development of disease, and carry over into later adulthood when the diagnosis of AD more commonly occurs.

New insights into the genetic etiology of Alzheimer’s disease and related dementias

https://www.nature.com/articles/s41588-022-01024-z
Bellenguez C, Küçükali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, Naj AC, Campos-Martin R, Grenier-Boley B, Andrade V, Holmans PA, Boland A, Damotte V, van der Lee SJ, Costa MR, Kuulasmaa T, Yang Q, de Rojas I, Bis JC, Yaqub A, Prokic I, Chapuis J, Ahmad S, Giedraitis V, Aarsland D, Garcia-Gonzalez P, Abdelnour C, Alarcón-Martín E, Alcolea D, Alegret M, Alvarez I, Álvarez V, Armstrong NJ, Tsolaki A, Antúnez C, Appollonio I, Arcaro M, Archetti S, Pastor AA, Arosio B, Athanasiu L, Bailly H, Banaj N, Baquero M, Barral S, Beiser A, Pastor AB, Below JE, Benchek P, Benussi L, Berr C, Besse C, Bessi V, Binetti G, Bizarro A, Blesa R, Boada M, Boerwinkle E, Borroni B, Boschi S, Bossù P, Bråthen G, Bressler J, Bresner C, Brodaty H, Brookes KJ, Brusco LI, Buiza-Rueda D, Bûrger K, Burholt V, Bush WS, Calero M, Cantwell LB, Chene G, Chung J, Cuccaro ML, Carracedo Á, Cecchetti R, Cervera-Carles L, Charbonnier C, Chen HH, Chillotti C, Ciccone S, Claassen JAHR, Clark C, Conti E, Corma-Gómez A, Costantini E, Custodero C, Daian D, Dalmasso MC, Daniele A, Dardiotis E, Dartigues JF, de Deyn PP, de Paiva Lopes K, de Witte LD, Debette S, Deckert J, Del Ser T, Denning N, DeStefano A, Dichgans M, Diehl-Schmid J, Diez-Fairen M, Rossi PD, Djurovic S, Duron E, Düzel E, Dufouil C, Eiriksdottir G, Engelborghs S, Escott-Price V, Espinosa A, Ewers M, Faber KM, Fabrizio T, Nielsen SF, Fardo DW, Farotti L, Fenoglio C, Fernández-Fuertes M, Ferrari R, Ferreira CB, Ferri E, Fin B, Fischer P, Fladby T, Fließbach K, Fongang B, Fornage M, Fortea J, Foroud TM, Fostinelli S, Fox NC, Franco-Macías E, Bullido MJ, Frank-García A, Froelich L, Fulton-Howard B, Galimberti D, García-Alberca JM, García-González P, Garcia-Madrona S, Garcia-Ribas G, Ghidoni R, Giegling I, Giorgio G, Goate AM, Goldhardt O, Gomez-Fonseca D, González-Pérez A, Graff C, Grande G, Green E, Grimmer T, Grünblatt E, Grunin M, Gudnason V, Guetta-Baranes T, Haapasalo A, Hadjigeorgiou G, Haines JL, Hamilton-Nelson KL, Hampel H, Hanon O, Hardy J, Hartmann AM, Hausner L, Harwood J, Heilmann-Heimbach S, Helisalmi S, Heneka MT, Hernández I, Herrmann MJ, Hoffmann P, Holmes C, Holstege H, Vilas RH, Hulsman M, Humphrey J, Biessels GJ, Jian X, Johansson C, Jun GR, Kastumata Y, Kauwe J, Kehoe PG, Kilander L, Ståhlbom AK, Kivipelto M, Koivisto A, Kornhuber J, Kosmidis MH, Kukull WA, Kuksa PP, Kunkle BW, Kuzma AB, Lage C, Laukka EJ, Launer L, Lauria A, Lee CY, Lehtisalo J, Lerch O, Lleó A, Longstreth W Jr, Lopez O, de Munain AL, Love S, Löwemark M, Luckcuck L, Lunetta KL, Ma Y, Macías J, MacLeod CA, Maier W, Mangialasche F, Spallazzi M, Marquié M, Marshall R, Martin ER, Montes AM, Rodríguez CM, Masullo C, Mayeux R, Mead S, Mecocci P, Medina M, Meggy A, Mehrabian S, Mendoza S, Menéndez-González M, Mir P, Moebus S, Mol M, Molina-Porcel L, Montrreal L, Morelli L, Moreno F, Morgan K, Mosley T, Nöthen MM, Muchnik C, Mukherjee S, Nacmias B, Ngandu T, Nicolas G, Nordestgaard BG, Olaso R, Orellana A, Orsini M, Ortega G, Padovani A, Paolo C, Papenberg G, Parnetti L, Pasquier F, Pastor P, Peloso G, Pérez-Cordón A, Pérez-Tur J, Pericard P, Peters O, Pijnenburg YAL, Pineda JA, Piñol-Ripoll G, Pisanu C, Polak T, Popp J, Posthuma D, Priller J, Puerta R, Quenez O, Quintela I, Thomassen JQ, Rábano A, Rainero I, Rajabli F, Ramakers I, Real LM, Reinders MJT, Reitz C, Reyes-Dumeyer D, Ridge P, Riedel-Heller S, Riederer P, Roberto N, Rodriguez-Rodriguez E, Rongve A, Allende IR, Rosende-Roca M, Royo JL, Rubino E, Rujescu D, Sáez ME, Sakka P, Saltvedt I, Sanabria Á, Sánchez-Arjona MB, Sanchez-Garcia F, Juan PS, Sánchez-Valle R, Sando SB, Sarnowski C, Satizabal CL, Scamosci M, Scarmeas N, Scarpini E, Scheltens P, Scherbaum N, Scherer M, Schmid M, Schneider A, Schott JM, Selbæk G, Seripa D, Serrano M, Sha J, Shadrin AA, Skrobot O, Slifer S, Snijders GJL, Soininen H, Solfrizzi V, Solomon A, Song Y, Sorbi S, Sotolongo-Grau O, Spalletta G, Spottke A, Squassina A, Stordal E, Tartan JP, Tárraga L, Tesí N, Thalamuthu A, Thomas T, Tosto G, Traykov L, Tremolizzo L, Tybjærg-Hansen A, Uitterlinden A, Ullgren A, Ulstein I, Valero S, Valladares O, Broeckhoven CV, Vance J, Vardarajan BN, van der Lugt A, Dongen JV, van Rooij J, van Swieten J, Vandenberghe R, Verhey F, Vidal JS, Vogelgsang J, Vyhnalek M, Wagner M, Wallon D, Wang LS, Wang R, Weinhold L, Wiltfang J, Windle G, Woods B, Yannakoulia M, Zare H, Zhao Y, Zhang X, Zhu C, Zulaica M; EADB; GR@ACE; DEGESCO; EADI; GERAD; Demgene; FinnGen; ADGC; CHARGE; Farrer LA, Psaty BM, Ghanbari M, Raj T, Sachdev P, Mather K, Jessen F, Ikram MA, de Mendonça A, Hort J, Tsolaki M, Pericak-Vance MA, Amouyel P, Williams J, Frikke-Schmidt R, Clarimon J, Deleuze JF, Rossi G, Seshadri S, Andreassen OA, Ingelsson M, Hiltunen M, Sleegers K, Schellenberg GD, van Duijn CM, Sims R, van der Flier WM, Ruiz A, Ramirez A, Lambert JC.
Nature Genetics 2022 Apr;54(4):412-436. doi: 10.1038/s41588-022-01024-z.
Epub 2022 Apr 4
doi: 10.1038/s41588-022-01024-z
Abstract
Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

March 2022

Does ApoE4 Mean Alzheimer’s? Not For Everyone

https://www.beingpatient.com/apoe4-alzheimers-gene-race-indian/?fbclid=IwAR09faAuHO2nlM5K5ieNCjO7-kKuTCxyb2KTAQ9E5z01XO5SkXgboAXOyVk
By Simon Spichak, MSc Being Patient March 31st, 2022 ApoE4 has long been understood to boost Alzheimer's risk. For the first time, scientists studied this Alzheimer's risk factor gene in the American Indian population. The results raise more questions than they answer.

APOE ε4, Alzheimer’s disease neuropathology and sleep disturbance, in individuals with and without dementia

https://link.springer.com/article/10.1186/s13195-022-00992-y
Jonathan Blackman, Seth Love, Lindsey Sinclair, Richard Cain & Elizabeth Coulthard
Alzheimer’s Research & Therapy Volume 14, article number 47, (2022)
Published: 30 March 2022
DOI: https://doi.org/10.1186/s13195-022-00992-y
Abstract
Background
Apolipoprotein E epsilon 4 (APOE-ε4) carrier status is an established risk factor for Alzheimer’s disease (AD) dementia. It has also been linked with sleep disturbance in healthy older adults and increased insomnia risk. This association may be driven by the effect of APOE-ε4 on AD pathological change, itself associated with sleep abnormalities. To assess this relationship, we have evaluated post-mortem neuropathological findings in patients with and without cognitive impairment and AD pathology, who had extensive clinical assessment within 12 months of death.
Methods
This retrospective cohort study used UK Brain Banks Network data. Eligible subjects were aged over 50, with pre-mortem neuropsychiatry inventory scores of sleep disturbance (NPI-K), neurocognitive testing and functional cognitive status assessment (Clinical Dementia Rating scale). Neuropathological data included Thal phase, Braak stage and CERAD scores (measures of Aβ plaque distribution, tangle distribution and neuritic plaque density, respectively) combined to form the National Institute on Aging Alzheimer’s Association (NIA-AA) ABC score reflecting AD neuropathology. Participants with other significant intracerebral pathology or pathological features of non-AD dementia were excluded.
Multivariate linear regression was performed with NPIK Global Score (NPIK frequency score multiplied by severity score) as the dependent variable and APOE-ε4 heterozygosity or homozygosity as independent variables. Covariates included age, gender, APOE-ε2 status and ABC NPI measures reflecting depression and anxiety. Further models stratified by ABC score and functional cognitive status were also produced.
Results
Seven hundred twenty-eight records were identified. Two hundred two participants were included in the final analysis: mean (SD) age 84.0 (9.2) and MMSE 14.0 (11.8). Mean sleep disturbance scores were highest in ε4 homozygosity (n=11), 4.55 (5.4); intermediate in ε4 heterozygosity (n=95), 2.03 (4.0); and lowest in non-ε4 carriers (n=96), 1.36 (3.3). Within the full sample, controlling for pathological status, age, gender, depression, anxiety and CDR-SOB status, APOE-ε4 homozygosity was associated with sleep disturbance (β 2.53, p=0.034). APOE-ε4 heterozygosity was similarly associated in individuals without dementia (β 1.21, p=0.048).
Conclusion
These findings lend weight to the hypothesis that APOE-ε4 affects sleep by mechanisms independent of AD pathological change. Evaluation of those mechanisms would enhance understanding of sleep disturbance pathways and potentially provide treatment targets.

APOE-ε4 modulates the association among plasma Aβ42/Aβ40, vascular diseases, neurodegeneration and cognitive decline in non-demented elderly adults

https://www.nature.com/articles/s41398-022-01899-w?fbclid=IwAR0cFKrak6JfYNuAmTnNKW-KgFlM357Hn85UqnBmmRrlg5ruIEhpF9Ksr4k
Dai Shi, Siwei Xie, Anqi Li, Qingyong Wang, Hongbo Guo, Ying Han, Huaxi Xu, Wen-Biao Gan, Lei Zhang & Tengfei Guo
Translational Psychiatry volume 12, Article number: 128 (2022)
Published: 29 March 2022
DOI: https://doi.org/10.1038/s41398-022-01899-w
Abstract
Including apolipoprotein E-ε4 (APOE-ε4) status and older age into consideration may increase the accuracy of plasma Aβ42/Aβ40 detecting Aβ+ individuals, but the rationale behind this remains to be fully understood. Besides, both Aβ pathology and vascular diseases are related to neurodegeneration and cognitive decline, but it is still not fully understood how APOE-ε4 modulates these relationships. In this study, we examined 241 non-demented Alzheimer’s Disease Neuroimaging Initiative participants to investigate the associations among age, white matter hyperintensities (WMH), hypertension, hyperlipidemia, body mass index (BMI), plasma Aβ42/Aβ40 measured by liquid chromatography tandem mass spectrometry, and 18F-florbetapir Aβ PET as well as their prediction of longitudinal adjusted hippocampal volume (aHCV) and cognition in APOE-ε4 carriers and non-carriers. We found older age predicted faster WMH increase (p = 0.024) and cortical Aβ accumulation (p = 0.043) in APOE-ε4 non-carriers only, whereas lower plasma Aβ42/Aβ40 predicted faster cortical Aβ accumulation (p < 0.018) regardless of APOE-ε4 status. While larger WMH and underweight predicted (p < 0.05) faster decreases in aHCV and cognition in APOE-ε4 non-carriers, lower plasma Aβ42/Aβ40 predicted (p < 0.031) faster decreases in aHCV and cognition in APOE-ε4 carriers. Higher Aβ PET also predicted faster rates of aHCV (p = 0.010) in APOE-ε4 carriers only, but was related to faster rates of cognitive decline (p < 0.022) regardless of APOE-ε4 status. These findings may provide novel insights into understanding different mechanisms underlie neurodegeneration and cognitive decline in non-demented elderly adults with and without APOE-ε4 allele, which may help the design of anti-Alzheimer’s clinical trials.

Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice

https://www.nature.com/articles/s41398-022-01881-6?fbclid=IwAR1hwPf7i8goJgomdfGSGQ0dy5LYjol8qcdk6z5b_t5nr1u9o_g7UdUWvB8
André Miguel Miranda, Archana Ashok, Robin Barry Chan, Bowen Zhou, Yimeng Xu, Laura Beth McIntire, Estela Area-Gomez, Gilbert Di Paolo, Karen E. Duff, Tiago Gil Oliveira & Tal Nuriel
Translational Psychiatry volume 12, Article number: 129 (2022)
Published: 29 March 2022
DOI: https://doi.org/10.1038/s41398-022-01881-6
Abstract
Including apolipoprotein E-ε4 (APOE-ε4) status and older age into consideration may increase the accuracy of plasma Aβ42/Aβ40 detecting Aβ+ individuals, but the rationale behind this remains to be fully understood. Besides, both Aβ pathology and vascular diseases are related to neurodegeneration and cognitive decline, but it is still not fully understood how APOE-ε4 modulates these relationships. In this study, we examined 241 non-demented Alzheimer’s Disease Neuroimaging Initiative participants to investigate the associations among age, white matter hyperintensities (WMH), hypertension, hyperlipidemia, body mass index (BMI), plasma Aβ42/Aβ40 measured by liquid chromatography tandem mass spectrometry, and 18F-florbetapir Aβ PET as well as their prediction of longitudinal adjusted hippocampal volume (aHCV) and cognition in APOE-ε4 carriers and non-carriers. We found older age predicted faster WMH increase (p = 0.024) and cortical Aβ accumulation (p = 0.043) in APOE-ε4 non-carriers only, whereas lower plasma Aβ42/Aβ40 predicted faster cortical Aβ accumulation (p < 0.018) regardless of APOE-ε4 status. While larger WMH and underweight predicted (p < 0.05) faster decreases in aHCV and cognition in APOE-ε4 non-carriers, lower plasma Aβ42/Aβ40 predicted (p < 0.031) faster decreases in aHCV and cognition in APOE-ε4 carriers. Higher Aβ PET also predicted faster rates of aHCV (p = 0.010) in APOE-ε4 carriers only, but was related to faster rates of cognitive decline (p < 0.022) regardless of APOE-ε4 status. These findings may provide novel insights into understanding different mechanisms underlie neurodegeneration and cognitive decline in non-demented elderly adults with and without APOE-ε4 allele, which may help the design of anti-Alzheimer’s clinical trials.

ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease

https://www.sciencedirect.com/science/article/abs/pii/S0197458022000550?fbclid=IwAR3PFSZCuP0QRpaomgmyJzRAm4JAuIYMNxBJcsiQHPiuKM9qXymW_wKVm64
Yonghe Li, Jesse R. Macyczko, Chia-Chen Liu, Guojun Bu
Neurobiology of Aging Volume 115, July 2022, Pages 20-28
Available online 22 March 2022
DOI: https://doi.org/10.1016/j.neurobiolaging.2022.03.011
Highlights
• ApoE4 provokes neuroinflammation and exacerbates amyloid and tau pathologies.
• Genetic knock-down or depletion of apoE alleviates amyloid and tau pathologies.
• ApoE reduction via its receptor LDLR attenuates AD pathologies.
• ApoE4 reduction by apoE specific ASOs and siRNAs alleviates AD pathologies.
Abstract
APOE4 is the first identified genetic risk factor and remains as the strongest predictor for late-onset Alzheimer's disease (AD). Studies of AD patients, AD patient-specific induced pluripotent stem cell-derived neurons and cerebral organoids, and human apoE4-expressing and apoE-deficient mouse models clearly demonstrate that apoE4 provokes neuroinflammation, impairs cerebrovasculature, and exacerbates amyloid and tau pathologies. ApoE expression is greatly up-regulated in disease-associated microglia in mouse models of amyloidosis and in human microglia from AD brains. Importantly, genetic knock-down or depletion of apoE in mice greatly attenuates neuroinflammation and alleviates amyloid and tau pathologies. Similar beneficial effects can be achieved when apoE reduction is induced by the overexpression of apoE metabolic receptor LDLR. Toward therapeutic implications, administration of apoE antisense oligonucleotides or apoE siRNAs leads to significant pharmacologic effects, i.e., significant alleviation of AD pathologies in mouse models. Therefore, apoE reduction represents a promising therapeutic strategy for the treatment of AD patients carrying the APOE ε4 allele. In this review, we summarize evidence and rationale on why and how we target apoE4 reduction for AD therapy.

Determining whether Sex and Zygosity modulates the association between ApoE4 and Psychosis in Neurodegenerative Disease Cohorts using the ONDRI platform

https://www.sciencedirect.com/science/article/abs/pii/S1064748122002378?fbclid=IwAR1nkgPFGHsee-ti_428C0Rv0NQRgmYHCJWlTkyPHpklh-EaiyfX-NV5HdY
Mila Valcic HBSc, Sandra Black MD, Morris Freedman MD, Michael Borrie MD, Andrew Frank MD, Sanjeev Kumar MD, Stephen Pasternak MD, PhD, Bruce Pollock MD, PhD, Tarek Rajji MD, Dallas Seitz MD, PhD, David Tang-Wai MD, Carmela Tartaglia MD, Mario Masellis MD, PhD, Anthony Lang MD, David Breen MD, David Grimes MD, Mandar Jog MD, Connie Marras MD, PhD, Rick Swartz MD, PhD, Gustavo Saposnik MD, PhD, Donna Kwan PhD, Brian Tan MSc, Rob Hegele MD, Allison A. Dilliott PhD, John Robinson MD, Ekaterina Rogaeva PhD, Sali Farhan PhD, Paula McLaughlin PhD, Stephen Strother PhD, Malcolm Binns PhD, Thomas Steeves MD, Pawel Kostyrko MD, Komal Talib BSc, Luis Fornazzari MD, Nathan Churchill PhD, Tom A. Schweizer PhD, David G. Munoz MD, Corinne E. Fischer MD
The American Journal of Geriatric Psychiatry Volume 30, Issue 4, Supplement, April 2022, Pages S90-S91
Available online 16 March 2022
Introduction
The Apolipoprotein E (APOE) gene has been implicated in Alzheimer's disease (AD), as individuals with the APOE ε4 allele show an increased risk of developing AD compared to individuals with the more common APOE ε3 allele. Previous work by our group using a large dataset has suggested that having two copies of the APOE ε4 allele increases the likelihood of psychosis in female, but not male, carriers while one allele had no effect. It is not clear whether or not this effect extends to psychotic patients with Parkinson's disease (PD). The objective of this study was to determine the effect of the APOE ε4 allele dose on the presence of psychotic symptoms (delusions and/or hallucinations) and potential sex-specific effects in a combined AD and PD patient cohort.
Methods
Data on AD and PD patients in the Ontario Neurodegenerative Disease Research Institute (ONDRI) was compiled (N=266). Patients with missing data and/or an NPI total severity score of 0 were excluded, and the final sample size was N=187. APOE genotype and NPI data was gathered. Patients were classified as E4(-), E4, or E44 based on the number of APOE ε4 alleles they carry (0, 1, 2 alleles, respectively). Fisher's Exact Test was performed to determine the association between the presence of psychotic symptoms and the number of APOE ε4 alleles.
Results
Results from Fisher's Exact Test revealed a sex-specific effect, as there was a positive association between having 2 APOE ε4 alleles and the presence of delusions in females (p= .027). There was no effect of one allele and no effect in males, suggesting this effect is limited to females homozygous for APOE ε4. There was no significant association between hallucinations and the number of APOE ε4 alleles in males or females.

Conclusions
The findings of this study demonstrate that females homozygous for APOE ε4 showed a significant association with presence of delusions, not hallucinations, while the same was not discovered in males or individuals with one allele. Our findings suggest that sex and zygosity moderate the effect of APOE ε4 on delusions in a combined AD/PD cohort. Further studies are required to identify underlying mechanisms.

Association of a wide range of chronic diseases and apolipoprotein E4 genotype with subsequent risk of dementia in community-dwelling adults: A retrospective cohort study

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00065-7/fulltext
Xianwen Shang, Zhuoting Zhu, Xueli Zhang, Yu Huang, Xiayin Zhang, Jiahao Liu, Wei Wang, Shulin Tang, Honghua Yu, Zongyuan Ge, Xiaohong Yang, and Mingguang He
eClinicalMedicine 2022;45: 101335
Published online 13 March 2022
DOI: https://doi.org/10.1016/j. eclinm.2022.101335
Summary
Background
Identifying independent and interactive associations of a wide range of diseases and multimorbidity and apolipoprotein E4 (APOE4) with dementia may help promote cognitive health. The main aim of the present study was to investigate associations of such diseases and their multimorbidity with incident dementia.
Methods
In this retrospective cohort study, we included 471,485 individuals of European ancestry from the UK Biobank, aged 38–73 years at baseline (2006–10). Dementia was identified using inpatient records and death registers. The follow-up period was between March 16, 2006, and Jan 31, 2021.
Findings
During a median follow-up of 11·9 years, 6189 cases of incident all-cause dementia (503 young-onset cases, 5686 late-onset cases) were documented. In multivariable-adjusted analysis, 33 out of 63 major diseases were associated with an increased risk of dementia. The hazard ratio (HR [95% CI]) ranged from 1·12 (1·06–1·19) for obesity to 14·22 (12·33–16·18) for Parkinson's disease. In addition to conventional diseases, respiratory disorders, musculoskeletal disorders, digestive disorders, painful conditions, and chronic kidney disease were associated with increased dementia risk. A larger HR for dementia was observed for a larger number of diseases (3·97 [3·51–4·48] for ≥6 diseases versus no disease). These individual diseases and multimorbidity were more predictive of young-onset dementia than of late-onset dementia. Dementia risk score incorporating multimorbidity, age, and APOE4 status had strong prediction performance (area under the curve [95% CI]: 82·2% [81·7–82·7%]). APOE4 was more predictive of late-onset dementia (HR [95% CI]: 2·90 [2·75–3·06]) than of young-onset dementia (1·26 [1·03–1·54]). Associations of painful conditions, depression, obesity, diabetes, stroke, Parkinson's disease, high cholesterol, and their multimorbidity with incident dementia were stronger among non-APOE4 carriers.
Interpretation
Besides conventional diseases, numerous diseases are associated with an increased risk of dementia. These individual diseases and multimorbidity are more predictive of young-onset dementia, whereas APOE4 is more predictive of late-onset dementia. Individual diseases and multimorbidity are stronger predictors of dementia in non-APOE4 carriers. Although multiple risk factors have been adjusted for in the analysis, potential confounding from unknown factors may have biased the associations.

Cerebrovascular response to exercise interacts with individual genotype and amyloid-beta deposition to influence response inhibition with aging

https://www.sciencedirect.com/science/article/abs/pii/S0197458022000355?via%3Dihub
Jacqueline A. Palmer, Carolyn S. Kaufman, Eric D. Vidoni, Robyn A. Honea, Jeffrey M. Burns b, Sandra A. Billinger
Neurobiology of Aging Volume 114, June 2022, Pages 15-26
Available online 4 March 2022
DOI: https://doi.org/10.1016/j.neurobiolaging.2022.02.014
Abstract
The etiology of cognitive dysfunction associated with Alzheimer's disease (AD) and dementia is multifactorial. Yet, mechanistic interactions among key neurobiological factors linked to AD pathology are unclear. This study tested the effect of interactions between cerebrovascular function, individual genotype, and structural brain pathology on response inhibition performance, an early and sensitive indicator of cognitive executive dysfunction with aging. We quantified cerebrovascular response (CVR) to moderate-intensity aerobic exercise using transcranial doppler ultrasound and global amyloid-beta (Aβ) deposition using positron emission tomography in a group of cognitively normal older adults genotyped as APOE4 carriers and noncarriers. We quantified response inhibition during a cognitive Stroop test. Individuals with blunted CVR possessed greater Aβ deposition. There was CVR-by-carrier status-by-Aβ interaction on response inhibition. Blunted CVR was associated with impaired response inhibition specifically in APOE4 carriers. Despite having greater Aβ deposition, APOE4 carriers with higher CVR demonstrated better response inhibition. Cerebrovascular interactions with individual genotype and structural brain pathology may provide a physiologically-informed target for precision-medicine approaches for early treatment and prevention of cognitive dysfunction with aging.

The role of lipids in the development of Alzheimer's disease

https://medicalxpress.com/news/2022-03-role-lipids-alzheimer-disease.html?fbclid=IwAR0VHYFYVK4nZ335QCdsW-CtppUMcFiv8USOtkN7jjK9vWL3dLevpDJc4VE
by University of Geneva, MedicalXpress, MARCH 1, 2022
Neurons in the brain coexist with and rely on many other cell types to function properly. Astrocytes, which take their name from their star shape, ensure the survival of neurons by feeding and detoxifying them with the help of a multifunctional protein, APOE. One of three forms of this protein, APOE4, significantly increases the risk of developing Alzheimer's disease, but the mechanisms at play are unknown. A collaboration between the University of Geneva (UNIGE), the European Molecular Biology Laboratory (EMBL), the University of Zurich and the pharmaceutical company AbbVie has discovered a potential mechanism: far from ceasing to function, APOE4 is on the contrary more efficient. By triggering astrocytic lipid secretion, it causes the accumulation of potentially toxic lipids that are harmful to neurons, and thus might contribute to the development of Alzheimer's disease. These results published in the journal Cell Reports, shed new light on the neurodegenerative mechanisms of a disease that affects nearly 50 million people worldwide. …

Isoform- and cell-state-specific lipidation of ApoE in astrocytes

https://www.cell.com/cell-reports/fulltext/S2211-1247(22)00162-0
Karina Lindner, Katharina Beckenbauer,Larissa C. van Ek, Kevin Titeca, Sherida M. de Leeuw, Khader Awwad, Franziska Hanke, Alla V. Korepanova, Vladimir Rybin, Elizabeth Louise van der Kam, Eric G. Mohler, Christian Tackenberg, Viktor Lakics, Anne-Claude Gavin
Cell Reports VOLUME 38, ISSUE 9, 110435, MARCH 01, 2022
MARCH 01, 2022
DOI: https://doi.org/10.1016/j.celrep.2022.110435
Highlights
• The N terminus of ApoE binds to PIPs and TAG in an isoform-specific manner
• Lean astrocytes secrete cholesterol-loaded ApoE; this is unaffected by polymorphism
• Fatty astrocytes chronically exposed to fatty acids produce TAG-rich ApoE particles
• APOE4 boosts TAG secretion, whereas APOE2 is less active and behaves as APOE-KO
Summary
Apolipoprotein E transports lipids and couples metabolism between astrocytes and neurons. The E4 variant (APOE4) affects these functions and represents a genetic predisposition for Alzheimer's disease, but the molecular mechanisms remain elusive. We show that ApoE produces different types of lipoproteins via distinct lipidation pathways. ApoE forms high-density lipoprotein (HDL)-like, cholesterol-rich particles via the ATP-binding cassette transporter 1 (ABCA1), a mechanism largely unaffected by ApoE polymorphism. Alternatively, ectopic accumulation of fat in astrocytes, a stress-associated condition, redirects ApoE toward the assembly and secretion of triacylglycerol-rich lipoproteins, a process boosted by the APOE4 variant. We demonstrate in vitro that ApoE can detect triacylglycerol in membranes and spontaneously assemble lipoprotein particles (10–20 nm) rich in unsaturated triacylglycerol, and that APOE4 has remarkable properties behaving as a strong triacylglycerol binder. We propose that fatty APOE4 astrocytes have reduced ability to clear toxic fatty acids from the extracellular milieu, because APOE4 reroutes them back to secretion.

February 2022

The Link between APOE4 Presence and Neuropsychological Test Performance among Mexican Americans and Non-Hispanic Whites of the Multiethnic Health & Aging Brain Study – Health Disparities Cohort

https://karger.com/dem/article/51/1/26/827997/The-Link-between-APOE4-Presence-and
Sid E. O’Bryant;Robert C. Barber; Nicole Philips; Leigh A. Johnson; James R. Hall; Kumudu Subasinghe; Melissa Petersen; Arthur W. Toga; Kristine Yaffe; Robert A. Rissman
Dementia and Geriatric Cognitive Disorders (2022) 51 (1): 26–31
FEBRUARY 28 2022
DOI: https://doi.org/10.1159/000521898
Abstract
Introduction:
The APOEε4 allele is the single strongest genetic risk for late-onset Alzheimer’s disease (AD). Prior work demonstrates that not only the APOEε4 allele varies by race/ethnicity but also the risk for AD and cognitive impairment conveyed by the APOEε4 allele varies by the racial/ethnic group as well as genetic ancestry. Here, we sought to examine the link between the APOEε4 and neuropsychological functioning among Mexican Americans (MAs).
Methods:
Data were examined from 1,633 (852 MAs and 781 non-Hispanic Whites [NHWs]) participants of the Health & Aging Brain Study – Health Disparities (HABS-HD) and were enrolled with all requisite data to be included into the current analyses.
Results:
The frequency of both ε4 and ε2 alleles was significantly lower among MAs as compared to NHWs. Among MAs, APOEε4 allele presence was associated specifically with poorer immediate and delayed memory (Wechsler Memory Scale – Third Edition [WMS-III] Logical Memory and Spanish-English Verbal Learning Test [SEVLT]). Among NHWs, APOEε4 allele presence was associated with poorer immediate and delayed memory as well as worse executive functioning (Trials B) and verbal fluency (Animal naming).
Discussion/Conclusion:
The APOEε4 allele was associated with poorer cognition across multiple domains among NHWs; however, allele presence was specifically associated with poorer memory performance among MAs. When combined with prior work, the current findings demonstrate that the risk factors associated with cognitive dysfunction differ among MAs as compared to NHWs and require additional investigation.

APOE genotype, hippocampus, and cognitive markers of Alzheimer’s disease in American Indians: Data from the Strong Heart Study
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9363523/
Astrid Suchy-Dicey, Barbara Howard, WT Longstreth, Jr, Eric M. Reiman, and Dedra Buchwald
Alzheimers & Dementia 2022 Dec; 18(12): 2518–2526
Published online 2022 Feb 10
doi: 10.1002/alz.12573
Abstract
Background:
The apolipoprotein E (APOE) ε4 allele confers higher risk of neurodegeneration and Alzheimer’s disease (AD), but differs by race/ethnicity. We examined this association in American Indians.
Methods:
The Strong Heart Study is a population-based cohort of American Indians who were 64 to 95 years of age in 2010 to 2013. APOE ε4 status, brain imaging, and neuropsychological testing was collected in N = 811 individuals. Summary statistics, graphics, and generalized linear regressions—adjusted for sociodemographics, clinical features, and intracranial volume with bootstrap variance estimator—compared APOE ε4 carriers with non-carriers.
Results:
APOE ε4 carriers comprised 22% of the population (0.7% homozygotes). Participants were mean 73 years, 67% female, and 54% had some college education. The majority were obese (>50%), hypertensive (>80%), and diabetic (>50%). Neither imaging findings nor multidomain cognitive testing showed any substantive differences between APOE ε4 carriers and non-carriers.
Conclusion:
We found no evidence of neurodegenerative risk from APOE ε4 in American Indians. Additional studies are needed to examine potential protective features.

APOE genetics influence murine gut microbiome

https://www.nature.com/articles/s41598-022-05763-1?fbclid=IwAR1c_TYM0PQ8lvtyNe4ptmVpdkil-Wlc-GQPk2H9psCsg39wVO6hT_vcU1c
Diana J. Zajac, Stefan J. Green, Lance A. Johnson & Steven Estus
Scientific Reports volume 12, Article number: 1906 (2022)
Published: 03 February 2022
DOI: https://doi.org/10.1038/s41598-022-05763-1
Abstract
Apolipoprotein E (APOE) alleles impact pathogenesis and risk for multiple human diseases, making them primary targets for disease treatment and prevention. Previously, we and others reported an association between APOE alleles and the gut microbiome. Here, we evaluated effects of APOE heterozygosity and tested whether these overall results extended to mice maintained under ideal conditions for microbiome analyses. To model human APOE alleles, this study used APOE targeted replacement (TR) mice on a C57Bl/6 background. To minimize genetic drift, homozygous APOE3 mice were crossed to homozygous APOE2 or homozygous APOE4 mice prior to the study, and the resulting heterozygous progeny crossed further to generate the study mice. To maximize environmental homogeneity, mice with mixed genotypes were housed together and used bedding from the cages was mixed and added back as a portion of new bedding. Fecal samples were obtained from mice at 3-, 5- and 7-months of age, and microbiota analyzed by 16S ribosomal RNA gene amplicon sequencing. Linear discriminant analysis of effect size (LefSe) identified taxa associated with APOE status, depicted as cladograms to show phylogenetic relatedness. The influence of APOE status was tested on alpha-diversity (Shannon H index) and beta-diversity (principal coordinate analyses and PERMANOVA). Individual taxa associated with APOE status were identified by classical univariate analysis. Whether findings in the APOE mice were replicated in humans was evaluated by using published microbiome genome wide association data. Cladograms revealed robust differences with APOE in male mice and limited differences in female mice. The richness and evenness (alpha-diversity) and microbial community composition (beta-diversity) of the fecal microbiome was robustly associated with APOE status in male but not female mice. Classical univariate analysis revealed individual taxa that were significantly increased or decreased with APOE, illustrating a stepwise APOE2-APOE3–APOE4 pattern of association with heterozygous animals trending as intermediate in the stepwise pattern. The relative abundance of bacteria from the class Clostridia, order Clostridiales, family Ruminococacceae and related genera increased with APOE2 status. The relative abundance of Erysipelotrichia increased with APOE4 status, a finding that extended to humans. In this study, wherein mice were maintained in an ideal fashion for microbiome studies, gut microbiome profiles were strongly and significantly associated with APOE status in male APOE-TR mice. Erysipelotrichia are increased with APOE4 in both mice and humans. APOE allelic effects appeared generally intermediate in heterozygous animals. Further evaluation of these findings in humans, as well as studies evaluating the impact of the APOE-associated microbiota on disease-relevant phenotypes, will be necessary to determine if alterations in the gut microbiome represent a novel mechanism whereby APOE alleles impact disease.

Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis

https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-022-00516-0?fbclid=IwAR2yY8DsodOGGmH3Fk9Q7w6sIlIlFkmLJ8lygPq35aL1LH0PE6yW0W3I7jg
Thomas E. Mahan, Chao Wang, Xin Bao, Ankit Choudhury, Jason D. Ulrich & David M. Holtzman
Molecular Neurodegeneration volume 17, Article number: 13 (2022)
Published: 02 February 2022
DOI: https://doi.org/10.1186/s13024-022-00516-0
Abstract
Background
One of the key pathological hallmarks of Alzheimer disease (AD) is the accumulation of the amyloid-β (Aβ) peptide into amyloid plaques. The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD and has been shown to influence the accumulation of Aβ in the brain in an isoform-dependent manner. ApoE can be produced by different cell types in the brain, with astrocytes being the largest producer of apoE, although reactive microglia also express high levels of apoE. While studies have shown that altering apoE levels in the brain can influence the development of Aβ plaque pathology, it is not fully known how apoE produced by specific cell types, such as astrocytes, contributes to amyloid pathology.
Methods
We utilized APOE knock-in mice capable of having APOE selectively removed from astrocytes in a tamoxifen-inducible manner and crossed them with the APP/PS1-21 mouse model of amyloidosis. We analyzed the changes to Aβ plaque levels and assessed the impact on cellular responses to Aβ plaques when astrocytic APOE is removed.
Results
Tamoxifen administration was capable of strongly reducing apoE levels in the brain by markedly reducing astrocyte apoE, while microglial apoE expression remained. Reduction of astrocytic apoE3 and apoE4 led to a large decrease in Aβ plaque deposition and less compact plaques. While overall Iba1+ microglia were unchanged in the cortex after reducing astrocyte apoE, the expression of the disease-associated microglial markers Clec7a and apoE were lower around amyloid plaques, indicating decreased microglial activation. Additionally, astrocyte GFAP levels are unchanged around amyloid plaques, but overall GFAP levels are reduced in the cortex of female apoE4 mice after a reduction in astrocytic apoE. Finally, while the amount of neuritic dystrophy around remaining individual plaques was increased with the removal of astrocytic apoE, the overall amount of cortical amyloid-associated neuritic dystrophy was significantly decreased.
Conclusion
This study reveals an important role of astrocytic apoE3 and apoE4 on the deposition and accumulation of Aβ plaques as well as on certain Aβ-associated downstream effects.

January 2022

ApoE4 Is Associated with Lower Body Mass, Particularly Fat Mass, in Older Women with Cognitive Impairment

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8838979/#:~:text=Additionally%2C%20the%20impact%20of%20APOE,MCI%2C%20independent%20of%20cognitive%20decline.
Takafumi Ando, Kazuaki Uchida, Taiki Sugimoto, Ai Kimura, Naoki Saji, Shumpei Niida, and Takashi Sakurai
Nutrients 2022 Feb; 14(3): 539
Published online 2022 Jan 26
doi: 10.3390/nu14030539
Abstract
A lower body mass is associated with the progression of Alzheimer’s disease (AD) and the risk of mortality in patients with AD; however, evidence of genetic determinants of decreased body mass in cognitively impaired older adults is limited. We therefore investigated the genetic effect of APOE-ε4 on body composition in older adults with mild cognitive impairment (MCI) and early-to-moderate-stage AD. A total of 1631 outpatients (aged 65–89 years) with MCI and early-to-moderate-stage AD were evaluated for the association between body composition and APOE-ε4 status. After adjusting for covariates, including cognitive function evaluated with the Mini-Mental State Examination, the presence of the APOE-ε4 was associated with lower weight (β = −1.116 ± 0.468 kg per presence, p = 0.017), fat mass (β = −1.196 ± 0.401 kg per presence, p = 0.003), and percentage of body fat (β = −1.700 ± 0.539% per presence, p = 0.002) in women but not in men. Additionally, the impact of APOE-ε4 on measures of body composition in women was more remarkable in MCI than in AD patients. The presence of the APOE-ε4 allele was associated with lower fat mass, particularly in women with MCI, independent of cognitive decline.

Isoform-dependent lysosomal degradation and internalization of apolipoprotein E requires autophagy proteins

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8917355/
Gianna M. Fote, Nicolette R. Geller, Nikolaos E. Efstathiou, Nathan Hendricks, Demetrios G. Vavvas, Jack C. Reidling, Leslie M. Thompson, and Joan S. Steffan Journal of Cell Science, 2022 Jan 15; 135(2): jcs258687
Published online 2022 Jan 25
doi: 10.1242/jcs.258687
ABSTRACT
The human apolipoprotein E4 isoform (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), and lysosomal dysfunction has been implicated in AD pathogenesis. We found, by examining cells stably expressing each APOE isoform, that APOE4 increases lysosomal trafficking, accumulates in enlarged lysosomes and late endosomes, alters autophagic flux and the abundance of autophagy proteins and lipid droplets, and alters the proteomic contents of lysosomes following internalization. We investigated APOE-related lysosomal trafficking further in cell culture, and found that APOE from the post-Golgi compartment is degraded through autophagy. We found that this autophagic process requires the lysosomal membrane protein LAMP2 in immortalized neuron-like and hepatic cells, and in mouse brain tissue. Several macroautophagy-associated proteins were also required for autophagic degradation and internalization of APOE in hepatic cells. The dysregulated autophagic flux and lysosomal trafficking of APOE4 that we observed suggest a possible novel mechanism that might contribute to AD pathogenesis.

First person – Gianna Fote

https://journals.biologists.com/jcs/article/135/2/jcs259758/274106/First-person-Gianna-Fote?fbclid=IwAR18od7vKG7ufINUZAteBFwG3V2lx1Uqhq_fsHYEh3zmLb9UWTCIGvil3DU
Journal of Cell Science (2022) 135 (2): jcs259758
25 JANUARY 2022
DOI: https://doi.org/10.1242/jcs.259758
ABSTRACT
First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Gianna Fote is first author on ‘ Isoform-dependent lysosomal degradation and internalization of apolipoprotein E requires autophagy proteins’, published in JCS. Gianna conducted the research described in this article while a MD/PhD student in Joan S. Steffan and Leslie M. Thompson's lab at the University of California Irvine School of Medicine, USA, working on the influence of genetic variants on molecular mechanisms of autophagy, and therapeutic modulation of autophagic balance in neurological disease.

Don’t forget about tau: the effects of ApoE4 genotype on Alzheimer’s disease cerebrospinal fluid biomarkers in subjects with mild cognitive impairment—data from the Dementia Competence Network

https://link.springer.com/article/10.1007/s00702-022-02461-0?fbclid=IwAR1Kq8LioVLFbchQIlBAJqT5B2aspUG4hy63XH4g0zMfFZ68USRG8BXnr2c

Gloria S. Benson, Chris Bauer, Lucrezia Hausner, Samuel Couturier, Piotr Lewczuk, Oliver Peters, Michael Hüll, Holger Jahn, Frank Jessen, Johannes Pantel, Stefan J. Teipel, Michael Wagner, Johannes Schuchhardt, Jens Wiltfang, Johannes Kornhuber & Lutz Frölich
Journal of Neural Transmission, Volume 129, pages 477–486, (2022)
Published: 21 January 2022
DOI: https://doi.org/10.1007/s00702-022-02461-0
Abstract
ApoE4, the strongest genetic risk factor for Alzheimer’s disease (AD), has been shown to be associated with both beta-amyloid (Aβ) and tau pathology, with the strongest evidence for effects on Aβ, while the association between ApoE4 and tau pathology remains inconsistent. This study aimed to investigate the associations between ApoE4 with CSF Aβ42, total tau (t-tau), phospho-tau181 (p-tau), and with the progression of decline in a large cohort of MCI subjects, both progressors to AD and other dementias, as well as non-progressors. We analyzed associations of CSF Aβ42, p-tau and t-tau with ApoE4 allele frequency cross-sectionally and longitudinally over 3 years of follow-up in 195 individuals with a diagnosis of MCI-stable, MCI-AD converters and MCI progressing to other dementias from the German Dementia Competence Network. In the total sample, ApoE4 carriers had lower concentrations of CSF Aβ42, and increased concentrations of t-tau and p-tau compared to non-carriers in a gene dose-dependent manner. Comparisons of these associations stratified by MCI-progression groups showed a significant influence of ApoE4 carriership and diagnostic group on all CSF biomarker levels. The effect of ApoE4 was present in MCI-stable individuals but not in the other groups, with ApoE4 + carriers having decreased CSF Aβ 42 levels, and increased concentration of t-tau and p-tau. Longitudinally, individuals with abnormal t-tau and Aβ42 had a more rapid progression of cognitive and clinical decline, independently of ApoE4 genotype. Overall, our results contribute to an emerging framework in which ApoE4 involves mechanisms associated with both CSF amyloid-β burden and tau aggregation at specific time points in AD pathogenesis.

Identifying differential regulatory control of APOEɛ4 on African versus European haplotypes as potential therapeutic targets

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12534
Karen Nuytemans, Marina Lipkin, Liyong Wang, Derek Van Booven, Antony J. Griswold, Farid Rajabli, Katrina Celis, Oded Oron, Natalia Hofmann, Sophie Rolati, Catherine Garcia-Serje, Shanshan Zhang, Fulai Jin, Mariana Argenziano, Struan F.A. Grant, Alessandra Chesi, Christopher D. Brown, Juan I. Young, Derek M. Dykxhoorn, Margaret A. Pericak-Vance, Jeffery M. Vance
Alzheimers & Dementia 2022 Oct;18(10):1930-1942
Epub 2022 Jan 3
doi: 10.1002/alz.12534
Abstract
We previously demonstrated that in Alzheimer’s disease (AD) patients, European apolipoprotein E (APOE) ε4 carriers express significantly more APOEε4 in their brains than African AD carriers. We examined single nucleotide polymorphisms near APOE with significant frequency differences between African and European/Japanese APOE ε4 haplotypes that could contribute to this difference in expression through regulation. Two enhancer massively parallel reporter assay (MPRA) approaches were performed, supplemented with single fragment reporter assays. We used Capture C analyses to support interactions with the APOE promoter. Introns within TOMM40 showed increased enhancer activity in the European/Japanese versus African haplotypes in astrocytes and microglia. This region overlaps with APOE promoter interactions as assessed by Capture C analysis. Single variant analyses pinpoints rs2075650/rs157581, and rs59007384 as functionally different on these haplotypes. Identification of the mechanisms for differential regulatory function for APOE expression between African and European/Japanese haplotypes could lead to therapeutic targets for APOE ε4 carriers.

2021

December 2021

Identification of small molecule drugs that target apolipoprotein E4-catalyzed amyloid-β fibrillization: A new therapeutic approach to Alzheimer’s disease

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.054678
Noah R Johnson, Athena Ching-Jung Wang, Christina M Coughlan, Stefan H Sillau, Esteban M Lucero, Lisa Viltz, Neil Markham, Cody Allen, A. Ranjitha Dhanasekaran, Heidi J Chial, Huntington Potter

Alzheimer’s & Dementia Volume17, IssueS9 December 2021 e054678
First published: 31 December 2021
DOI: https://doi.org/10.1002/alz.054678
Abstract
Background
Carrying the ε4 allele of the apolipoprotein E (APOE) gene is the strongest risk factor for Alzheimer’s disease (AD) besides age itself. Having one copy of APOE4 triples the risk for AD, whereas being homozygous for APOE4 increases the risk by greater than 12-fold. As one potential mechanism, apoE, and especially apoE4, acts as a catalyst to accelerate the polymerization rate of amyloid-β (Aβ) into neurotoxic oligomers and filaments. Thus, inhibiting this catalytic process is a promising therapeutic approach to preventing AD. Repurposing a known drug to inhibit the apoE4-Aβ interaction would have numerous benefits such as faster, less expensive testing in clinical trials, and a greater chance of making it to market.
Method
We developed an apoE4-Aβ fibrillization assay and screened two small molecule drug repurposing libraries containing more than 3,000 compounds with a history of use in human clinical trials. The cytotoxicity and efficacy of hit compounds were evaluated in transgenic mouse and rat primary neurons. We also modeled changes in cognition using MMSE scores and clinical diagnoses of National Alzheimer’s Coordinating Center (NACC) participants using time slopes and Cox proportional hazards, respectively, and adjusted for age and sex.
Result
Our high-throughput screen identified 31 hit compounds that inhibited apoE4-catalyzed Aβ fibrillization in a dose-dependent manner. Five of those hit compounds were non-toxic, blood-brain barrier permeable, and reduced apoE4-induced Aβ and tau neuropathology in AD cell culture models. One hit compound was the anti-depressant imipramine, which, when taken by AD patients, was associated with improved cognition (P=0.0490) and increased incidence of receiving an improved clinical diagnosis (P<0.0001), compared to all other anti-depressants. Another hit compound was the anti-psychotic olanzapine, which, when taken by AD patients who were APOE4 carriers, was associated with improved cognition (P=0.0235) and improved clinical diagnosis (P=0.0435), compared to all other anti-psychotics.
Conclusion
We identified five novel inhibitors of the apoE4-Aβ interaction, two of which were associated with clinical improvements when prescribed to AD patients for their normal indications. These findings validate an apoE-centric approach to developing new AD therapeutics. This set of small molecules may be useful for preventing or reversing AD, particularly in APOE4 carriers.

APOE4 Allele, Sex, and Dementia Risk in Parkinson’s Disease: Lessons From a Longitudinal Cohort

https://journals.sagepub.com/doi/abs/10.1177/08919887211060019?journalCode=jgpb&fbclid=IwAR1eehQGWOSWbqd3PKFnBigTaKc1Ld5YGfrT6eE3IjbsY1eNTItVYHUHzq0&
Chizoba C. Umeh, MD, Abhimanyu Mahajan, MD, MHS , Aleksandra Mihailovic, Sc.M., and Gregory M. Pontone, MD, MHS
Journal of Geriatric Psychiatry and Neurology 2022;35(6):810-815
First published online December 27, 2021
doi:10.1177/08919887211060019
Abstract
Introduction
The effect of APOE4 allele on dementia risk is well established in Alzheimer’s disease and Parkinson’s disease (PD). However, it is unknown if sex modifies this relationship. We sought to determine the effect of sex on the relationship between APOE4 status and incident cognitive decline in PD.
Methods
Data from the prospectively collected longitudinal National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) and Neuropathology Data Set (NDS) were analyzed. The NACC develops and maintains data from approximately 29 National Institutes of Aging-funded Alzheimer's Disease Research Centers. Further details may be found at the NACC web site (www.alz.washington.edu). The visit at which diagnosis of PD was made was termed the baseline visit. All patients with a PD diagnosis but without dementia at the baseline visit were included in the analyses.
Results
Presence of APOE4 allele was associated with higher odds (OR = 7.4; P < .001) of subsequent diagnosis of dementia and with a faster time to developing dementia (P = .04). Those with APOE4 allele were more likely to have neuropathology associated with Alzheimer’s disease than those without APOE4 allele. We did not find any difference by sex. There were no differences between Lewy body pathology or neuron loss in the substantia nigra between the 2 groups. Sex was not associated with dementia risk in PD (OR = 0.53, P = .15) or with the time to dementia onset (P = .22). Sex did not modify the relationship between the APOE4 allele and dementia onset in PD patients (P = .12)
Conclusions
APOE4 allele status in PD may be a predictor of cognitive decline in PD but does not appear to be modified by sex.

APOE4 derived from astrocytes leads to blood–brain barrier impairment

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9586546/
Rosemary J Jackson, Jonah C Meltzer, Huong Nguyen, Caitlin Commins, Rachel E Bennett, Eloise Hudry, and Bradley T Hyman
Brain 2022 Oct; 145(10): 3582–3593
Published online 2021 Dec 27
doi: 10.1093/brain/awab478
Abstract
Apolipoprotein E (ApoE) is a multifaceted secreted molecule synthesized in the CNS by astrocytes and microglia, and in the periphery largely by the liver. ApoE has been shown to impact the integrity of the blood–brain barrier, and, in humans, the APOE4 allele of the gene is reported to lead to a leaky blood–brain barrier. We used allele specific knock-in mice expressing each of the common (human) ApoE alleles, and longitudinal multiphoton intravital microscopy, to directly monitor the impact of various ApoE isoforms on blood–brain barrier integrity. We found that humanized APOE4, but not APOE2 or APOE3, mice show a leaky blood–brain barrier, increased MMP9, impaired tight junctions, and reduced astrocyte end-foot coverage of blood vessels. Removal of astrocyte-produced ApoE4 led to the amelioration of all phenotypes while the removal of astrocyte-produced ApoE3 had no effect on blood–brain barrier integrity. This work shows a cell specific gain of function effect of ApoE4 in the dysfunction of the BBB and implicates astrocyte production of ApoE4, possibly as a function of astrocytic end foot interactions with vessels, as a key regulator of the integrity of the blood–brain barrier.

The detrimental effects of APOE4 on risk for Alzheimer's disease may result from altered dendritic spine density, synaptic proteins, and estrogen receptor alpha

https://www.sciencedirect.com/science/article/abs/pii/S0197458021003626?fbclid=IwAR0ibvnzYaSYh7VX1xNHfgiFCehuv0sFbkSY8EC1TzIe-MhcW7g72C4uLoc
Lisa R. Taxier, Sarah M. Philippi, Jason M. York, Mary Jo LaDu, Karyn M. Frick
Neurobiology of Aging Volume 112, April 2022, Pages 74-86
Available online 24 December 2021
DOI: https://doi.org/10.1016/j.neurobiolaging.2021.12.006
Abstract
Women carriers of APOE4, the greatest genetic risk factor for late-onset Alzheimer's disease (AD), are at highest risk of developing AD, yet factors underlying interactions between APOE4 and sex are not well characterized. Here, we examined how sex and APOE3 or APOE4 genotypes modulate object and spatial memory, dendritic spine density and branching, and protein expression in 6-month-old male and female E3FAD and E4FAD mice (APOE+/+/5xFAD+/−). APOE4 negatively impacted object recognition and spatial memory, with male E3FADs exhibiting the best memory across 2 object-based tasks. In both sexes, APOE4 reduced basal dendritic spine density in the medial prefrontal cortex and dorsal hippocampus. APOE4 reduced dorsal hippocampal levels of PDS-95, synaptophysin, and phospho-CREB, yet increased levels of ERα. E4FAD females exhibited strikingly increased GFAP levels, in addition to the lowest levels of PSD-95 and pCREB. Overall, our results suggest that APOE4 negatively impacts object memory, dendritic spine density, and levels of hippocampal synaptic proteins and ERα. However, the general lack of sex differences or sex by genotype interactions suggests that the sex-specific effects of APOE4 on AD risk may be related to factors unexplored in the present study.

Apolipoprotein E Proteinopathy Is a Major Dementia-Associated Pathologic Biomarker in Individuals with or without the APOE Epsilon 4 Allele
https://ajp.amjpathol.org/article/S0002-9440(21)00533-2/fulltext
Jozsef Gal, Yuriko Katsumata, Haining Zhu, Sukanya Srinivasan, Jing Chen, Lance Allen Johnson, Wang-Xia Wang, Lesley Renee Golden, Donna M. Wilcock, Gregory A. Jicha, Matthew D. Cykowski, Peter Tobias Nelson
NEUROPATHOLOGY| VOLUME 192, ISSUE 3, P564-578, MARCH 2022
Published: December 23, 2021
DOI:https://doi.org/10.1016/j.ajpath.2021.11.013
The amygdala is vulnerable to multiple or “mixed” mis-aggregated proteins associated with neurodegenerative conditions that can manifest clinically with amnestic dementia; the amygdala region is often affected even at earliest disease stages. With the original intent of identifying novel dementia-associated proteins, the detergent-insoluble proteome was characterized from the amygdalae of 40 participants from the University of Kentucky Alzheimer’s Disease Center autopsy cohort. These individuals encompassed a spectrum of clinical conditions (cognitively normal to severe amnestic dementia). Polypeptides from the detergent-insoluble fraction were interrogated using liquid chromatography-electrospray ionization-tandem mass spectrometry. As anticipated, portions of peptides previously associated with neurologic diseases were enriched from subjects with dementia. Among all detected peptides, Apolipoprotein E (ApoE) stood out: even more than the expected Tau, APP/Aβ, and α-Synuclein peptides, ApoE peptides were strongly enriched in dementia cases, including from individuals lacking the APOE ε4 genotype. The amount of ApoE protein detected in detergent-insoluble fractions was robustly associated with levels of complement proteins C3 and C4. Immunohistochemical staining of APOE ε3/ε3 subjects’ amygdalae confirmed ApoE co-localization with C4 in amyloid plaques. Thus, analyses of human amygdala proteomics indicate that rather than being only an “upstream” genetic risk factor, ApoE is an aberrantly aggregated protein in its own right, and show that the ApoE protein may play active disease-driving mechanistic roles in persons lacking the APOE ε4 allele.

APOE ε4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue: a Finnish biobank, autopsy and clinical study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8696243/
Samu N. Kurki, Jonas Kantonen, Karri Kaivola, Laura Hokkanen, Mikko I. Mäyränpää, Henri Puttonen, FinnGen, Juha Martola, Minna Pöyhönen, Mia Kero, Jarno Tuimala, Olli Carpén, Anu Kantele, Olli Vapalahti,Marjaana Tiainen, Pentti J. Tienari, Kai Kaila, Johanna Hästbacka, and Liisa Myllykangas
Acta Neuropathologica Communications 2021; 9: 199
Published online 2021 Dec 23
doi: 10.1186/s40478-021-01302-7
Abstract
Apolipoprotein E ε4 allele (APOE4) has been shown to associate with increased susceptibility to SARS-CoV-2 infection and COVID-19 mortality in some previous genetic studies, but information on the role of APOE4 on the underlying pathology and parallel clinical manifestations is scarce. Here we studied the genetic association between APOE and COVID-19 in Finnish biobank, autopsy and prospective clinical cohort datasets. In line with previous work, our data on 2611 cases showed that APOE4 carriership associates with severe COVID-19 in intensive care patients compared with non-infected population controls after matching for age, sex and cardiovascular disease status. Histopathological examination of brain autopsy material of 21 COVID-19 cases provided evidence that perivascular microhaemorrhages are more prevalent in APOE4 carriers. Finally, our analysis of post-COVID fatigue in a prospective clinical cohort of 156 subjects revealed that APOE4 carriership independently associates with higher mental fatigue compared to non-carriers at six months after initial illness. In conclusion, the present data on Finns suggests that APOE4 is a risk factor for severe COVID-19 and post-COVID mental fatigue and provides the first indication that some of this effect could be mediated via increased cerebrovascular damage. Further studies in larger cohorts and animal models are warranted.

Cadmium exposure modulates the gut-liver axis in an Alzheimer’s disease mouse model

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8674298/
Angela Zhang, Megumi Matsushita, Liang Zhang, Hao Wang, Xiaojian Shi, Haiwei Gu, Zhengui Xia, and Julia Yue Cui
Communications Biology 2021; 4: 1398
Published online 2021 Dec 15
doi: 10.1038/s42003-021-02898-1
Abstract
The human Apolipoprotein E4 (ApoE4) variant is the strongest known genetic risk factor for Alzheimer’s disease (AD). Cadmium (Cd) has been shown to impair learning and memory at a greater extent in humanized ApoE4 knock-in (ApoE4-KI) mice as compared to ApoE3 (common allele)-KI mice. Here, we determined how cadmium interacts with ApoE4 gene variants to modify the gut-liver axis. Large intestinal content bacterial 16S rDNA sequencing, serum lipid metabolomics, and hepatic transcriptomics were analyzed in ApoE3- and ApoE4-KI mice orally exposed to vehicle, a low dose, or a high dose of Cd in drinking water. ApoE4-KI males had the most prominent changes in their gut microbiota, as well as a predicted down-regulation of many essential microbial pathways involved in nutrient and energy homeostasis. In the host liver, cadmium-exposed ApoE4-KI males had the most differentially regulated pathways; specifically, there was enrichment in several pathways involved in platelet activation and drug metabolism. In conclusion, Cd exposure profoundly modified the gut-liver axis in the most susceptible mouse strain to neurological damage namely the ApoE4-KI males, evidenced by an increase in microbial AD biomarkers, reduction in energy supply-related pathways in gut and blood, and an increase in hepatic pathways involved in inflammation and xenobiotic biotransformation.

Aduhelm Phase 3 Data: ARIA Is Common, Sometimes Serious

https://www.alzforum.org/news/research-news/aduhelm-phase-3-data-aria-common-sometimes-serious
ALZForum, 14 Dec 2021
• Overall, about one-third of people taking Aduhelm developed ARIA-E.
• Of these, a quarter were symptomatic, 3 percent were serious.
• Having brain microhemorrhage at baseline, or APOE4, increased risk.

November 2021

Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease

https://jamanetwork.com/journals/jamaneurology/fullarticle/2786606
Stephen Salloway, MD; Spyros Chalkias, MD; Frederik Barkhof, MD; Patrick Burkett, MD; Jerome Barako, MD; Derk Purcell, MD; Joyce Suhy, PhD; Fiona Forrestal, MSc; Ying Tian, PhD; Kimberly Umans, PhD; Guanfang Wang, PhD; Priya Singhal, MD; Samantha Budd Haeberlein, PhD; Karen Smirnakis, MD
JAMA Neurology 2022;79(1):13-21
November 22, 2021
doi:10.1001/jamaneurol.2021.4161
Key Points
Question
What are the characteristics of amyloid-related imaging abnormalities (ARIA) during aducanumab treatment in individuals with early Alzheimer disease?
Findings
In an integrated safety data set of 2 phase 3 clinical trials (EMERGE and ENGAGE) including 3285 participants, 425 patients (41.3%) in the combined 10 mg/kg aducanumab group (n = 1029) experienced ARIA; ARIA-edema occurred in 362 patients (35.2%), and 94 of these patients (26.0%) experienced associated symptoms (eg, headache, confusion, dizziness, and nausea). ARIA-microhemorrhage and ARIA–superficial siderosis occurred in 197 patients (19.1%) and 151 patients (14.7%), respectively.
Meaning
Amyloid-related imaging abnormalities occurred in approximately 40% of participants in the phase 3 studies of aducanumab, and approximately one-quarter of these patients experienced symptoms.
Abstract
Importance
The EMERGE and ENGAGE phase 3 randomized clinical trials of aducanumab provide a robust data set to characterize amyloid-related imaging abnormalities (ARIA) that occur with treatment with aducanumab, an amyloid-β (Aβ)–targeting monoclonal antibody, in patients with mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia.
Objective
To describe the radiographic and clinical characteristics of ARIA that occurred in EMERGE and ENGAGE. Design, Setting, and Participants Secondary analysis of data from the EMERGE and ENGAGE trials, which were 2 double-blind, placebo-controlled, parallel-group, phase 3 randomized clinical trials that compared low-dose and high-dose aducanumab treatment with placebo among participants at 348 sites across 20 countries. Enrollment occurred from August 2015 to July 2018, and the trials were terminated early (March 21, 2019) based on a futility analysis. The combined studies consisted of a total of 3285 participants with Alzheimer disease who received 1 or more doses of placebo (n = 1087) or aducanumab (n = 2198; 2752 total person-years of exposure) during the placebo-controlled period. Primary data analyses were performed from November 2019 to July 2020, with additional analyses performed through July 2021.
Interventions
Participants were randomly assigned 1:1:1 to high-dose or low-dose intravenous aducanumab or placebo once every 4 weeks. Dose titration was used as a risk-minimization strategy.
Main Outcomes and Measures
Brain magnetic resonance imaging was used to monitor patients for ARIA; associated symptoms were reported as adverse events.
Results
Of 3285 included participants, the mean (SD) age was 70.4 (7.45) years; 1706 participants (52%) were female, 2661 (81%) had mild cognitive impairment due to Alzheimer disease, and 1777 (54%) used symptomatic medications for Alzheimer disease. A total of 764 participants from EMERGE and 709 participants from ENGAGE were categorized as withdrawn before study completion, most often owing to early termination of the study by the sponsor. Unless otherwise specified, all results represent analyses from the 10-mg/kg group. During the placebo-controlled period, 425 of 1029 patients (41.3%) experienced ARIA, with serious cases occurring in 14 patients (1.4%). ARIA-edema (ARIA-E) was the most common adverse event (362 of 1029 [35.2%]), and 263 initial events (72.7%) occurred within the first 8 doses of aducanumab; 94 participants (26.0%) with an event exhibited symptoms. Common associated symptoms among 103 patients with symptomatic ARIA-E or ARIA-H were headache (48 [46.6%]), confusion (15 [14.6%]), dizziness (11 [10.7%]), and nausea (8 [7.8%]). Incidence of ARIA-E was highest in aducanumab-treated participants who were apolipoprotein E ε4 allele carriers. Most events (479 of 488 [98.2%]) among those with ARIA-E resolved radiographically; 404 of 488 (82.8%) resolved within 16 weeks. In the placebo group, 29 of 1076 participants (2.7%) had ARIA-E (apolipoprotein E ε4 carriers: 16 of 742 [2.2%]; noncarriers, 13 of 334 [3.9%]). ARIA-microhemorrhage and ARIA–superficial siderosis occurred in 197 participants (19.1%) and 151 participants (14.7%), respectively. Conclusions and Relevance In this integrated safety data set from EMERGE and ENGAGE, the most common adverse event in the 10-mg/kg group was ARIA-E, which occurred in 362 of the 1029 patients (35.2%) in the 10-mg/kg group with at least 1 postbaseline MRI scan, with 94 patients (26.0%) experiencing associated symptoms. The most common associated symptom was headache.
From Text:
The incidence of ARIA-E was higher in aducanumab-treated participants who were ApoE ε4 carriers than in those who were noncarriers (Table 1), and the incidence of ARIA-E was highest in ApoE ε4 carriers (290 of 674 [43.0%]) vs noncarriers (72 of 355 [20.3%]) in the 10-mg/kg group. Among ApoE ε4 carriers in the 10-mg/kg group, the incidence of ARIA-E was 66.0% in homozygous carriers (105 of 159) and 35.9% in heterozygous carriers (185 of 515). In the placebo group, 29 of 1076 participants (2.7%) had ARIA-E (ApoE ε4 carriers, 16 of 742 [2.2%]; noncarriers, 13 of 334 [3.9%]). The incidence of ARIA-E in the 3-mg/kg group was higher than in the 6-mg/kg group, reflecting the higher proportion of ApoE ε4 carriers in the 3-mg/kg group. In the 10-mg/kg group, 109 of 1029 participants (10.6%) had 1 or more ARIA-E events (109 of 362 [30.1%] among those with ARIA-E). Discontinuation of treatment was protocol mandated for serious ARIA-E (regardless of radiographic severity) and radiographically severe or serious ARIA-H (eFigure 1B in Supplement 2). Overall, 64 participants (6.2%) discontinued treatment due to ARIA. Discontinuations due to ARIA were higher for ApoE ε4 carriers than noncarriers (Table 1).

Epilepsy Contributes to White Matter Alzheimer’s Disease Pathology and Dysregulates Microglial Function

https://cms.aesnet.org/abstractslisting/epilepsy-contributes-to-white-matter-alzheimer%E2%80%99s-disease-pathology-and-dysregulates-microglial-function
Aaron Barbour, David Isaacs, David Irwin, Frances Jensen
Abstract number : 2.349, Submission category : 14. Neuropathology of Epilepsy, Year : 2021, Submission ID : 1825879 Source : www.aesnet.org
Presentation date : 12/9/2021 12:00:00 PM
Published date : Nov 22, 2021, 06:50 AM
Rationale:
Epilepsy is highly comorbid with Alzheimer’s Disease (AD) with up to 22% of AD patients with clinically identifiable seizures. Once largely considered a side effect of ß-amyloid (Aß) and tau induced neuronal hyperexcitability, recent data point to epilepsy as having a key role in the progression of AD and a bidirectional relationship with epilepsy inducing pathological features consistent with those seen in AD and vice versa. Both epilepsy and AD promote neuroinflammation and microglial dysfunction which contributes to the accumulation of Aß plaques. In addition, apolipoprotein E4 (APOE4) is the most prevalent risk factor for AD and has been linked to seizures independent of AD as well as microglial dysfunction. Thus, we hypothesized that seizures exacerbate AD neuropathology and that APOE4 and microglial phagocytic and immune dysregulation may underlie this relationship. Methods:
To test our hypothesis, we examined human temporal cortex from AD cases with (AD+Sz) and without (AD-Sz) known seizure history, and controls for Aß coverage and levels of APOE4, Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) and C-C Motif Chemokine Ligand 5 (CCL5), given their roles in microglial homeostasis, phagocytosis, and chemotaxis, respectively. Aß coverage was analyzed by quantitative immunohistochemistry (IHC), and APOE4, TREM2, and CCL5 concentrations were measured by Luminex Multiplex assays of cortical lysate. Controls to AD and AD+Sz to AD-Sz were compared via unpaired t-tests. Potential correlations between the multiplex analytes and Aß1-42 were examined via simple linear regressions.
Results:
As expected, quantitative immunohistochemistry revealed that when grouped together, all AD cases had significantly elevated Aß compared to controls in both the grey matter (GM) (n=17-22, p < 0.0001) and white matter (WM) (p < 0.01) of temporal cortical tissue. In addition, we found that AD+Sz have higher Aß coverage in cortical WM than AD-Sz (n=6-16, p< 0.05), with no significant differences found in the GM (p=0.3028). Luminex multiplex assay revealed a significant increase in APOE4 concentrations in all AD compared to control (n=5-20, p< 0.01) with a trend towards an increase in AD+Sz compared to AD-Sz (n=10, p=0.06). Further, TREM2 concentrations were reduced all AD cases compared to control (n=5-20, p< 0.05) and in AD+Sz compared to AD-Sz (n=10, p< 0.05). CCL5 was significantly increased in all AD compared to controls (n=5-20, p< 0.05) with no significant difference between AD+Sz and AD-Sz (n=10). However, CCL5 was positively correlated with Aß across all groups (p < 0.05, R2=0.189).
Conclusions: Overall, our data highlight a novel role of seizures to elevate Ab pathology in the WM of AD temporal cortex and that APOE4 and microglial dysregulation may underlie the worsened pathology, suggesting that therapies targeting microglia may attenuate disease progression in AD patients with epilepsy.

Effects of functional variants of vitamin C transporter genes on apolipoprotein E E4-associated risk of cognitive decline: The Nakajima study

https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0259663&fbclid=IwAR2wEdGBRQ2N27jq-_SxaDVvuXFBFr__lwhjcV9YK-Ttc0VESCZ5OAi5m7Y
Koji Hayashi, Moeko Noguchi-Shinohara, Takehiro Sato, Kazuyoshi Hosomichi, Takayuki Kannon, Chiemi Abe, Chiaki Domoto, Sohshi Yuki-Nozaki, Ayaka Mori, Mai Horimoto, Masami Yokogawa, Kenji Sakai, Kazuo Iwasa, Kiyonobu Komai, Mai Ishimiya, Hiroyuki Nakamura, Natsuko Ishida, Yukio Suga, Junko Ishizaki, Akihito Ishigami, Atsushi Tajima, Masahito Yamada
PLoS One 2021 Nov 15;16(11):e0259663
Published: November 15, 2021
DOI: https://doi.org/10.1371/journal.pone.0259663
Abstract
Apolipoprotein E E4 (APOE4) is a risk factor for cognitive decline. A high blood vitamin C (VC) level reduces APOE4-associated risk of developing cognitive decline in women. In the present study, we aimed to examine the effects of functional variants of VC transporter genes expressed in the brain (SLC2A1, SLC2A3, and SLC23A2) on APOE4-associated risk of developing cognitive decline. This case–control study involved 393 Japanese subjects: 252 cognitively normal and 141 cognitively impaired individuals (87 mild cognitive impairment and 54 dementia). Database searches revealed that rs1279683 of SLC23A2, and rs710218 and rs841851 of SLC2A1 are functional variants that are significantly associated with the altered expression of the respective genes and genotyped as three single nucleotide variants (SNVs). When stratified by SNV genotype, we found a significant association between APOE4 and cognitive decline in minor allele carriers of rs1279683 (odds ratio [OR] 2.02, 95% CI, 1.05–3.87, p = 0.035) but not in the homozygote carriers of the major allele. Significant associations between APOE4 and cognitive decline were also observed in participants with major allele homozygotes of rs710218 (OR 2.35, 95% CI, 1.05–5.23, p = 0.037) and rs841851 (OR 3.2, 95% CI, 1.58–6.46, p = 0.0012), but not in minor allele carriers of the respective SNVs. In contrast, the three functional SNVs showed no significant effect on cognitive decline. Our results imply that functional SNVs of VC transporter genes can affect APOE4-associated risk of developing cognitive decline via altered VC levels in the brain.

Biogen Investigates Death of 75-Year-Old on Aduhelm

https://www.biospace.com/article/biogen-investigates-death-in-75-year-old-alzheimer-s-patient-on-aduhelm/?fbclid=IwAR3h6kRmH-Cec0-DzDKiiVVoQwYVXTLfSPSCnENB-walKijkaZ5oQ4fi2_U
Mark Terry, BIOSPACE, Published: Nov 10, 2021
From the text:
Now the company is investigating the death of a 75-year-old woman who died of ARIA while receiving Aduhelm. There also appears to be a correlation between ARIA and a common gene associated with Alzheimer’s risk, APoE4. The Biogen studies found that patients receiving Aduhelm at the approved dose and who were carriers of the APoE4 gene variant had an incidence of 42% of ARIA compared to only 20% in noncarriers.

A brain proteomic signature of incipient Alzheimer’s disease in young APOE ε4 carriers identifies novel drug targets

https://www.science.org/doi/10.1126/sciadv.abi8178
JACKSON A. ROBERTS, VIJAY R. VARMA, YANG AN, SUDHIR VARMA, JULIÁN CANDIA, GIOVANNA FANTONI, VINOD TIWARI, CARLOS ANERILLAS, ANDREW WILLIAMSON, ATSUSHI SAITO, TINA LOEFFLER, IRENE SCHILCHER, RUIN MOADDEL, MOHAMMED KHADEER, JACQUELINE LOVETT, TOSHIKO TANAKA, OLGA PLETNIKOVA, JUAN C. TRONCOSO, DAVID A. BENNETT, MARILYN S. ALBERT, KAIWEN YU, MINGMING NIU, VAHRAM HAROUTUNIAN, BIN ZHANG, JUNMIN PENG, DEBORAH L. CROTEAU, SUSAN M. RESNICK, MYRIAM GOROSPE, VILHELM A. BOHR, LUIGI FERRUCCI, AND MADHAV THAMBISETTY
SCIENCE ADVANCES 10 Nov 2021 Vol 7, Issue 46
10 Nov 2021
DOI: 10.1126/sciadv.abi8178
Abstract
Aptamer-based proteomics revealed differentially abundant proteins in Alzheimer’s disease (AD) brains in the Baltimore Longitudinal Study of Aging and Religious Orders Study (mean age, 89 ± 9 years). A subset of these proteins was also differentially abundant in the brains of young APOE ε4 carriers relative to noncarriers (mean age, 39 ± 6 years). Several of these proteins represent targets of approved and experimental drugs for other indications and were validated using orthogonal methods in independent human brain tissue samples as well as in transgenic AD models. Using cell culture–based phenotypic assays, we showed that drugs targeting the cytokine transducer STAT3 and the Src family tyrosine kinases, YES1 and FYN, rescued molecular phenotypes relevant to AD pathogenesis. Our findings may accelerate the development of effective interventions targeting the earliest molecular triggers of AD.

Do Lipids Lubricate ApoE's Part in Alzheimer Mechanisms?

https://www.alzforum.org/news/conference-coverage/do-lipids-lubricate-apoes-part-alzheimer-mechanisms?fbclid=IwAR3vbuBvTibN3G0HZxF_qU2EuvCzkWbPJ4Y0XbO-epFHlt4WMFJKLIR8zsw
ALZForum 05 Nov 2021
• APOE4 glia process lipids poorly and become more inflamed under stress.
• APOE4 and cholesterol act together to boost Aβ production.
• Proteomic analysis suggests APOE4 accelerates many different aspects of AD.

October 2021

The Role of APOE and NF-κB in Alzheimer’s Disease

https://www.mdpi.com/2673-5601/1/4/27#:~:text=The%20accumulation%20of%20A%CE%B2%20plaques,400%20genes%20involved%20with%20inflammation.
Don A. Davies
Immuno 2021, 1(4), 391-399
Published: 28 October 2021
DOI: https://doi.org/10.3390/immuno1040027
Abstract
Apolipoprotein E (APOE) has three different isoforms, with APOE4 carriers representing a major risk factor for the development of Alzheimer’s disease (AD). AD is the most common form of dementia, and is a relentlessly progressive disorder that afflicts the aged, characterized by severe memory loss. Presently, AD does not have a cure, increasing the urgency for the development of novel therapeutics for the prevention/treatment of AD. The APOE4 isoform is associated with many pathological mechanisms, such as increased neuroinflammation and a reduction in β-amyloid (Aβ) clearance. The accumulation of Aβ plaques in the brain is a hallmark of AD. The presence of APOE4 can increase neuroinflammation via overactivation of the nuclear factor kappa B (NF-κB) pathway. The NF-κB pathway is a family of transcription factors involved with regulating over 400 genes involved with inflammation. AD is associated with sustained inflammation and an overactivation of the NF-κB pathway. Therefore, targeting the APOE4 isoform and suppressing the NF-κB pathway using anti-inflammatory compounds may result in the development of novel therapeutics for the prevention/treatment of AD.

Parasites Lost: Helminths, Pleiotropy, and The Prevention of Dementia

https://holisticprimarycare.net/topics/healthy-aging/parasites-lost-helminths-pleiotropy-and-the-prevention-of-dementia/
Michael McEvoy, Holistic Primary Care, 26 October 2021
The ability to link specific genetic features with particular diseases is among molecular biology’s greatest achievements.
But there’s a downside to that scientific triumph: it has oversimplified the picture of the relationships between genotype, environmental factors, gene expression, and health or illness, and created blind spots in our understanding. The truth is, there are many variables related to genotype that cannot be fit neatly into molecular biology’s linear cause-and-effect framework.
Through the lens of evolutionary biology and evolutionary genetics, we can better appreciate the complexities by which a particular genotype evolves and adapts to its environment. …
Includes discussion on
ApoE4 & Evolutionary Mismatch
ApoE4 & Pathogen Survival

The Relationship of APOE ε4, Race, and Sex on the Age of Onset and Risk of Dementia

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564142/
Danielle S. Powell, Pei-Lun Kuo, 1 Riaz Qureshi, Sally B. Coburn, David S. Knopman, Priya Palta, Rebecca Gottesman, Michael Griswold, Marilyn Albert, Jennifer A. Deal, and Alden L. Gross
Frontiers in Neurology 2021; 12: 735036
Published online 2021 Oct 20
doi: 10.3389/fneur.2021.735036
Abstract
Objective:
To investigate whether APOE ε4 genotype—an established risk factor for dementia—is associated with earlier age at diagnosis in addition to increased risk overall and in secondary analysis by race and sex. Methods:
We followed up 13,782 dementia-free individuals (n = 10,137 White, n = 3,645 Black, baseline age 60–66 years) in the Atherosclerosis Risk in Communities study for up to 30 years. Dementia was operationalized using standardized algorithms incorporating longitudinal cognitive change, proxy report, and hospital or death certificate dementia codes. We used a mixture of generalized gamma distributions to simultaneously estimate time to dementia, time to dementia-free death, and the proportion of individuals with dementia, by APOE ε4 status (≥1 vs. no alleles).
Results:
Median age of dementia onset among APOE ε4 carriers was 81.7 (Blacks) and 83.3 years (Whites) compared with 82.6 (Blacks) and 85.7 years (Whites) in non-APOE ε4 carriers (p > 0.05 Blacks; p < 0.01 Whites). Age of dementia diagnosis did not differ by sex in ε4 carriers, but among non-carriers, average age was earlier in males than females regardless of race. APOE ε4 carriers had on average a higher proportion of diagnoses; results did not differ by race or sex.
Conclusions:
APOE ε4 carrier status is associated with earlier age of dementia diagnosis with differences across race and sex. These findings clarify the causal role of APOE in dementia etiology, which could help better identify at-risk subgroups and may help facilitate better research trial recruitment and design.

Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer’s disease

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531903/
Alberto Serrano-Pozo, Zhaozhi Li, Ayush Noori, Huong N. Nguyen, Aziz Mezlini, Liang Li, Eloise Hudry, Rosemary J. Jackson, Bradley T. Hyman, and Sudeshna Das
Nature Aging 2021 Oct; 1(10): 919–931
Published online 2021 Oct 11
doi: 10.1038/s43587-021-00123-6
Abstract
The roles of APOEε4 and APOEε2—the strongest genetic risk and protective factors for Alzheimer’s disease—in glial responses remain elusive. We tested the hypothesis that APOE alleles differentially impact glial responses by investigating their effects on the glial transcriptome from elderly control brains with no neuritic amyloid plaques. We identified a cluster of microglial genes that are upregulated in APOEε4 and downregulated in APOEε2 carriers relative to APOEε3 homozygotes. This microglia-APOE cluster is enriched in phagocytosis—including TREM2 and TYROBP—and proinflammatory genes, and is also detectable in brains with frequent neuritic plaques. Next, we tested these findings in APOE knock-in mice exposed to acute (lipopolysaccharide challenge) and chronic (cerebral β-amyloidosis) insults and found that these mice partially recapitulate human APOE-linked expression patterns. Thus, the APOEε4 allele might prime microglia towards a phagocytic and proinflammatory state through an APOE–TREM2–TYROBP axis in normal aging as well as in Alzheimer’s disease.

NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547963/
Theresa Pohlkamp, Xunde Xian, Connie H Wong, Murat S Durakoglugil, Gordon Chandler Werthmann, Takaomi C Saido, Bret M Evers, Charles L White, III, Jade Connor, Robert E Hammer, and Joachim Herz
eLife 2021; 10: e72034
Published online 2021 Oct 7
doi: 10.7554/eLife.72034
Abstract
Apolipoprotein E4 (ApoE4) is the most important and prevalent risk factor for late-onset Alzheimer’s disease (AD). The isoelectric point of ApoE4 matches the pH of the early endosome (EE), causing its delayed dissociation from ApoE receptors and hence impaired endolysosomal trafficking, disruption of synaptic homeostasis, and reduced amyloid clearance. We have shown that enhancing endosomal acidification by inhibiting the EE-specific sodium-hydrogen exchanger 6 (NHE6) restores vesicular trafficking and normalizes synaptic homeostasis. Remarkably and unexpectedly, loss of NHE6 (encoded by the gene Slc9a6) in mice effectively suppressed amyloid deposition even in the absence of ApoE4, suggesting that accelerated acidification of EEs caused by the absence of NHE6 occludes the effect of ApoE on amyloid plaque formation. NHE6 suppression or inhibition may thus be a universal, ApoE-independent approach to prevent amyloid buildup in the brain. These findings suggest a novel therapeutic approach for the prevention of AD by which partial NHE6 inhibition reverses the ApoE4-induced endolysosomal trafficking defect and reduces plaque load.

Associations between race, APOE genotype, cognition, and mortality among urban middle-aged white and African American adults

https://www.nature.com/articles/s41598-021-98117-2
Jordan Weiss, Sharmin Hossain, Ana I. Maldonado, Botong Shen, Hind A. Beydoun, Mika Kivimaki, Michele K. Evans, Alan B. Zonderman & May A. Beydoun
Scientific Reports 11, 19849 (2021)
Published 06 October 2021
DOI: https://doi.org/10.1038/s41598-021-98117-2
Abstract
We examined associations between cognition and mortality and how these relationships vary by race and Apolipoprotein E (APOE) genotype, in a longitudinal study of 2346 middle-aged White and African American adults (30–64 years at baseline) from the Healthy Aging in Neighborhoods of Diversity across the Life Span cohort study. Baseline cognition spanned global mental status, and several domains obtained using principal components analysis (PCA; PCA1: verbal memory/fluency; PCA2: attention/working memory; PCA3: executive function/visuo-spatial abilities). Cox regression models evaluated associations between cognition and all-cause and cardiovascular disease (CVD)-mortality. Interactions between cognition and APOE2 as well as APOE4 allelic dose were tested, and race was a key effect modifier. Higher APOE4 dose was associated with increased CVD-mortality (hazard ratio [HR] per allele = 1.37; 95% CI 1.01–1.86, p = 0.041); APOE2 dosage’s association with CVD-mortality was non-significant (HR = 0.60; 95% CI 0.35–1.03, p = 0.065). Higher PCA3 was associated with lower all-cause (HR = 0.93; 95% CI 0.87–0.99, p = 0.030) and CVD (HR = 0.85; 95% CI 0.77–0.95, p = 0.001) mortality risks, the latter association being more pronounced among Whites. PCA2 interacted synergistically with APOE2 dosage, reducing risks for all-cause mortality (PCA2 × APOE2: − 0.33 ± 0.13, p = 0.010) and CVD mortality (PCA2 × APOE2: − 0.73 ± 0.31, p = 0.019). In conclusion, greater executive function/visuo-spatial abilities were associated with reduced CVD-specific mortality, particularly among Whites. Greater “attention/working memory” coupled with higher APOE2 dosage was linked with reduced all-cause and CVD mortality risks.

September 2021

Apolipoprotein E ɛ4–related effects on cognition are limited to the Alzheimer’s disease spectrum

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8811053/
Alberto Fernández, Lucía Vaquero, Ricardo Bajo, Pilar Zuluaga
GeroScience 2022 Feb; 44(1): 195–209
Published online 2021 Sep 30
doi: 10.1007/s11357-021-00450-x
Abstract
Whether the deleterious effects of APOE4 are restricted to the Alzheimer’s disease (AD) spectrum or cause cognitive impairment irrespectively of the development of AD is still a matter of debate, and the focus of this study. Our analyses included APOE4 genotype, neuropsychological variables, amyloid-βeta (Aβ) and Tau markers, FDG-PET values, and hippocampal volumetry data derived from the healthy controls sample of the ADNI database. We formed 4 groups of equal size (n = 30) based on APOE4 carriage and amyloid-PET status. Baseline and follow-up (i.e., 48 months post-baseline) results indicated that Aβ-positivity was the most important factor to explain poorer cognitive performance, while APOE4 only exerted a significant effect in Aβ-positive subjects. Additionally, multiple regression analyses evidenced that, within the Aβ-positive sample, hippocampal volumetry explained most of the variability in cognitive performance for APOE4 carriers. These findings represent a strong support for the so-called preclinical/prodromal hypothesis, which states that the reported differences in cognitive performance between healthy carriers and non-carriers are mainly due to the APOE4’s capability to increase the risk of AD. Moreover, our results reinforce the notion that a synergistic interaction of Aβ and APOE4 elicits a neurodegenerative process in the hippocampus that might be the main cause of impaired cognitive performance.

ReCODE: A Personalized, Targeted, Multi-Factorial Therapeutic Program for Reversal of Cognitive Decline

https://www.mdpi.com/2227-9059/9/10/1348
Rao, R.V.; Kumar, S.; Gregory, J.; Coward, C.; Okada, S.; Lipa, W.; Kelly, L.; Bredesen, D.E.
Biomedicines 2021, 9, 1348
29 September 2021
DOI: https://doi.org/10.3390/biomedicines9101348
Abstract
Background:
Alzheimer’s disease (AD) is the major cause of age-associated cognitive decline, and in the absence of effective therapeutics is progressive and ultimately fatal, creating a dire need for successful prevention and treatment strategies. We recently reported results of a successful proof-of-concept trial, using a personalized, precision medicine protocol, but whether such an approach is readily scalable is unknown.
Objective:
In the case of AD, there is not a single therapeutic that exerts anything beyond a marginal, unsustained, symptomatic effect. This suggests that the monotherapeutic approach of drug development for AD may not be an optimal one, at least when used alone. Using a novel, comprehensive, and personalized therapeutic system called ReCODE (reversal of cognitive decline), which proved successful in a small, proof-of-concept trial, we sought to determine whether the program could be scaled to improve cognitive and metabolic function in individuals diagnosed with subjective cognitive impairment, mild cognitive impairment, and early-stage AD.
Methods:
255 individuals submitted blood samples, took the Montreal Cognitive Assessment (MoCA) test, and answered intake questions. Individuals who enrolled in the ReCODE program had consultations with clinical practitioners, and explanations of the program were provided. Participants had follow-up visits that included education regarding diet, lifestyle choices, medications, supplements, repeat blood sample analysis, and MoCA testing between 2 and 12 months after participating in the ReCODE program. Pre- and post-treatment measures were compared using the non-parametric Wilcoxon signed rank test.
Results and Conclusions:
By comparing baseline to follow-up testing, we observed that MoCA scores either significantly improved or stabilized in the entire participant pool—results that were not as successful as those in the proof-of-concept trial, but more successful than anti-amyloid therapies—and other risk factors including blood glucose, high-sensitivity C-reactive protein, HOMA-IR, and vitamin D significantly improved in the participant pool. Our findings provide evidence that a multi-factorial, comprehensive, and personalized therapeutic program designed to mitigate AD risk factors can improve risk factor scores and stabilize or reverse the decline in cognitive function. Since superior results were obtained in the proof-of-concept trial, which was conducted by a small group of highly trained and experienced physicians, it is possible that results from the use of this personalized approach would be enhanced by further training and experience of the practicing physicians. Nonetheless, the current results provide further support indicating the potential of such an approach for the prevention and reversal of cognitive decline.
And from the results section: In general, participants did not have other co-morbid conditions, and about 70% of them possessed at least one ApoE4 allele, a major genetic risk factor for AD development [9,16,17].

APOE4 is associated with elevated blood lipids and lower levels of innate immune biomarkers in a tropical Amerindian subsistence population

https://elifesciences.org/articles/682
Angela R Garcia, Caleb Finch, Margaret Gatz, Thomas Kraft, Daniel Eid Rodriguez, Daniel Cummings, Mia Charifson, Kenneth Buetow, Bret A Beheim, Hooman Allayee, Gregory S Thomas, Jonathan Stieglitz, Michael D Gurven, Hillard Kaplan, Benjamin C Trumble
e Life 10:e68231
Version of Record published September 29, 2021
DOI: https://doi.org/10.7554/eLife.68231
Abstract
In post-industrial settings, apolipoprotein E4 (APOE4) is associated with increased cardiovascular and neurological disease risk. However, the majority of human evolutionary history occurred in environments with higher pathogenic diversity and low cardiovascular risk. We hypothesize that in high-pathogen and energy-limited contexts, the APOE4 allele confers benefits by reducing innate inflammation when uninfected, while maintaining higher lipid levels that buffer costs of immune activation during infection. Among Tsimane forager-farmers of Bolivia (N = 1266, 50% female), APOE4 is associated with 30% lower C-reactive protein, and higher total cholesterol and oxidized LDL. Blood lipids were either not associated, or negatively associated with inflammatory biomarkers, except for associations of oxidized LDL and inflammation which were limited to obese adults. Further, APOE4 carriers maintain higher levels of total and LDL cholesterol at low body mass indices (BMIs). These results suggest that the relationship between APOE4 and lipids may be beneficial for pathogen-driven immune responses and unlikely to increase cardiovascular risk in an active subsistence population.

High-fat diet increases gliosis and immediate early gene expression in APOE3 mice, but not APOE4 mice

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-021-02256-2?fbclid=IwAR0WXX_8W7jL6X0dg7C1hTPDqWH4ZtQ9fGFvLAa4voaJFul5JyYheeibQTo
Nahdia S. Jones, Katarina Q. Watson & G. William Rebeck
Journal of Neuroinflammation volume 18, Article number: 214 (2021)
Published: 18 September 2021
DOI: https://doi.org/10.1186/s12974-021-02256-2
Abstract
Background
APOE4 is the strongest genetic risk factor for Alzheimer’s disease (AD), and obesity is a strong environmental risk factor for AD. These factors result in multiple central nervous system (CNS) disturbances and significantly increase chances of AD. Since over 20% of the US population carry the APOE4 allele and over 40% are obese, it is important to understand how these risk factors interact to affect neurons and glia in the CNS.
Methods
We fed male and female APOE3 and APOE4 knock-in mice a high-fat diet (HFD-45% kcal fat) or a "control" diet (CD-10% kcal fat) for 12 weeks beginning at 6 months of age. At the end of the 12 weeks, brains were collected and analyzed for gliosis, neuroinflammatory genes, and neuronal integrity.
Results
APOE3 mice on HFD, but not APOE4 mice, experienced increases in gliosis as measured by GFAP and Iba1 immunostaining. APOE4 mice on HFD showed a stronger increase in the expression of Adora2a than APOE3 mice. Finally, APOE3 mice on HFD, but not APOE4 mice, also showed increased neuronal expression of immediate early genes cFos and Arc.
Conclusions
These findings demonstrate that APOE genotype and obesity interact in their effects on important processes particularly related to inflammation and neuronal plasticity in the CNS. During the early stages of obesity, the APOE3 genotype modulates a response to HFD while the APOE4 genotype does not. This supports a model where early dysregulation of inflammation in APOE4 brains could predispose to CNS damages from various insults and later result in the increased CNS damage normally associated with the APOE4 genotype.

Perioperative neurocognitive and functional neuroimaging trajectories in older APOE4 carriers compared with non-carriers: secondary analysis of a prospective cohort study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8693648/
Jeffrey N. Browndyke, Mary C. Wright, Rosa Yang, Ayesha Syed, John Park, Ashley Hall, Katherine Martucci, Michael J. Devinney, Leslie Shaw, Teresa Waligorska, Eugene W. Moretti, Heather E. Whitson, Harvey J. Cohen, Joseph P. Mathew, Miles Berger
British Journal of Anaesthesia 2021 Dec; 127(6): 917–928
Published online 2021 Sep 14 doi: 10.1016/j.bja.2021.08.012
Abstract
Background
Cognitive dysfunction after surgery is a major issue in older adults. Here, we determined the effect of APOE4 on perioperative neurocognitive function in older patients.
Methods
We enrolled 140 English-speaking patients ≥60 yr old scheduled for noncardiac surgery under general anaesthesia in an observational cohort study, of whom 52 underwent neuroimaging. We measured cognition; Aβ, tau, p-tau levels in CSF; and resting-state intrinsic functional connectivity in six Alzheimer's disease-risk regions before and 6 weeks after surgery.
Results
There were no significant APOE4-related differences in cognition or CSF biomarkers, except APOE4 carriers had lower CSF Aβ levels than non-carriers (preoperative median CSF Aβ [median absolute deviation], APOE4 305 pg ml−1 [65] vs 378 pg ml−1 [38], respectively; P=0.001). Controlling for age, APOE4 carriers had significantly greater preoperative functional connectivity than non-carriers between several brain regions implicated in Alzheimer's disease, including between the left posterior cingulate cortex and left angular gyrus (β [95% confidence interval, CI], 0.218 [0.137–0.230]; PFWE=0.016). APOE4 carriers, but not non-carriers, experienced significant connectivity decreases from before to 6 weeks after surgery between several brain regions including between the left posterior cingulate cortex and left angular gyrus (β [95% CI], –0.196 [–0.256 to –0.136]; PFWE=0.001). Most preoperative and postoperative functional connectivity differences did not change after controlling for preoperative CSF Aβ levels.
Conclusions
Postoperative change trajectories for cognition and CSF Aβ, tau or p-tau levels did not differ between community dwelling older APOE4 carriers and non-carriers. APOE4 carriers showed greater preoperative functional connectivity and greater postoperative decreases in functional connectivity in key Alzheimer's disease-risk regions, which occur via Aβ-independent mechanisms.

APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420022/
Brandon C. Farmer, Holden C. Williams, Nicholas A. Devanney, Margaret A. Piron,1 Grant K. Nation, David J. Carter, Adeline E. Walsh,1 Rebika Khanal, Lyndsay E. A. Young, Jude C. Kluemper, Gabriela Hernandez, Elizabeth J. Allenger, Rachel Mooney, Lesley R. Golden, Cathryn T. Smith, J. Anthony Brandon, Vedant A. Gupta, Philip A. Kern, Matthew S. Gentry, Josh M. Morganti, Ramon C. Sun, and Lance A. Johnson
Molecular Neurodegeneration 2021; 16: 62
Published online 2021 Sep 6
doi: 10.1186/s13024-021-00483-y
Abstract
Background
Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer’s disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field.
Methods
Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4.
Results
Single-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of 13C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increased lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggest an E4-associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the Ε4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing female mice, a subgroup analysis revealed that young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis.
Conclusions
Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a ‘Warburg like’ endophenotype that is observable in young females decades prior to clinically manifest AD.

Association of APOE4 genotype and treatment with cognitive outcomes in breast cancer survivors over time

https://www.nature.com/articles/s41523-021-00327-4?fbclid=IwAR2aoo1Ei7Qqx0OZIn8vC7IE-EuIBoYAjaL7YH0hMQ15MXcZFU0wCarZHio
Kathleen Van Dyk, Catherine M. Crespi, Julienne E. Bower, Judith E. Carroll, Laura Petersen & Patricia A. Ganz
npj Breast Cancer volume 7, Article number: 112 (2021)
Published: 03 September 2021
Abstract
This prospective longitudinal study of breast cancer survivors (n = 167) examined the association of apolipoprotein ε4 (APOE ε4) genotype with cognition and interactions with chemotherapy or endocrine therapy up to 6 years after treatment. In general, we found no effects of ε4 across timepoints and treatment exposures; post hoc analysis at 3–6 years suggested a trend towards worse cognition in the domains of attention and learning among ε4 carriers exposed to endocrine therapy. Further study is needed.

ApoE4 attenuates autophagy via FoxO3a repression in the brain

https://www.nature.com/articles/s41598-021-97117-6?fbclid=IwAR3kXC58jzhtSg7LL1tsnIvEAiyXWFYBAkjIH6NJBT9mQ1MDZWzowbtlZZQ
Hee-Young Sohn, Seong-Ik Kim, Jee-Yun Park, Sung-Hye Park, Young Ho Koh, Joon Kim & Chulman Jo Scientific Reports volume 11, Article number: 17604 (2021)
Published: 02 September 2021
DOI: https://doi.org/10.1038/s41598-021-97117-6
Abstract
Apolipoprotein E (ApoE) plays multiple roles in lipid transport, neuronal signaling, glucose metabolism, mitochondrial function, and inflammation in the brain. It is also associated with neurodegenerative diseases, and its influence differs depending on the isoform. In particular, the ε4 allele of APOE is the highest genetic risk factor for developing late-onset Alzheimer’s disease (AD). However, the mechanism by which ApoE4 contributes to the pathogenesis of AD remains unclear. We investigated the effect of ApoE4 on autophagy in the human brains of ApoE4 carriers. Compared to non-carriers, the expression of FoxO3a regulating autophagy-related genes was significantly reduced in ApoE4 carriers, and the phosphorylation level of FoxO3a at Ser253 increased in ApoE4 carriers, indicating that FoxO3a is considerably repressed in ApoE4 carriers. As a result, the protein expression of FoxO3a downstream genes, such as Atg12, Beclin-1, BNIP3, and PINK1, was significantly decreased, likely leading to dysfunction of both autophagy and mitophagy in ApoE4 carriers. In addition, phosphorylated tau accumulated more in ApoE4 carriers than in non-carriers. Taken together, our results suggest that ApoE4 might attenuate autophagy via the repression of FoxO3a in AD pathogenesis. The regulation of the ApoE4-FoxO3a axis may provide a novel therapeutic target for the prevention and treatment of AD with the APOE4 allele.

APOE4 Affects Basal and NMDAR-Mediated Protein Synthesis in Neurons by Perturbing Calcium Homeostasis

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528497/
Sarayu Ramakrishna, Vishwaja Jhaveri, Sabine C. Konings, Bharti Nawalpuri, Sumita Chakraborty, Bjørn Holst, Benjamin Schmid, Gunnar K. Gouras, Kristine K. Freude, and Ravi S. Muddashetty
Journal of Neuroscience 2021 Oct 20; 41(42): 8686–8709
Epub 2021 Sep 2
doi: 10.1523/JNEUROSCI.0435-21.2021
Abstract
Apolipoprotein E (APOE), one of the primary lipoproteins in the brain has three isoforms in humans, APOE2, APOE3, and APOE4. APOE4 is the most well-established risk factor increasing the predisposition for Alzheimer's disease (AD). The presence of the APOE4 allele alone is shown to cause synaptic defects in neurons and recent studies have identified multiple pathways directly influenced by APOE4. However, the mechanisms underlying APOE4-induced synaptic dysfunction remain elusive. Here, we report that the acute exposure of primary cortical neurons or synaptoneurosomes to APOE4 leads to a significant decrease in global protein synthesis. Primary cortical neurons were derived from male and female embryos of Sprague Dawley (SD) rats or C57BL/6J mice. Synaptoneurosomes were prepared from P30 male SD rats. APOE4 treatment also abrogates the NMDA-mediated translation response indicating an alteration of synaptic signaling. Importantly, we demonstrate that both APOE3 and APOE4 generate a distinct translation response which is closely linked to their respective calcium signature. Acute exposure of neurons to APOE3 causes a short burst of calcium through NMDA receptors (NMDARs) leading to an initial decrease in protein synthesis which quickly recovers. Contrarily, APOE4 leads to a sustained increase in calcium levels by activating both NMDARs and L-type voltage-gated calcium channels (L-VGCCs), thereby causing sustained translation inhibition through eukaryotic translation elongation factor 2 (eEF2) phosphorylation, which in turn disrupts the NMDAR response. Thus, we show that APOE4 affects basal and activity-mediated protein synthesis responses in neurons by affecting calcium homeostasis.

August 2021

Testing for Interactions Between APOE and Klotho Genotypes on Cognitive, Dementia, and Brain Imaging Metrics in UK Biobank

https://content.iospress.com/articles/journal-of-alzheimers-disease/jad210181
Rachana Tank, Joey Ward, Carlos Celis-Morales, Daniel J Smith, Kristin E Flegal, Donald M Lyall
Journal of Alzheimers Disease 2021;83(1):51-55
Published: 31 August 2021
doi: 10.3233/JAD-210181.
Abstract
Recent research suggests genetic variation in the Klotho locus may modify the association between APOE ɛ4 and cognitive impairment. We tested for associations and interactions between these genotypes versus risk of dementia, cognitive abilities, and brain structure in older UK Biobank participants. Klotho status was indexed with rs9536314 heterozygosity (versus not), in unrelated people with versus without APOE ɛ4 genotype, corrected for various confounders. APOE ɛ4 associated with increased risk of dementia, worse cognitive abilities, and brain structure. Klotho was associated with better reasoning. There were no interactions; potentially suggesting an age- and pathology-dependent Klotho effect.

APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation

https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(21)00383-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2213671121003830%3Fshowall%3Dtrue
Se-In Lee, Woojin Jeong, Heejin Lim, Sukhee Cho, Hyein Lee, Yonghee Jang, Joonho Cho, Simsung Bae, Yuan-Ta Lin, Li-Huei Tsai, Dae Won Moon, Jinsoo Seo Stem Cell Reports VOLUME 16, ISSUE 9, P2128-2137, SEPTEMBER 14, 2021
Published: August 26, 2021
DOI: https://doi.org/10.1016/j.stemcr.2021.07.017
Highlights
• ApoE4 ACM induces neuronal lipid raft expansion and Aβ42 overproduction
• Co-localization of lipid rafts and APP increases in neurons by ApoE4 ACM
• Increasing cholesterol in media recapitulates the effects of ApoE4 ACM on neurons
• Cholesterol depletion in ApoE4 ACM abolishes its effects on neurons
Summary
The ε4 allele of APOE-encoding apolipoprotein (ApoE) is one of the strongest genetic risk factors for Alzheimer’s disease (AD). One of the overarching questions is whether and how this astrocyte-enriched risk factor initiates AD-associated pathology in neurons such as amyloid-β (Aβ) accumulation. Here, we generate neurons and astrocytes from isogenic human induced pluripotent stem cells (hiPSCs) carrying either APOE ε3 or APOE ε4 allele and investigate the effect of astrocytic ApoE4 on neuronal Aβ production. Secretory factors in conditioned media from ApoE4 astrocytes significantly increased amyloid precursor protein (APP) levels and Aβ secretion in neurons. We further found that increased cholesterol secretion from ApoE4 astrocytes was necessary and sufficient to induce the formation of lipid rafts that potentially provide a physical platform for APP localization and facilitate its processing. Our study reveals the contribution of ApoE4 astrocytes to amyloidosis in neurons by expanding lipid rafts and facilitating Aβ production through an oversupply of cholesterol.

The influence of ApoE4 on the clinical outcomes and pathophysiology of degenerative cervical myelopathy

https://insight.jci.org/articles/view/149227?fbclid=IwAR3XEJgVt4oSdbDAlKF4O-kGl6XjPXy1EXqYKQovQ-F3xk0F8kaiD0x1ecM
Alexa Desimone, James Hong, Sydney T. Brockie, Wenru Yu, Alex M. Laliberte, and Michael G. Fehlings
JCI Insight 2021;6(15):e149227
Published August 9, 2021
DOI: https://doi.org/10.1172/jci.insight.149227
Abstract
Degenerative cervical myelopathy (DCM) is the most common cause of nontraumatic spinal cord injury in adults worldwide. Surgical decompression is generally effective in improving neurological outcomes and halting progression of myelopathic deterioration. However, a subset of patients experience suboptimal neurological outcomes. Given the emerging evidence that apolipoprotein E4 (ApoE4) allelic status influences neurodegenerative conditions, we examined whether the presence of the ApoE4 allele may account for the clinical heterogeneity of treatment outcomes in patients with DCM. Our results demonstrate that human ApoE4+ DCM patients have a significantly lower extent of improvement after decompression surgery. Functional analysis of our DCM mouse model in targeted-replacement mice expressing human ApoE4 revealed delayed gait recovery, forelimb grip strength, and hind limb mechanical sensitivity after decompression surgery, compared with their ApoE3 counterparts. This was accompanied by an exacerbated proinflammatory response resulting in higher concentrations of TNF-α, IL-6, CCL3, and CXCL9. At the site of injury, there was a significant decrease in gray matter area, an increase in the activation of microglia/macrophages, and increased astrogliosis after decompression surgery in the ApoE4 mice. Our study is the first to our knowledge to investigate the pathophysiological underpinnings of ApoE4 in DCM, which suggests a possible personalized medicine approach for the treatment of DCM in ApoE4 carriers.

July 2021

Herpes simplex virus, early neuroimaging markers and incidence of Alzheimer’s disease

https://www.nature.com/articles/s41398-021-01532-2
Morgane Linard, Marion Baillet, Luc Letenneur, Isabelle Garrigue, Gwenaëlle Catheline, Jean-François Dartigues, Karine Peres & Catherine Helmer
Translational Psychiatry volume 11, Article number: 414 (2021)
Published: 31 July 2021 Abstract
While previous studies suggest the implication of herpes simplex virus (HSV) in the onset of Alzheimer’s disease (AD), no study has investigated its association with early neuroimaging markers of AD. In the Three-City and the AMI cohorts, the associations between HSV infection and (i) hippocampal volume (n = 349), (ii) white matter alterations in the parahippocampal cingulum and fornix using diffusion tensor imaging (n = 260), and (iii) incidence of AD (n = 1599) were assessed according to APOE4 status. Regardless of APOE4 status, infected subjects presented (i) significantly more microstructural alterations of the parahippocampal cingulum and fornix, (ii) lower hippocampal volumes only when their anti-HSV IgG level was in the highest tercile—reflecting possibly more frequent reactivations of the virus (p = 0.03 for subjects with a high anti-HSV IgG level while there was no association for all infected subjects, p = 0.19), and (iii) had no increased risk of developing AD. Nevertheless, among APOE4 carriers, infected subjects presented lower hippocampal volumes, although not significant (p = 0.09), and a two or three times higher risk of developing AD (adjusted Hazard ratio (aHR) = 2.72 [1.07–6.91] p = 0.04 for infected subjects and aHR = 3.87 [1.45–10.28] p = 0.007 for infected subjects with an anti-HSV IgG level in the highest tercile) while no association was found among APOE4 noncarriers. Our findings support an association between HSV infection and AD and a potential interaction between HSV status and APOE4. This reinforces the need to further investigate the infectious hypothesis of AD, especially the associated susceptibility factors and the possibility of preventive treatments.

Apolipoprotein E Genotype, Meat, Fish, and Egg Intake in Relation to Mortality Among Older Adults: A Longitudinal Analysis in China

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329349/
Xurui Jin, Shangzhi Xiong, Changzheng Yuan, Enying Gong, Xian Zhang, Yao Yao, Yu Leng, Zhangming Niu, Yi Zeng, and Lijing L. Yan
Frontiers in Medicine (Lausanne), 2021 Jul 20;8:697389
Published online 20 Jul 2021
doi: 10.3389/fmed.2021.697389
Abstract
Introduction: The interactions between apolipoprotein E (APOE) genotype and diet pattern changes were found significant in several trials, implying that APOE gene may modify the effect of animal protein-rich food on health outcomes. We aim to study the interaction of APOE genotype with the effect of meat, fish and egg intake on mortality.
Methods: This population-based study enrolled 8,506 older adults (mean age: 81.7 years, 52.3% female) from the Chinese Longitudinal Healthy Longevity Study. The intake frequency of meat, fish and egg was assessed by 3-point questions at baseline. Cox regression was conducted to calculate the hazard ratios for all-cause mortality of intake levels of meat, fish and egg. The analyses were stratified by APOE genotype and sex. The analyses were performed in 2020.
Results: In the multivariable-adjusted models, meat and fish intake was associated with all-cause mortality (high vs. low intake: meat: HR: 1.14, 95% CI: 1.01, 1.28; fish: HR: 0.83, 95% CI: 0.73, 0.95). APOE genotype have significant interactions with meat and fish intake (Ps < 0.05). Compared with low fish intake, high fish intake was associated with lower risk of mortality (HR: 0.74, 95% CI: 0.56–0.98) only among the APOE ε4 carriers. High meat intake was significantly associated with higher risks of mortality (HR: 1.13, 95% CI: 1.04–1.25) only among the APOE ε4 non-carriers. The interactive relationship was restricted among the male. No significant findings were observed between egg and mortality among carriers or non-carriers.
Conclusions: Among Chinese older adults, the significance of associations of mortality with reported meat or fish intake depended on APOE-E4 carriage status. If validated by other studies, our findings provide evidence for gene-based “precision” lifestyle recommendations.

Influence of Physical Activity Levels and Functional Capacity on Brain β-Amyloid Deposition in Older Women

https://www.frontiersin.org/articles/10.3389/fnagi.2021.697528/full
Raquel Pedrero-Chamizo, Cassandra Szoeke, Lorraine Dennerstein, Stephen Campbell
Frontiers in Aging Neuroscience, 09 July 2021 Sec. Alzheimer's Disease and Related Dementias, Volume 13 - 2021
09 July 2021
DOI: https://doi.org/10.3389/fnagi.2021.697528
Physical activity (PA) and Alzheimer's disease are associated. However, how PA influences the cerebral β-amyloid (Aβ) burden remains unclear. The aim of this study was to determine if PA levels and/or functional capacity (FC) are associated with Aβ plaque deposition, and whether these associations differed according to APOE-ε4 genotype. A total of 117 women (69.7 ± 2.6 years; 33.3% APOE-ε4-carriers) from the Women's Healthy Ageing Project cohort (WHAP) were analyzed. PA was measured using the International Physical Activity Questionnaire and, FC was evaluated using the Timed Up and Go test (TUGt). Positron emission tomography with F-18 Florbetaben was carried out to assess cerebral Aβ burden, and quantified using standardized uptake value rations. The sample was split into PA and TUGt tertiles (T1, T2 and T3), and compared according to APOE-ε4 genotype (positive/negative). There were no significant differences in Aβ accumulation according to PA tertiles and APOE-ε4 genotype. Regarding FC, APOE-ε4+ participants in the first TUGt tertile (high performance) obtained significant lower Aβ accumulations compared with the other two tertiles (p < 0.05). Comparing between genotypes, greater Aβ depositions were found between T2 and T3 in APOE-ε4+ compared with those who were APOE-ε4– (p < 0.05). Values of TUGt ≥ 6.5 s (APOE-ε4+) and 8.5 s (APOE-ε4–) were associated with an increased risk of having higher Aβ retention. In conclusion, low performance in TUGt is associated with a negative effect on brain pathology with increasing cerebral Aβ depositions in older women who are APOE-ε4+. In physically active older women (> 600 METs·min/week), higher PA levels are not associated with reduction in Aβ depositions.

Can Physical Activity Reduce the Risk of Cognitive Decline in Apolipoprotein e4 Carriers? A Systematic Review

https://www.mdpi.com/1660-4601/18/14/7238
Jose Luis Perez-Lasierra, Jose Antonio Casajús, José Antonio Casasnovas, Jose Miguel Arbones-Mainar, Antonio Lobo, Elena Lobo, Belén Moreno-Franco and Alejandro Gonzalez-Agüero
International Journal of Environmental Research and Public Health 2021, 18(14), 7238
Published: 6 July 2021
DOI: https://doi.org/10.3390/ijerph18147238
Abstract
Physical activity (PA) reduces the risk of cognitive decline (CD) in the general population. However, little is known about whether the presence of the apolipoprotein E epsilon 4 allele (APOE e4) could modify this beneficial effect. The aim of this systematic review was to analyze and synthetize the scientific evidence related to PA levels and CD risk in cognitively healthy APOE e4 carriers. Four electronic databases were analyzed. Only original articles with longitudinal study design were selected to analyze the relationship between PA and CD in APOE e4 carriers. Five studies were included in the systematic review. All studies except one stated that PA is a protective factor against CD in APOE e4 carriers. Moreover, partial support was found for the hypothesis that a greater amount and intensity of PA are more beneficial in CD prevention. The results support the idea that PA is a protective factor against CD in APOE e4 carriers. Nevertheless, it would be necessary to carry out further studies that would allow these findings to be contrasted.

June 2021

LPC-DHA/EPA-Enriched Diets Increase Brain DHA and Modulate Behavior in Mice That Express Human APOE4

https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.690410/full?fbclid=IwAR04uCa-nUzVojBl5VV0WwPAJABHU-_a9z0YKA3DbMV_ajar3mBPNfXWm2A
Sarah B. Scheinman, Dhavamani Sugasini, Monay Zayed, Poorna C. R. Yalagala, Felecia M. Marottoli, Papasani V. Subbaiah, Leon M. Tai
Frontiers in Neuroscience, 30 June 2021 Sec. Neurodegeneration Volume 15 - 2021
30 Jun 2021
DOI: https://doi.org/10.3389/fnins.2021.690410
Compared with APOE3, APOE4 is associated with greater age-related cognitive decline and higher risk of neurodegenerative disorders. Therefore, development of supplements that target APOE genotype-modulated processes could provide a great benefit for the aging population. Evidence suggests a link between APOE genotype and docosahexaenoic acid (DHA); however, clinical studies with current DHA supplements have produced negative results in dementia. The lack of beneficial effects with current DHA supplements may be related to limited bioavailability, as the optimal form of DHA for brain uptake is lysophosphatidylcholine (LPC)-DHA. We previously developed a method to enrich the LPC-DHA content of krill oil through lipase treatment (LT-krill oil), which resulted in fivefold higher enrichment in brain DHA levels in wild-type mice compared with untreated krill oil. Here, we evaluated the effect of a control diet, diet containing krill oil, or a diet containing LT-krill oil in APOE3- and APOE4-targeted replacement mice (APOE-TR mice; treated from 4 to 12 months of age). We found that DHA levels in the plasma and hippocampus are lower in APOE4-TR mice and that LT-krill oil increased DHA levels in the plasma and hippocampus of both APOE3- and APOE4-TR mice. In APOE4-TR mice, LT-krill oil treatment resulted in higher levels of the synaptic vesicle protein SV2A and improved performance on the novel object recognition test. In conclusion, our data demonstrate that LPC-DHA/EPA-enriched krill oil can increase brain DHA and improve memory-relevant behavior in mice that express APOE4. Therefore, long-term use of LT-krill oil supplements may on some level protect against age-related neurodegeneration.

Effects of Apolipoprotein Ε ε4 allele on early postoperative cognitive dysfunction after anesthesia

https://link.springer.com/article/10.1007/s00101-021-00972-1
Deng-feng Ding, Ping Wang, Yuan-xu Jiang, Xue-ping Zhang, Wei Shi & Yao-wen Luo
Anaesthesist 70 (Suppl 1), 60–67 (2021)
Published 18 June 2021
DOI: https://doi.org/10.1007/s00101-021-00972-1
Abstract
Background
Postoperative cognitive dysfunction (POCD) is one of the main causes of morbidity after noncardiac surgery; however, the pathogenic mechanisms of POCD have remained unclear until now. In this study, we performed a pilot study to investigate the association between apolipoprotein E (ApoE) ε4 and POCD in older patients undergoing intravenous anesthesia (IVA) and inhalation anesthesia (IAA).
Methods
In total, 180 patients from Shenzhen People’s Hospital were recruited and randomly divided into an IVA group and an IAA group. The IVA group and IAA group received propofol and sevoflurane treatment, respectively. Within 7 days after surgery, the mini-mental state examination (MMSE) was used daily to assess the cognitive function of both groups of patients. The genotypes of the ApoE gene were detected using the restriction fragment length polymorphism technique. In addition, the serum levels of (soluble protein-100β) S 100β and (Interleukin- 6) L 6 were also analyzed.
Results
Compared to the preoperative and IVA groups, the MMSE score in the IAA group significantly decreased at 3 days after surgery. Furthermore, the IAA group had a higher percentage of patients who scored less than 25 points than the IVA group at 3 days after surgery. The decrease in the MMSE score was closely related to the ApoE ε4 allele in the IAA group, but this correlation was not observed in the IVA group. The levels of S 100β and IL 6 were increased sharply in patients with the ε4/ε4 genotype who received IAA compared with IVA at 1 day after surgery.
Conclusion
The results of the study indicated that the ApoΕ ε4/ε4 genotype was a risk factor for early POCD in older patients undergoing sevoflurane anesthesia.

APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β

https://www.nature.com/articles/s43587-021-00073-z
Axel Montagne, Angeliki M. Nikolakopoulou, Mikko T. Huuskonen, Abhay P. Sagare, Erica J. Lawson, Divna Lazic, Sanket V. Rege, Alexandra Grond, Edward Zuniga, Samuel R. Barnes, Jacob Prince, Meghana Sagare, Ching-Ju Hsu, Mary J. LaDu, Russell E. Jacobs & Berislav V. Zlokovic
Nature Aging volume 1, pages506–520 (2021)
14 June 2021
DOI: https://doi.org/10.1038/s43587-021-00073-z
Abstract
Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer’s disease (AD), leads to vascular dysfunction, amyloid-β pathology, neurodegeneration and dementia. How these different pathologies contribute to advanced-stage AD remains unclear. Using aged APOE knock-in mice crossed with 5xFAD mice, we show that, compared to APOE3, APOE4 accelerates blood–brain barrier (BBB) breakdown, loss of cerebral blood flow, neuronal loss and behavioral deficits independently of amyloid-β. BBB breakdown was associated with activation of the cyclophilin A-matrix metalloproteinase-9 BBB-degrading pathway in pericytes. Suppression of this pathway improved BBB integrity and prevented further neuronal loss and behavioral deficits in APOE4;5FAD mice while having no effect on amyloid-β pathology. Thus, APOE4 accelerates advanced-stage BBB breakdown and neurodegeneration in Alzheimer’s mice via the cyclophilin A pathway in pericytes independently of amyloid-β, which has implication for the pathogenesis and treatment of vascular and neurodegenerative disorder in AD.

Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer’s Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231952/
Martin Tolar, John Hey, Aidan Power, and Susan Abushakra
International Journal of Molecular Sciences 2021 Jun; 22(12): 6355
Published online 14 Jun 2021
doi: 10.3390/ijms2212655
Abstract
A large body of clinical and nonclinical evidence supports the role of neurotoxic soluble beta amyloid (amyloid, Aβ) oligomers as upstream pathogenic drivers of Alzheimer’s disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species of Aβ provide compelling evidence that inhibition of Aβ oligomer toxicity represents an effective approach to slow or stop disease progression: (1) only agents that target soluble Aβ oligomers show clinical efficacy in AD patients; (2) clearance of amyloid plaque does not correlate with clinical improvements; (3) agents that predominantly target amyloid monomers or plaque failed to show clinical effects; and (4) in positive trials, efficacy is greater in carriers of the ε4 allele of apolipoprotein E (APOE4), who are known to have higher brain concentrations of Aβ oligomers. These trials also show that inhibiting Aβ neurotoxicity leads to a reduction in tau pathology, suggesting a pathogenic sequence of events where amyloid toxicity drives an increase in tau formation and deposition. The late-stage agents with positive clinical or biomarker data include four antibodies that engage Aβ oligomers (aducanumab, lecanemab, gantenerumab, and donanemab) and ALZ-801, an oral agent that fully blocks the formation of Aβ oligomers at the clinical dose.

Autocrine Effects of Brain Endothelial Cell-Produced Human Apolipoprotein E on Metabolism and Inflammation in vitro

https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.668296/full
Felecia M. Marottoli, Troy N. Trevino, Xue Geng, Zarema Arbieva, Pinal Kanabar, Mark Maienschein-Cline, James C. Lee, Sarah E. Lutz, Leon M. Tai
Frontiers in Cell and Developmental Biology, Sec. Stem Cell Research, Volume 9, 2001
09 June 2021
DOI: https://doi.org/10.3389/fcell.2021.668296
Reports of APOE4-associated neurovascular dysfunction during aging and in neurodegenerative disorders has led to ongoing research to identify underlying mechanisms. In this study, we focused on whether the APOE genotype of brain endothelial cells modulates their own phenotype. We utilized a modified primary mouse brain endothelial cell isolation protocol that enabled us to perform experiments without subculture. Through initial characterization we found, that compared to APOE3, APOE4 brain endothelial cells produce less apolipoprotein E (apoE) and have altered metabolic and inflammatory gene expression profiles. Further analysis revealed APOE4 brain endothelial cultures have higher preference for oxidative phosphorylation over glycolysis and, accordingly, higher markers of mitochondrial activity. Mitochondrial activity generates reactive oxygen species, and, with APOE4, there were higher mitochondrial superoxide levels, lower levels of antioxidants related to heme and glutathione and higher markers/outcomes of oxidative damage to proteins and lipids. In parallel, or resulting from reactive oxygen species, there was greater inflammation in APOE4 brain endothelial cells including higher chemokine levels and immune cell adhesion under basal conditions and after low-dose lipopolysaccharide (LPS) treatment. In addition, paracellular permeability was higher in APOE4 brain endothelial cells in basal conditions and after high-dose LPS treatment. Finally, we found that a nuclear receptor Rev-Erb agonist, SR9009, improved functional metabolic markers, lowered inflammation and modulated paracellular permeability at baseline and following LPS treatment in APOE4 brain endothelial cells. Together, our data suggest that autocrine signaling of apoE in brain endothelial cells represents a novel cellular mechanism for how APOE regulates neurovascular function.

Association Between Elevated Depressive Symptoms and Cognitive Function Moderated by APOE4 Status: Framingham Offspring Study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172078/? fbclid=IwAR1gGanDzLc1IUViw5SdYh0Rs5Xt8iR43sRuOxtyMI4dh3vXmw_NnKT95vM Ryan J. Piers, Yulin Liu, Ting F.A. Ang, Qiushan Tao, Rhoda Au and Wendy Q. Qiue
Journal of Alzheimers Disease 2021; 80(3): 1269–1279
2021 Jun 2
doi: 10.3233/JAD-200998
Abstract
Background:
Depression and Apolipoprotein E4 (APOE4) are associated with decreased cognitive function and differences in brain structure.
Objective:
This study investigated whether APOE4 status moderates the association between elevated depressive symptoms, cognitive function, and brain structure.
Methods:
Stroke- and dementia-free participants (n = 1,968) underwent neuropsychological evaluation, brain MRI, and depression screening. Linear and logistic regression was used to examine all associations. Secondary analyses were performed using interaction terms to assess effect modification by APOE4 status.
Results:
Elevated depressive symptoms were associated with lower cognitive performance in several domains. In stratified analyses, elevated depressive symptoms were associated with poorer visual short- and long-term memory performance for APOE4 + participants. Elevated depressive symptoms were not associated with any brain structure in this study sample.
Conclusion:
Elevated depressive symptoms impact cognitive function in non-demented individuals. Having the APOE4 allele may exacerbate the deleterious effects of elevated depressive symptoms on visual memory performance. Screening for elevated depressive symptoms in both research studies and clinical practice may be warranted to avoid false positive identification of neurodegeneration, particularly among those who are APOE4 +.

May 2021

Mechanistic insight into the capacity of natural polar phenolic compounds to abolish Alzheimer's disease-associated pathogenic effects of apoE4 forms

https://www.sciencedirect.com/science/article/abs/pii/S0891584921003105?fbclid=IwAR0XaCDwQszWOMKO6TqYmod-r36zZgvNXupNfOqUK0gg9c1ZSGfOmLmDhjw
Christina Mountaki, Ioannis Dafnis, Eirini A. Panagopoulou, Paraskevi B. Vasilakopoulou, Michalis Karvelas c, Antonia Chiou, Vaios T. Karathanos, Angeliki Chroni
Free Radical Biology and Medicine Volume 171, 1 August 2021, Pages 284-301
Version of Record 25 May 2021
DOI: https://doi.org/10.1016/j.freeradbiomed.2021.05.022
Highlights
• Polar phenols rescue apoE4 forms-associated oxidative stress in neuroblastoma cells.
• Kaempferol modulates the pathogenic conformation of an apoE4 form.
• Resveratrol induces changes in cell membrane fluidity.
• Natural polar phenols abolish AD-related functions of apoE4 forms.
Abstract
Polar phenols found in plant foods have been suggested to act protectively against pathogenic processes underlying Alzheimer's disease (AD), such as oxidative stress. The major risk factor for AD is apolipoprotein E4 (apoE4) and apoE4 forms can affect AD-related processes. It was shown previously that the hereditary apoE4 mutant apoE4[L28P], as well as the apoE4 fragment apoE4-165, induce neuronal oxidative stress. The effect of polar phenols on AD-related pathogenic functions of apoE4 forms is largely unexplored. The aim was to examine the effect of Corinthian currant polar phenolic extract and specific polar phenols resveratrol, quercetin, kaempferol and epigallocatechin gallate on AD-related functions of apoE4 forms. The polar phenolic extract and the individual compounds restored the viability of human neuroblastoma SK-N-SH cells in the presence of lipoprotein-associated apoE4[L28P] and prevented changes in cellular redox status. Furthermore, resveratrol, quercetin, kaempferol and epigallocatechin gallate prevented redox status changes induced by Aβ42 uptake in SK-N-SH cells treated with lipid-free apoE4[L28P] or apoE4-165. Investigation of the molecular mechanism of action of these polar phenols showed that resveratrol prevented cellular Aβ42 uptake via changes in cell membrane fluidity. Interestingly, kaempferol prevented cellular Aβ42 uptake by apoE4[L28P], but not by apoE4-165, due to a modulating effect on apoE4[L28P] secondary structure and stability. The action of quercetin and epigallocatechin gallate could be attributed to free radical-scavenging or other protective activity. Overall, it is shown for the first time that natural compounds could modify the structure of apoE4 forms and ameliorate AD-related pathogenic effects of apoE4 forms.

Precision Health: Genomics as Part of Clinical Decision Making, ACAM Webinar by Sharon Hausman-Cohen

https://www.youtube.com/watch?v=-NMp-cZF_pE
May 17, 2021
This webinar covers the following topics
-Intro to genomics
-Genomics and cardiac risk
-Genomics and cognitive function (The discussion of cognition starts at about 28:30)
Dr. Sharon Hausman-Cohen, MD is the Chief Medical Officer and co-founder of IntellxxDNA and Resilient Health Austin. Dr. Hausman-Cohen received both her masters degree and medical degree from Harvard Medical School. She is a fellow of the American Academy of Family Medicine and a diplomate of the American Board of Integrative Medicine. Dr. Hausman-Cohen has been in the field of integrative medicine for over 25 years. She and her co-founder developed IntellxxDNA as an answer to an unmet need in the integrative and functional medicine community; the need for an accurate, evidence-based genomics tool geared at helping functional and integrative physicians practice personalized medicine. They envisioned and created a tool that could help identify root causes of cognitive decline, environmentally acquired illness and other chronic illnesses, and one that could also help clinicians know how to address these genomic factors. The IntellxxDNA™ clinical decision support tool is now being used to make genomics actionable and understandable and is being used as part of medical decision making by Integrative and Functional Medicine physicians across the country. Dr. Hausman-Cohen has taught extensively across the country at conferences for physicians as well as for community members and will be featured in a documentary being released in 2021 on the “Future of Healthcare”. She has published review papers discussing Alzheimer’s disease and neurocognition genomics as well as a paper on the Genomics of Detoxification: “How Genomics can be Used for Targeting Potential Intervention and Prevention Strategies for Environmentally Acquired Illness." She was also one of the co-authors along with Dr. Dale Bredesen on his landmark paper, "Reversal of Cognitive Decline: 100 patients".

Differences in Recycling of Apolipoprotein E3 and E4—LDL Receptor Complexes—A Mechanistic Hypothesis

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126166/
Meewhi Kim and Ilya Bezprozvanny
International Journal of Molecular Sciences May 2021
Published online 2021 May 10
doi: 10.3390/ijms22095030
Apolipoprotein E (ApoE) is a protein that plays an important role in the transport of fatty acids and cholesterol and in cellular signaling. On the surface of the cells, ApoE lipoparticles bind to low density lipoprotein receptors (LDLR) that mediate the uptake of the lipids and downstream signaling events. There are three alleles of the human ApoE gene. Presence of ApoE4 allele is a major risk factor for developing Alzheimer’s disease (AD) and other disorders late in life, but the mechanisms responsible for biological differences between different ApoE isoforms are not well understood. We here propose that the differences between ApoE isoforms can be explained by differences in the pH-dependence of the association between ApoE3 and ApoE4 isoforms and LDL-A repeats of LDLR. As a result, the following endocytosis ApoE3-associated LDLRs are recycled back to the plasma membrane but ApoE4-containing LDLR complexes are trapped in late endosomes and targeted for degradation. The proposed mechanism is predicted to lead to a reduction in steady-state surface levels of LDLRs and impaired cellular signaling in ApoE4-expressing cells. We hope that this proposal will stimulate experimental research in this direction that allows the testing of our hypothesis.

ApoE4 attenuates cortical neuronal activity in young behaving apoE4 rats

https://www.sciencedirect.com/science/article/pii/S0969996121001224?via%3Dihub
Ilona Har-Paz b, Elor Arieli a, Anan Moran a
Neurobiology of Disease Volume 155, July 2021, 105373
Version of Record 8 May 2021
DOI: https://doi.org/10.1016/j.nbd.2021.105373
Highlights
• Young adult hApoE4 rats show impaired extra-hippocampal taste aversion learning.
• ApoE4 decreases basal and taste-evoked firing rates in both excitatory and inhibitory cortical neurons
• ApoE4 does not disrupt cortical neuronal taste information coding before learning
• ApoE4 impairs changes in palatability coding of cortical neurons required for learning
Abstract
The E4 allele of apolipoprotein E (apoE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). However, apoE4 may cause innate brain abnormalities before the appearance of AD-related neuropathology. Understanding these primary dysfunctions is vital for the early detection of AD and the development of therapeutic strategies. Recently we reported impaired extra-hippocampal memory in young apoE4 mice, a deficit that was correlated with attenuated structural pre-synaptic plasticity in cortical and subcortical regions. Here we tested the hypothesis that these early structural deficits impact learning via changes in basal and stimuli evoked neuronal activity. We recorded extracellular neuronal activity from the gustatory cortex (GC) of three-month-old humanized apoE4 (hApoE4) and wildtype rats expressing rat apoE (rAE), before and after conditioned taste aversion (CTA) training. Despite normal sucrose drinking behavior before CTA, young hApoE4 rats showed impaired CTA learning, consistent with our previous results in target-replacement apoE4 mice. This behavioral deficit was correlated with decreased basal and taste-evoked firing rates in both putative excitatory and inhibitory GC neurons. Further taste coding analyses at the single neuron and ensemble levels revealed that GC neurons of the hApoE4 group correctly classified tastes, but were unable to undergo plasticity to support learning. These results suggest that apoE4 impacts brain excitability and plasticity early in life that may act as an initiator for later AD pathologies.

April 2021

Surgery Performed Under Propofol Anesthesia Induces Cognitive Impairment and Amyloid Pathology in ApoE4 Knock-In Mouse Model

https://www.frontiersin.org/articles/10.3389/fnagi.2021.658860/full?fbclid=IwAR32LSUEC3Pdr0uxztheVrQMY4O87qNs-qqf50s0jhwgCC_RT-p5jqxNetU
Jong-Ho Kim, Harry Jung, Yeonkyeong Lee, Jong-Hee Sohn
Frontiers in Aging Neuroscience, 26 April 2021 Sec. Alzheimer's Disease and Related Dementias Volume 13 - 2021
26 April 2021
https://doi.org/10.3389/fnagi.2021.658860
Background:
Postoperative cognitive dysfunction (POCD) following anesthesia and surgery is a common and severe complication, especially in elderly patients. A pre-existing cognitive impairment may impart susceptibility to further cognitive dysfunction; the mechanism remains unclear. We hypothesized that the specific impacts of anesthesia and surgery on individuals with preclinical Alzheimer’s disease (AD) may render them more susceptible to an increase in the risk of cognitive impairment. The aim of this study was to compare the cognitive impairment between normal adult mice and those with preclinical AD after propofol anesthesia and surgery.
Methods:
We performed abdominal surgery in cognitively pre-symptomatic, 5-month-old male mice with sporadic AD (apolipoprotein E4 allele, ApoE4-KI) and age-matched (C57BL/6J) controls. Propofol anesthesia (170 mg/kg) was induced via retro-orbital injection over 2 h. Morris water maze (MWM) and Y-maze tests were conducted 2 days before and 2, 4, and 7 days after surgery. The mean escape latencies and spontaneous alternation percentages were the major outcomes. Neuronal apoptosis in hippocampal sections was evaluated using the terminal dUTP nick-end labeling (TUNEL) assay. Hippocampal amyloid beta (Aβ) levels were assessed via quantitative immunohistochemistry (IHC).
Results:
The control mice exhibited increased mean escape latencies of MWM at postoperative 2 and 4, but not at day 7; ApoE4-KI mice exhibited such increases at postoperative days 2, 4 and 7. Significant differences between ApoE4-KI and control mice in terms of the mean escape latencies were evident at days 2 and 7 (both P < 0.05). However, performance on a non-hippocampal memory tasks (Y-maze test) did not differ. More TUNEL-positive neurons were evident in the hippocampal CA3 region of ApoE4-KI mice at postoperative days 2 and 4, but not at day 7 compared to the control group (both P < 0.05). IHC revealed significantly elevated Aβ deposition in the hippocampal CA3 region of ApoE4-KI mice at postoperative days 4 and 7 compared to control mice (both P < 0.05).
Conclusions:
Propofol anesthesia followed by surgery induced persistent changes in cognition, and pathological hippocampal changes in pre-symptomatic, but vulnerable AD mice. It would be appropriate to explore whether preclinical AD patients are more vulnerable to POCD development.

Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073598/
Nicholas G. Norwitz, Nabeel Saif, Ingrid Estrada Ariza, and Richard S. Isaacson
Nutrients 2021 Apr; 13(4): 1362
Published online 2021 Apr 19
doi: 10.3390/nu13041362
Abstract

The ApoE4 allele is the most well-studied genetic risk factor for Alzheimer’s disease, a condition that is increasing in prevalence and remains without a cure. Precision nutrition targeting metabolic pathways altered by ApoE4 provides a tool for the potential prevention of disease. However, no long-term human studies have been conducted to determine effective nutritional protocols for the prevention of Alzheimer’s disease in ApoE4 carriers. This may be because relatively little is yet known about the precise mechanisms by which the genetic variant confers an increased risk of dementia. Fortunately, recent research is beginning to shine a spotlight on these mechanisms. These new data open up the opportunity for speculation as to how carriers might ameliorate risk through lifestyle and nutrition. Herein, we review recent discoveries about how ApoE4 differentially impacts microglia and inflammatory pathways, astrocytes and lipid metabolism, pericytes and blood–brain barrier integrity, and insulin resistance and glucose metabolism. We use these data as a basis to speculate a precision nutrition approach for ApoE4 carriers, including a low-glycemic index diet with a ketogenic option, specific Mediterranean-style food choices, and a panel of seven nutritional supplements. Where possible, we integrate basic scientific mechanisms with human observational studies to create a more complete and convincing rationale for this precision nutrition approach. Until recent research discoveries can be translated into long-term human studies, a mechanism-informed practical clinical approach may be useful for clinicians and patients with ApoE4 to adopt a lifestyle and nutrition plan geared towards Alzheimer’s risk reduction.

The Alzheimer’s disease risk factor APOE4 drives pro-inflammation in human astrocytes via HDAC-dependent repression of TAGLN3

https://www.biorxiv.org/content/10.1101/2021.04.16.440108v1?rss=1&fbclid=IwAR2Q2n-BXNenq_gKngYiYKCq3423QVToJ9t9WhwmMsAx9C386_UoFA9OPYQ
Laurie Arnaud, Philippe Benech, Louise Greetham, Delphine Stephan, Angélique Jimenez, Nicolas Jullien, Laura García-González, Philipp O. Tsvetkov, François Devred, Ignacio Sancho-Martinez, Juan-Carlos Izpisua Belmonte, Kevin Baranger, Santiago Rivera, Emmanuel Nivet
bioRxiv 2021.04.16.440108
Posted April 16, 2021 (PREPRINT)
doi: https://doi.org/10.1101/2021.04.16.440108
ABSTRACT
The Apolipoprotein E4 (APOE4) is the major allelic risk factor for late-onset Alzheimer’s disease (AD). APOE4 associates with a pro-inflammatory phenotype increasingly considered as critical in AD initiation and progression. Yet, the mechanisms driving an APOE4-dependent neuroinflammation remain unelucidated. Leveraging patient specific human induced Pluripotent Stem Cells (iPSCs) we demonstrate inflammatory chronicity and hyperactivated responses upon cytokines in human APOE4 astrocytes via a novel mechanism. We uncovered that APOE4 represses Transgelin 3 (TAGLN3), a new interacting partner of IκBα, thus increasing the NF-kB activity. The transcriptional repression of TAGLN3 was shown to result from an APOE4-dependent histone deacetylase (HDAC) activity. The functional relevance of TAGLN3 was demonstrated by the attenuation of APOE4-driven neuroinflammation after TAGLN3 supplementation. Importantly, TAGLN3 downregulation was confirmed in the brain of AD patients. Our findings highlight the APOE4-TAGLN3 axis as a new pathogenic pathway that paves the way for the development of therapeutics to prevent maladaptive inflammatory responses in APOE4 carriers, while placing TAGLN3 downregulation as a potential biomarker of AD.

Interplay Between Microglia and Alzheimer’s Disease—Focus on the Most Relevant Risks: APOE Genotype, Sex and Age

https://www.frontiersin.org/articles/10.3389/fnagi.2021.631827/full?fbclid=IwAR1z0VHd1CCqJ5v64urgtRLPG5CVXb03Hy61WiD59YL9RzOR0V1AH3ySwZw
Yanting Chen, Tingting Hong, Feng Chen, Yuanhong Sun, Yan Wang, Lili Cui
Frontiers in Aging Neuroscience, 08 April 2021 Sec. Alzheimer's Disease and Related Dementiasn Volume 13 - 2021
08 April 2021
DOI: https://doi.org/10.3389/fnagi.2021.631827
As the main immune cells of the central nervous system (CNS), microglia regulates normal development, homeostasis and general brain physiology. These functions put microglia at the forefront of CNS repair and recovery. Uncontrolled activation of microglia is related to the course of neurodegenerative diseases such as Alzheimer’s disease. It is clear that the classic pathologies of amyloid β (Aβ) and Tau are usually accompanied by the activation of microglia, and the activation of microglia also serves as an early event in the pathogenesis of AD. Therefore, during the occurrence and development of AD, the key susceptibility factors for AD—apolipoprotein E (APOE) genotype, sex and age—may further interact with microglia to exacerbate neurodegeneration. In this review, we discuss the role of microglia in the progression of AD related to the three risk factors for AD: APOE genotype, sex and aging. APOE-expressing microglia accumulates around Aβ plaques, and the presence of APOE4 may disrupt the phagocytosis of Aβ aggregates and aggravate neurodegeneration in Tau disease models. In addition, females have a high incidence of AD, and normal female microglia and estrogen have protective effects under normal conditions. However, under the influence of AD, female microglia seem to lose their protective effect and instead accelerate the course of AD. Aging, another major risk factor, may increase the sensitivity of microglia, leading to the exacerbation of microglial dysfunction in elderly AD. Obviously, in the role of microglia in AD, the three main risk factors of APOE, sex, and aging are not independent and have synergistic effects that contribute to the risk of AD. Moreover, new microglia can replace dysfunctional microglia after microglial depletion, which is a new promising strategy for AD treatment.

Is Alzheimer’s Reversible? Getting to the Root Causes

https://drhyman.com/blog/2021/04/21/podcast-ep167/?fbclid=IwAR0Dno9xJ0GMs7Qz2VtJ_fdwBikDKT2YZhF3PR5cQcltZ8CLVPHnE4kDS0w
EPISODE 167 THE DOCTOR'S FARMACY (Dr Mark Hyman’s Podcast)
Interview with Dr Dale Bredesen
April 2021
“Dr. Dale Bredesen and I talk about the many factors that lead to inflammation in the brain, cognitive decline, and eventually Alzheimer’s. Exposure to toxins like mercury and mold, nutrient deficiencies, hormonal imbalances, and an overload of sugar are some of the most common contributors. Genetics play a part, too—Dr. Bredesen breaks down the different ways the ApoE4 gene increases Alzheimer’s risk and how it impacts the general population.”

March 2021

Cholesterol, Atherosclerosis, and APOE in Vascular Contributions to Cognitive Impairment and Dementia (VCID): Potential Mechanisms and Therapy

https://www.frontiersin.org/articles/10.3389/fnagi.2021.647990/full?fbclid=IwAR0FsQEur_MbBSnOqHZ5zVj-IpAjXZuYnjr5Gc5M5R_NyAFPY_o1mloKcMA
Michael Tran Duong, Ilya M. Nasrallah, David A. Wolk, Catherine C. Y. Chang, Ta-Yuan Chang
Frontiers in Aging Neuroscience, 25 March 2021 Sec. Alzheimer's Disease and Related Dementias Volume 13 - 2021
25 March 2021
DOI: https://doi.org/10.3389/fnagi.2021.647990
Vascular contributions to cognitive impairment and dementia (VCID) are a common cause of cognitive decline, yet limited therapies exist. This cerebrovascular disease results in neurodegeneration via acute, chronic, local, and systemic mechanisms. The etiology of VCID is complex, with a significant impact from atherosclerosis. Risk factors including hypercholesterolemia and hypertension promote intracranial atherosclerotic disease and carotid artery stenosis (CAS), which disrupt cerebral blood flow and trigger ischemic strokes and VCID. Apolipoprotein E (APOE) is a cholesterol and phospholipid carrier present in plasma and various tissues. APOE is implicated in dyslipidemia and Alzheimer disease (AD); however, its connection with VCID is less understood. Few experimental models for VCID exist, so much of the present information has been drawn from clinical studies. Here, we review the literature with a focus on the clinical aspects of atherosclerotic cerebrovascular disease and build a working model for the pathogenesis of VCID. We describe potential intermediate steps in this model, linking cholesterol, atherosclerosis, and APOE with VCID. APOE4 is a minor isoform of APOE that promotes lipid dyshomeostasis in astrocytes and microglia, leading to chronic neuroinflammation. APOE4 disturbs lipid homeostasis in macrophages and smooth muscle cells, thus exacerbating systemic inflammation and promoting atherosclerotic plaque formation. Additionally, APOE4 may contribute to stromal activation of endothelial cells and pericytes that disturb the blood-brain barrier (BBB). These and other risk factors together lead to chronic inflammation, atherosclerosis, VCID, and neurodegeneration. Finally, we discuss potential cholesterol metabolism based approaches for future VCID treatment.

Special Considerations for ApoE4 Carriers Part 2

https://www.facebook.com/drdalebredesen/videos/437699944228178
Dale Bredesen,MD Facebook page
Recorded video, discussion with Dr Dale Bredesen, Dr Ram Rao and Julie G.
March 25, 2021
(part 1 on March 12,2021)

Special Considerations for ApoE4 Carriers

https://www.facebook.com/drdalebredesen/videos/195605911904299
Dale Bredesen, MD Facebook page
Recorded video, discussion with Dr Dale Bredesen, Dr Ram Rao and Julie G.
March 12, 2021
“Join us as we discuss special considerations for the 75 million Americans with ApoE4, and the many who do not know their status.”

Interaction between APOE ε4 and dietary protein intake on cognitive decline: A longitudinal cohort study

https://www.clinicalnutritionjournal.com/article/S0261-5614(21)00143-6/abstract
Yun Zhang, Xurui Jin, Michael W. Lutz, Sang-Yhun Ju, Keyang Liu, Guang Guo, Yi Zeng, Yao Yao
Clinical Nutrition Volume 40, ISSUE 5, P2716-2725, May 2021
Published 15 March 2021
DOI:https://doi.org/10.1016/j.cln
Summary
Objective
To exam the association of cognitive decline with APOE ε4 allele carriage and dietary protein intake and investigate whether there is a gene-diet (GxD) interaction of APOE ε4 allele carriage and dietary protein intake on cognitive decline in a nationwide cohort of older adults. Methods
A cohort study of participants from Chinese Longitudinal Healthy Longevity Survey was conducted from 2008 to 2014. A total of 3029 participants (mean age of 77.0 years, SD = 9.0; 49.3% were women) was enrolled. We genotyped APOE ε4 allele for each participant and calculated the diversity of dietary protein intake (DDPI) by summing up the frequency of intake of the 6 protein-rich foods (meats, fish, eggs, nuts, dairy products, and bean products). We assessed cognitive function using the Mini-Mental State Examination (MMSE). We used ordinal regression model to estimate the independent and joint effects of APOE ε4 carrier and dietary protein intake on cognitive decline, adjusting for potential confounders of age, sex, education, socio-economic status, lifestyles, BMI, and cardiometabolic conditions.
Results
There was significant association between carrying APOE ε4 allele and faster cognitive decline (Odds ratio: 1.19, 95% CI = 1.00–1.42), independent of potential confounders. While the associations of DDPI and the intake of 6 protein-rich foods with cognitive decline did not reach any statistical significance. We observed significant interactions of APOE ε4 with DDPI and fish intake, at multiple correction-adjusted Ps < 0.05. In those who were APOE ε4 carriers rather than non-carriers, both high DDPI (OR = 0.54, 95% CI: 0.34–0.88) and daily fish intake (OR = 0.43, 95% CI: 0.22–0.78) were significantly associated with slower cognitive decline, respectively. We also found that frequent intake of fish benefits women more than men regarding the mitigating of cognitive decline among APOE ε4 allele carriers (P for interaction = 0.016).
Conclusions
The results of this study support the hypothesis that diversified protein food intake in addition to frequent fish intake may reduce the detrimental effect of APOE ε4 on cognitive health.

Preventing and Reversing Cognitive Decline

https://podcasts.apple.com/us/podcast/preventing-and-reversing-cognitive-decline/id1539158764?i=1000512410484&ign-itscg=30200&ign-itsct=podcast_box
Podcast, Warrior's Day Off
Mar 10, 2021
Dr. Dale Bredesen talks about his most recent New York Times bestselling book: The End of Alzheimer’s Program and his protocol for preventing and reversing cognitive decline. He discusses the steps to enhancing cognitive ability at any age. We will also hear an inspiring story from someone who followed Dr. Bredesen’s protocol and experienced life altering results.Dale Bredesen is a neuroscientist who has researched neurodegenerative diseases for over thirty years. His career has been gui...

APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218593/
Sienski G, Narayan P, Bonner JM, Kory N, Boland S, Arczewska AA, Ralvenius WT, Akay L, Lockshin E, He L, Milo B, Graziosi A, Baru V, Lewis CA, Kellis M, Sabatini DM, Tsai LH, Lindquist S.
Science Translational Medicine 2021 Mar 3;13(583):eaaz4564
2021 Mar 3
DOI: 10.1126/scitranslmed.aaz4564
Abstract
The E4 allele of the apolipoprotein E gene (APOE) has been established as a genetic risk factor for many diseases including cardiovascular diseases and Alzheimer's disease (AD), yet its mechanism of action remains poorly understood. APOE is a lipid transport protein, and the dysregulation of lipids has recently emerged as a key feature of several neurodegenerative diseases including AD. However, it is unclear how APOE4 perturbs the intracellular lipid state. Here, we report that APOE4, but not APOE3, disrupted the cellular lipidomes of human induced pluripotent stem cell (iPSC)-derived astrocytes generated from fibroblasts of APOE4 or APOE3 carriers, and of yeast expressing human APOE isoforms. We combined lipidomics and unbiased genome-wide screens in yeast with functional and genetic characterization to demonstrate that human APOE4 induced altered lipid homeostasis. These changes resulted in increased unsaturation of fatty acids and accumulation of intracellular lipid droplets both in yeast and in APOE4-expressing human iPSC-derived astrocytes. We then identified genetic and chemical modulators of this lipid disruption. We showed that supplementation of the culture medium with choline (a soluble phospholipid precursor) restored the cellular lipidome to its basal state in APOE4-expressing human iPSC-derived astrocytes and in yeast expressing human APOE4 Our study illuminates key molecular disruptions in lipid metabolism that may contribute to the disease risk linked to the APOE4 genotype. Our study suggests that manipulating lipid metabolism could be a therapeutic approach to help alleviate the consequences of carrying the APOE4 allele.

February 2021

Randomized crossover trial of a modified ketogenic diet in Alzheimer’s disease

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901512/
Matthew C. L. Phillips, Laura M. Deprez, Grace M. N. Mortimer, Deborah K. J. Murtagh, Stacey McCoy, Ruth Mylchreest, Linda J. Gilbertson, Karen M. Clark, Patricia V. Simpson, Eileen J. McManus, Jee-Eun Oh, Satish Yadavaraj, Vanessa M. King, Avinesh Pillai, Beatriz Romero-Ferrando, Martijn Brinkhuis, Bronwyn M. Copeland, Shah Samad, Shenyang Liao, and Jan A. C. Schepel
Alzheimers Research & Therapy 2021; 13: 51
Published online 2021 Feb 23.
doi: 10.1186/s13195-021-00783-x
Abstract
Background
Brain energy metabolism is impaired in Alzheimer’s disease (AD), which may be mitigated by a ketogenic diet. We conducted a randomized crossover trial to determine whether a 12-week modified ketogenic diet improved cognition, daily function, or quality of life in a hospital clinic of AD patients.
Methods
We randomly assigned patients with clinically confirmed diagnoses of AD to a modified ketogenic diet or usual diet supplemented with low-fat healthy-eating guidelines and enrolled them in a single-phase, assessor-blinded, two-period crossover trial (two 12-week treatment periods, separated by a 10-week washout period). Primary outcomes were mean within-individual changes in the Addenbrookes Cognitive Examination - III (ACE-III) scale, AD Cooperative Study - Activities of Daily Living (ADCS-ADL) inventory, and Quality of Life in AD (QOL-AD) questionnaire over 12 weeks. Secondary outcomes considered changes in cardiovascular risk factors and adverse effects.
Results
We randomized 26 patients, of whom 21 (81%) completed the ketogenic diet; only one withdrawal was attributed to the ketogenic diet. While on the ketogenic diet, patients achieved sustained physiological ketosis (12-week mean beta-hydroxybutyrate level: 0.95 ± 0.34 mmol/L). Compared with usual diet, patients on the ketogenic diet increased their mean within-individual ADCS-ADL (+ 3.13 ± 5.01 points, P = 0.0067) and QOL-AD (+ 3.37 ± 6.86 points, P = 0.023) scores; the ACE-III also increased, but not significantly (+ 2.12 ± 8.70 points, P = 0.24). Changes in cardiovascular risk factors were mostly favourable, and adverse effects were mild.
Conclusions
This is the first randomized trial to investigate the impact of a ketogenic diet in patients with uniform diagnoses of AD. High rates of retention, adherence, and safety appear to be achievable in applying a 12-week modified ketogenic diet to AD patients. Compared with a usual diet supplemented with low-fat healthy-eating guidelines, patients on the ketogenic diet improved in daily function and quality of life, two factors of great importance to people living with dementia.
From text:
Alternatively, the trend reversal may be explained by the higher prevalence of apolipoprotein E4 carriers among ketogenic diet patients in the second treatment period; ketone energy metabolism may be less beneficial for apolipoprotein E4 carriers [27, 31], although not all studies have shown this [14, 32].

APOE-ε4 Carrier Status and Gut Microbiota Dysbiosis in Patients With Alzheimer Disease

https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.619051/full
Min Hou, Gaolian Xu, Maosheng Ran, Wei Luo, Hui Wang
Frontiers in Neuroscience, 23 February 2021, Sec. Neurogenomics, Volume 15 – 2021
23 February 2021
DOI: https://doi.org/10.3389/fnins.2021.619051
Background:
Alternations in gut microbiota and a number of genes have been implicated as risk factors for the development of Alzheimer disease (AD). However, the interactions between the altered bacteria and risk genetic variants remain unclear.
Objective:
We aimed to explore associations of the risk genetic variants with altered gut bacteria in the onset of AD. Methods: We collected baseline data and stool and blood samples from 30 AD patients and 47 healthy controls in a case-control study. The rs42358/rs4512 (ApoE), rs3851179 (PICALM), rs744373 (BIN1), rs9331888 (CLU), rs670139 (MS4A4E), rs3764650 (ABCA7), rs3865444 (CD33), rs9349407 (CD2AP), rs11771145 (EPHA1), and rs3818361/rs6656401 (CR1) were sequenced, and microbiota composition was characterized using 16S rRNA gene sequencing. The associations of the altered gut bacteria with the risk genetics were analyzed.
Results:
Apolipoprotein ε4 allele and rs744373 were risk loci for the AD among 12 genetic variants. Phylum Proteobacteria; orders Enterobacteriales, Deltaproteobacteria, and Desulfovibrionales; families Enterobacteriaceae and Desulfovibrionaceae; and genera Escherichia–Shigella, Ruminococcaceae_UCG_002, Shuttleworthia, Anaerofustis, Morganelia, Finegoldia, and Anaerotruncus were increased in AD subjects, whereas family Enterococcaceae and genera Megamonas, Enterococcus, and Anaerostipes were more abundant in controls (P < 0.05). Among the altered microbiota, APOE ε4 allele was positively associated with pathogens: Proteobacteria.
Conclusion:
The interaction of APOE ε4 gene and the AD-promoting pathogens might be an important factor requiring for the promotion of AD. Targeting to microbiota might be an effective therapeutic strategy for AD susceptible to APOE ε4 allele. This needs further investigation.

The Human ApoE4 Variant Reduces Functional Recovery and Neuronal Sprouting After Incomplete Spinal Cord Injury in Male Mice

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930340/
Carlos A. Toro, Jens Hansen, Mustafa M. Siddiq, Kaitlin Johnson, Wei Zhao, Daniella Azulai, Dibash K. Das, William Bauman, Robert Sebra, Dongming Cai, Ravi Iyengar, and Christopher P. Cardozo
Frontiers in Cell Neuroscience 2021; 15: 626192
Published online 2021 Feb 18
doi: 10.3389/fncel.2021.626192
Abstract
Spinal cord injury (SCI) is a devastating form of neurotrauma. Patients who carry one or two apolipoprotein E (ApoE)4 alleles show worse functional outcomes and longer hospital stays after SCI, but the cellular and molecular underpinnings for this genetic link remain poorly understood. Thus, there is a great need to generate animal models to accurately replicate the genetic determinants of outcomes after SCI to spur development of treatments that improve physical function. Here, we examined outcomes after a moderate contusion SCI of transgenic mice expressing human ApoE3 or ApoE4. ApoE4 mice have worse locomotor function and coordination after SCI. Histological examination revealed greater glial staining in ApoE4 mice after SCI associated with reduced levels of neuronal sprouting markers. Bulk RNA sequencing revealed that subcellular processes (SCPs), such as extracellular matrix organization and inflammatory responses, were highly ranked among upregulated genes at 7 days after SCI in ApoE4 variants. Conversely, SCPs related to neuronal action potential and neuron projection development were increased in ApoE3 mice at 21 days. In summary, our results reveal a clinically relevant SCI mouse model that recapitulates the influence of ApoE genotypes on post SCI function in individuals who carry these alleles and suggest that the mechanisms underlying worse recovery for ApoE4 animals involve glial activation and loss of sprouting and synaptic activity.

APOE and Alzheimer’s Disease: From Lipid Transport to Physiopathology and Therapeutics

https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.630502/full
Mohammed Amir Husain, Benoit Laurent, Mélanie Plourde
Frontiers in Neuroscience, Sec. Neurodegeneration Volume 15 - 2021
DOI: https://doi.org/10.3389/fnins.2021.630502
16 February 2021
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by extracellular amyloid β (Aβ) and intraneuronal tau protein aggregations. One risk factor for developing AD is the APOE gene coding for the apolipoprotein E protein (apoE). Humans have three versions of APOE gene: ε2, ε3, and ε4 allele. Carrying the ε4 allele is an AD risk factor while carrying the ε2 allele is protective. ApoE is a component of lipoprotein particles in the plasma at the periphery, as well as in the cerebrospinal fluid (CSF) and in the interstitial fluid (ISF) of brain parenchyma in the central nervous system (CNS). ApoE is a major lipid transporter that plays a pivotal role in the development, maintenance, and repair of the CNS, and that regulates multiple important signaling pathways. This review will focus on the critical role of apoE in AD pathogenesis and some of the currently apoE-based therapeutics developed in the treatment of AD.
Overview
Polymorphism in the apolipoprotein E (APOE) gene is a major risk for developing late onset Alzheimer disease (LOAD), whose symptoms are more frequently appearing after the age of 65 years (Yamazaki et al., 2019). The ε4 allele of APOE gene is the strongest risk factor for LOAD (Yamazaki et al., 2019). The differences in the structure of apoE isoforms influence their ability to bind lipids, receptors, and amyloid-β (Aβ), which aggregates in plaques within the brain. Human and animal studies clearly indicate that apoE isoforms differentially regulate neuroinflammation, tau hyperphosphorylation, Aβ aggregation and clearance (Tachibana et al., 2019; Kloske and Wilcock, 2020; Vasilevskaya et al., 2020). ApoE regulates lipid homeostasis by mediating lipid transport from one tissue or cell type to another (Holtzman et al., 2012; Chernick et al., 2018; Zhao et al., 2018b). Since lipids such as cholesterol and triglycerides are insoluble in water, they must be carried in the circulation by hydrophile-lipophile particles named lipoproteins. These lipoproteins play a major role in the absorption and transport of dietary lipids between the small intestine, liver and peripheral tissues to the brain where they are essential. In the periphery, it is established how lipids travel in the blood using the different types of lipoproteins (Holtzman et al., 2012; Chernick et al., 2018; Zhao et al., 2018b), whereas within the CNS, lipoproteins are often designated as high-density lipoproteins (HDL)-like, yet their size, shape, and distribution remain unclear. ApoE, present in the CNS and the periphery, represents a critical link between these two compartments and could influence Alzheimer’s disease (AD) pathogenesis by disrupting the blood–brain barrier (BBB) integrity from both sides (Chernick et al., 2019). In this review, the possible mechanisms by which apoE exerts its modulatory effect on AD physiopathology are discussed and new therapeutic perspectives targeting apoE for AD treatment are also described.

Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model

https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.26043?af=R&fbclid=IwAR3RGDqGOzLSWY3K_F07VgrinsYWdGuF9X0WiecSKrVWVNf5y9UygBgwRoQ
Alexandra Litvinchuk PhD, Tien-Phat V. Huynh MD, PhD, Yang Shi PhD, Rosemary J. Jackson PhD, Mary B. Finn, Melissa Manis MS, Caroline M. Francis BA, Ainsley C. Tran BA, Patrick M. Sullivan PhD, Jason D. Ulrich PhD, Bradley T. Hyman MD, PhD, Tracy Cole PhD, David M. Holtzman MD
Annals of Neurology Volume89, Issue5 May 2021Pages 952-966
First published: 07 February 2021
DOI: https://doi.org/10.1002/ana.26043
Abstract
Objective
Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease, with the ε4 allele increasing risk in a dose-dependent fashion. In addition to ApoE4 playing a crucial role in amyloid-β deposition, recent evidence suggests that it also plays an important role in tau pathology and tau-mediated neurodegeneration. It is not known, however, whether therapeutic reduction of ApoE4 would exert protective effects on tau-mediated neurodegeneration.
Methods
Herein, we used antisense oligonucleotides (ASOs) against human APOE to reduce ApoE4 levels in the P301S/ApoE4 mouse model of tauopathy. We treated P301S/ApoE4 mice with ApoE or control ASOs via intracerebroventricular injection at 6 and 7.5 months of age and performed brain pathological assessments at 9 months of age.
Results
Our results indicate that treatment with ApoE ASOs reduced ApoE4 protein levels by ~50%, significantly protected against tau pathology and associated neurodegeneration, decreased neuroinflammation, and preserved synaptic density. These data were also corroborated by a significant reduction in levels of neurofilament light chain (NfL) protein in plasma of ASO-treated mice.
Interpretation
We conclude that reducing ApoE4 levels should be explored further as a therapeutic approach for APOE4 carriers with tauopathy including Alzheimer's disease. ANN NEUROL 2021;89:952–966