ApoE ε4 and health conditions besides (or maybe contributing to) Alzheimer’s

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Introduction

The ε4 variant of the ApoE gene is famous for its association with Alzheimer’s Disease but other conditions have also been linked to it.

Do remember that this gene variant alone does not cause a medical condition. Environmental, dietary, lifestyle, and other factors play strong epigenetic roles, and all those factors cannot be controlled in studies.

This wiki article attempts to address conditions that have been identified, although not necessarily confirmed, as associated with ApoE ε4. Don’t look at the list and think, “All this and Alzheimer's too? I’m doomed!” These conditions are interconnected and some may be contributory subsets to a diagnosis of Alzheimer's.

Remember, what's good for the body is good for the brain and vice versa. The diet/lifestyle strategies suggested for an ApoE ε4 carrier in our PRIMER: An introduction to ApoE4, biochemistry, and possible prevention strategies, other articles contained within this ApoE4.info wiki, and in the ApoE4.info discussion threads can positively influence all of these conditions.

Lastly, read the findings carefully, with some of the listed conditions the association with ApoE ε4 is weak, conflicted, and/or in need of further research.

High Cholesterol (Hypercholesterolemia)

Cholesterol is a complex subject with multiple expert opinions, this subheading discussion strictly addresses that ApoE ϵ4s tend to have higher cholesterol numbers, no discussion of positive/negative ramifications. For more information on the subject of lipids and cholesterol first read the lipid section in the PRIMER: An introduction to ApoE4, biochemistry, and possible prevention strategies, then see the ApoE4.info wiki article, Cholesterol, Lipids and Treatments, including statins

Hypercholesterolemia is a type of hyperlipidemia that refers to higher than normal levels of low-density lipoprotein (LDL) cholesterol, the so-called "bad cholesterol" or total cholesterol, but does not include triglycerides.

Studies supporting hypercholesterolemia in ApoE ϵ4s (not a complete list):

APOE4 was present in 21 of 51 hypercholesterolemic children (41.2%), and in nine of 51 control subjects (17.6%). The difference was significant (p<0.01). This finding indicates that APOE4 is associated with hypercholesterolemia in children.
ApoE2 and apoE4 increase the risk for heart disease: apoE2 increases atherogenic lipoprotein levels (it binds poorly to LDL receptors), and apoE4 increases LDL levels (it binds preferentially to triglyceride-rich, very low density lipoproteins, leading to downregulation of LDL receptors).
The apo E4 (Arg112-Cys) polymorphism has been associated with dementia and hypercholesterolemia.

Hypertriglyceridemia

Graph showing that triglycerides were higher in APOE4s vs APOE3s after eating a meal (post-prandial) Source: APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease https://www.frontiersin.org/articles/10.3389/fnagi.2020.00150/full (Hussein N. Yassine and Caleb E. Finch, 10 June 2020)

Hypertriglyceridemia is when there are too many triglycerides in the blood. Often caused by excess sugar, refined carbs and alcohol, ApoE4 is associated with higher levels of triglycerides.

From APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease(Hussein N. Yassine and Caleb E. Finch, 10 June 2020)

APOE4 carriers display both hypertriglyceridemia and hypercholesterolemia (Dallongeville et al., 1992; Carvalho-Wells et al., 2012).

and

The mechanism for hypertriglyceridemia in APOE4 may involve its stronger binding to VLDL, which decreases lipoprotein lipase mediated lipolysis (Li et al., 2013).

Higher triglyceride levels are associated with impaired cognitive function. (source: The Role of High Triglycerides Level in Predicting Cognitive Impairment: A Review of Current Evidence (Alina Mihaela Dimache et al, 20 June 2021)

Saturated Fat Sensitivity

ApoE4 carriers are well documented to hyper-absorb dietary fat. (Source: What We Know About Diet, Genes, and Dyslipidemia: Is There Potential for Translation? (Toni I. Pollin & Michael Quartuccio, 15 Oct 2013). ApoE4s often see higher total cholesterol and LDL-C (low density lipoprotein cholesterol) levels with saturated fat intake.

Cardiovascular Disease (CVD)

First some terms used in the cited references:

Cardiovascular Disease - Heart conditions that include diseased vessels, structural problems, and blood clots. Includes: Coronary Artery Disease, High Blood Pressure, Cardiac Arrest, Congestive Heart Failure, Arrythmia, Peripheral Artery Disease, Stroke.

Coronary Heart Disease - Plaque buildup in the wall of the arteries that supply blood to the heart (called coronary arteries) resulting in blockage or interruption of the heart muscle's blood supply.

Atherosclerosis - When plaque buildup causes the inside of the arteries to narrow over time.

Atherogenesis - The process of forming plaques in the intima layer of arteries.

Coronary Artery Disease - Also known as ischemic heart disease or "hardening of the arteries."

Myocardial infarction (MI) - More commonly known as a heart attack.

Some studies/findings:

APOE4 is associated with greater levels of atherosclerosis, potentially through increased LDL-C levels from defective VLDL remnant clearance as described above. Correspondingly, APOE4 carriers have shown a higher incidence of ischemic heart disease (Xu et al., 2016). The increased use of statins may have attenuated this adverse impact of APOE4 (Nieminen et al., 2008).
ApoE4 increases plasma LDL levels and the risk for atherosclerosis [11, 12, 25]. The lipoprotein-binding preference of apoE4 to large (30–80 nm), triglyceride-rich VLDL, is associated with elevated LDL levels. (ApoE3 and apoE2 preferentially bind to small, 9–16-nm spherical HDL particles enriched in phospholipids and surface proteins, primarily apoAI.) [Bold font added to quote.] [See link for referenced footnotes.]
APOE AND CARDIOVASCULAR DISEASE ApoE2 and apoE4 increase the number of atherogenic lipoproteins and accelerate atherogenesis (1, 3, 6). Understanding structural differences in apoE isoforms helped establish the molecular mechanism responsible for the associated pathology. First, the altered structure and impaired function of the receptor binding region of apoE2 increase triglyceride and cholesterol levels caused by delayed clearance of hepatic and intestinal remnant lipoproteins (β-VLDL), resulting in type III HLP (3, 22). Cys-158 in apoE2 affects the receptor binding region by altering salt bridges and lowering the positive potential (25). Second, the increase in plasma cholesterol, LDL, and apoB associated with apoE4 appears to reflect the influence of Arg-112 (1–3). Arg-112 alters the lipid binding region of apoE4 and changes the lipid binding preference from small phospholipid-rich HDL (apoE2 and apoE3) to large triglyceride-rich VLDL (apoE4). This difference is due to apoE4 domain interaction, in which the N- and C-terminal domains interact, resulting in a more compact structure.-Cys) polymorphism has been associated with dementia and hypercholesterolemia. [Bold font added to quote for emphasis.][See link for referenced footnotes.]
Conclusions: These data from a prospective study of apparently healthy men do not support the simple view of E2 as a protective factor and E4 as a susceptibility factor in predicting future risk of MI independent of lipid parameters. Nor did we observe any interaction between smoking and apoE4 allele on MI risk. [Bold font added to quote for emphasis.]
These results provide strong confirmation that in men, the ɛ4 association with CVD risk is essentially confined to smokers. Since ɛ4 non‐smokers show no major CVD risk, i.e. when the environmental insult is not present, this has important public health implications. No studies to date have examined this ɛ4: smoking effect in women, so it is not clear whether these effects are gender specific. The multifactorial nature of CHD/CVD implies not only independent effects of genes and environmental factors but also their interaction on risk. Thus our study of ɛ4: smoking interaction and association with measures of ROS [Reactive Oxygen Species] confirms and extends our understanding of the multifactorial basis of CHD/CVD risk. [Bold font added to quote for emphasis.]
The apo E4 (Arg112-Cys) polymorphism has been associated with dementia and hypercholesterolemia. We investigated the relation of APOE genotype to cardiovascular disease (CVD) in the Framingham Offspring Study.
Conclusions: The presence of the apo E2 or apo E4 alleles in men is associated with significantly greater CVD risk. This genotypic information may help to identify individuals at increased risk for CVD events. [Bold font added to quote for emphasis.]
Purpose: Although the apolipoprotein E genotype ϵ4 (apoE4) has been associated with high cholesterol levels, whether it is an independent predictor of coronary events is not certain.
Conclusion: The apoE4 genotype is a strong independent risk factor for coronary events in men, but not women. The association does not appear to be mediated by differences in total cholesterol levels. [Bold font added to quote.]

Heightened Immune response/ Infectious disease susceptibility

While ApoE ϵ4's pro-inflammatory state helped early man survive wounds, walk on dung, and other insults, that may have been of benefit against the endemic diseases of Africa, where ApoE ϵ4 originated. As man migrated, one theory is that new infectious diseases (the plague, small pox) placed ApoE ϵ4s at a disadvantage as compared to ϵ3s and this may be the primary reason ApoE ϵ3s outnumber ApoE ϵ4s. That's just a theory, there's still much to be learned in this area.

Some findings:

-As the ancestral human isoform, APOE4 may be beneficial in infectious environments with high pathogen loads (Trumble and Finch, 2019). Children carrying APOE4 in Brazilian slums, are more resistant to diarrhea and have better cognitive development (Oriá et al., 2010), while adult Tsimane farmer-foragers in Bolivia with APOE4 have better cognition during high parasitemia (Trumble et al., 2017). Moreover, in the highly infectious environment of rural Ghana, APOE4 carriers showed survival advantage as older adults and children, suggesting reproductive advantage (van Exel et al., 2017). APOE4 was also protective of HCV [hepatitis C virus] infection (Price et al., 2006). These findings are shown for APOE-TR mice in a model of infection by Cryptosporidium parvum: the APOE4-TR mice had faster recovery than E3 for intestinal inflammatory responses and mucosal damage (Azevedo et al., 2014).
-In humans, APOE4 increased serum interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-17, and tumor necrosis factor-α (TNF-α) responses to LPS (endotoxin) using in vivo and ex vivo assays. APOE4 carriers with severe sepsis had more thrombocytopenia. Correspondingly, APOE4-TR mice had greater responses IL-6 and TNF-α (the only cytokines assayed). In a murine monocyte-macrophage cell line stably transfected to produce equal amounts of human apoE3 or apoE4, LPS stimulation in apoE4-macrophages showed higher and lower concentrations of TNF-α (pro-inflammatory) and IL-10 (anti-inflammatory), for mRNA and protein levels. Furthermore, apoE4-macrophages had enhanced the transactivation of the key redox-sensitive transcription factor NF-κB (Jofre-Monseny et al., 2007). One mechanism for APOE4 associated higher inflammatory responses may relate to the increase in TLR4 activity by greater cell membrane cholesterol distribution from lower ABCA1 activity (Westerterp et al., 2013), as discussed above.
-Chronic inflammation increases AD risk with APOE4. Data from 2,656 members of the Framingham Heart Study offspring cohort examined longitudinal measures of serum C-reactive protein (CRP) in relation to the diagnoses of incident dementia, including AD, and brain volume. APOE4 coupled with chronic low-grade inflammation, defined as a CRP level of 8 mg/L or higher, was associated with an increased risk of AD compared to APOE4 without inflammation, and APOE2 and APOE3 with chronic inflammation (Tao et al., 2018).
-ApoE also influences susceptibility to parasitic, bacterial, and viral infections. In HIV-positive patients, apoE4 homozygosity hastens progression to AIDS and death and increases susceptibility to opportunistic infections. [Bold font added to quote]
-ApoE also modulates susceptibility to infectious disease and possibly immunoregulation (1, 3). ApoE4 enhances the infectivity of HIV in vitro and hastens progression to AIDS and death in HIV-positive subjects (23). [See link for referenced footnotes.]
-HSV1 [[Herpes simplex virus type 1 or oral herpes] infection is associated with increased risk of AD, and apoE4 is overrepresented in HSV-infected subjects (51). In HIV-positive patients, apoE4 homozygosity hastens progression to AIDS and death and increases susceptibility to opportunistic organisms (23). Cultured cells are more susceptible to infection with HIV in the presence of apoE4 than apoE3, reflecting enhancement of viral attachment and fusion. The structural differences between apoE4 and apoE3 may shed light on the mechanism by which apoE4 modulates infectivity and fusion.[Bold font added to quote for emphasis.][See link for referenced footnotes.]
Apolipoprotein-E protein is an endogenous immunomodulatory agent that affects both the innate and the adaptive immune responses. Since individuals with the APOE4 gene demonstrate worsened pathology and poorer outcomes in many neurological disorders, we examined isoform specific differences in the response of microglia, the primary cellular component of the brain’s innate immune response, in detail. Our data demonstrate that microglia derived from APOE4/4 targeted replacement mice demonstrate a pro-inflammatory phenotype that includes altered cell morphology

Issues of the Brain

Among its pleiotropic effects on aging, APOE4’s strongest effects are arguably on the brain. (Source: APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease(Hussein N. Yassine and Caleb E. Finch, 10 June 2020)

Slowed brain glucose uptake

The body’s primary source of energy is glucose, also known as Blood Sugar. The brain wants unimpaired glucose passage, because the brain needs fuel and lots of it. The brain uses more energy than any other human organ. While the brain constitutes only about 3% of the body's mass, it uses approximately 20%-25% of the body's energy and it needs that energy 24 hours a day.

ApoE4s have impaired cerebral glucose uptake which is one of the reasons ketosis (see Ketosis and Ketogenic Diet) can be of benefit, as ketones provide unimpaired fuel to the brain thus aiding its function. While ketones can provide significant help with cognition, note that they cannot entirely replace glucose for brain fuel.

There is a significant link between Alzheimer’s disease (AD) and impaired fuel metabolism, (see Insulin Resistance in the brain) specifically disturbed cerebral glucose metabolism. (Sources: Insulin resistance and reduced brain glucose metabolism in the aetiology of Alzheimer’s disease(Berger A.L., 30 Dec 2016) and Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: Implications for diagnostic and therapeutic strategies (Chen, Z, et al., Sep 2013))

ApoE4 carriers show reduced cerebral glucose metabolism by positron emission testing and reduced uptake of glucose into astrocytes. (Source: APOE alters glucose flux through central carbon pathways in astrocytes(Holden C. Williams et al, Mar 2020))

Some findings:

APOE4 is associated with glucose hypometabolism in the brain of older adults (Wolf et al., 2013), and with both markers of astrocytosis and microgliosis (Fernandez et al., 2019). In the Mayo Clinic study, older APOE4 carriers demonstrate greater glucose hypometabolism in AD-affected brain areas than non-carriers. These changes are not associated with fibrillary amyloid detected by PET imaging (Knopman et al., 2014), but smaller aggregates and oligomers may still be a factor. In the subgroup of participants between the ages of 30 and 60 years from this study (n = 62), there were no significant regional differences between APOE4 carriers and noncarriers (Knopman et al., 2014). The effect of APOE4 on glucose hypometabolism in younger (middle aged) cognitively normal adults is more evident in APOE4 homozygotes than heterozygotes (Mosconi et al., 2004; Reiman et al., 2004). Proposed mechanisms include changes in apoE protein expression levels, qualitative differences in apoE proteins (for example, aggregated vs. lipidated ApoE), a direct effect of apoE on nuclear transcription, and complex interactions with Aβ (Fernandez et al., 2019). Another mechanism involves apoE’s effect on endosomal trafficking. Brain endosomes are enlarged decades before the onset of cognitive decline in APOE4, particularly in pyramidal neurons in the inferior frontal lobe (Cataldo et al., 2000; Nixon, 2005). APOE-TR [transgenic] mice corroborate these postmortem findings, with enlarged endosomes and increased endosomal trafficking proteins in APOE4 vs. APOE3-TR brains in the entorhinal cortex area of APOE-TR mice (Nuriel et al., 2017b; Peng et al., 2019).

Vascular Dementia

This study, Is apolipoprotein E4 an important risk factor for vascular dementia? (Troy T Rohn 2014) analyzed 24 studies from 1994 to 2012 which examined the potential association of APOE polymorphism in Vascular Dementia (VaD). Fourteen of these studies showed a positive association but 9 found that the ApoE4 allele did not confer risk for VaD. Of the negative findings, 5 of the 9 were of Asian populations, the other 4 were from European populations, so environmental and/or genetic factors may have played a role in these studies.

From this paper’s Concluding Remarks:

Clearly, vascular risk factors including hypertension, stroke, atherosclerosis may increase the risk for VaD and it follows that harboring the APOE4 allele may also lead to enhanced vulnerability. However, conflicting reports on APOE polymorphism and enhanced VaD risk have been documented although the preponderance of data suggest the presence of the APOE4 allele does increase risk albeit to a lower extent to what has been found in AD…. Further studies are warranted to examine more clearly the potential connection between VaD and the APOE polymorphism. [Bold font added to quote for emphasis.]

Lewy Body Dementia

The research paper Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture(Ruth Chia et al, 15 Feb 21) is behind a paywall, but this article Genetic Study of Lewy Body Dementia Supports Ties to Alzheimer’s and Parkinson’s Diseases is a report on the research in this paper and says that five genes, including APOE may play a critical role in determining whether a person will suffer from Lewy body dementia.

This paper, APOE ε4 increases risk for dementia in pure synucleinopathies ,(Debby Tsuang, MD, MSc, et al., Feb 2013) identifies that the APOE ϵ4 allele is a strong risk factor across the Lewy Body Dementia (LBD) spectrum: -Pure Lewy body dementia -Alzheimer’s with Lewy bodies (a coexistence of Lewy bodies with Alzheimer’s but not pure Lewy Body Dementia) -Parkinson’s Disease Dementia (a dementia that occurs many years after diagnosis of Parkinson’s. Those with Parkinson’s often have Lewy bodies in their brain, however, PDD is also not pure Lewy Body Dementia) However, any ApoE ϵ4 genetic risk for Dementia with Lewy Bodies may be related to the frequent coexistence with Alzheimer’s Disease. How and if ApoE ϵ4 contributes to the development of Lewy Bodies is unclear. The above referenced paper discusses how several studies have examined ApoE in Dementia with Lewy Bodies (DLB) without making a distinction between pure Dementia with Lewy Bodies (pDLB) and Lewy Body Disease with coexisting levels of Alzheimer’s Disease neuropathologic changes (LBD-AD). From the paper:

Therefore, it is possible that all genetic risk for DLB [Dementia with Lewy bodies] associated with the APOEϵ4 allele is related to its frequent comorbidity with ADNCs [Alzheimer disease (AD) neuropathologic changes (NCs)] and is unrelated to LBDNCs [Lewy body disease (LBD) neuropathologic changes (NCs)] Furthermore, no studies have directly compared genetic risk factors between pDLB [pure Dementia with Lewy Bodies) and PDD [Parkinson’s Disease Dementia].

Parkinson's Disease Dementia

Parkinson's Disease Dementia (PDD) occurs many years after diagnosis of Parkinson’s. Those with Parkinson’s often have Lewy bodies in their brain, however, PDD is also not pure Lewy Body Dementia. From this paper APOE ε4 increases risk for dementia in pure synucleinopathies (Debby Tsuang, MD, MSc, et al., Feb 2013):

Data from genomewide association studies indicate that APOE is not a susceptibility gene for PD.30-32 While PD is clinically defined by motor symptoms, more than 50% of patients develop dementia within 10 years of diagnosis.33,34 Whether APOE acts as a modifier gene by influencing the manifestation of cognitive dysfunction in PD is still a matter of debate. [Bold font added to quote for emphasis.] [See link for referenced footnotes.]

Brain Arterial Disorders

Cerebral atherosclerosis (AS), small vessel disease (SVD), and cerebral amyloid angiopathy (CAA) are the most prevalent arterial disorders in the aged brain. The three are different, but ApoE is involved in all three disorders. All three disorders can lead to infarction (obstruction of the blood supply) and hemorrhage (bleeding) in the brain.

Cerebral atherosclerosis (AS)

Cerebral atherosclerosis (AS) is the thickening and hardening of the walls of the arteries in the brain. From this paper Vascular pathology in the aged human brain (Grinberg, L.T. & Thal, D.R. Acta, Feb 2010)

ApoE and its receptors are critically involved in the pathogenesis of AS. ApoE-knockout mice and low-density lipoprotein (LDL) receptor knockout mice develop AS [8, 156]. Dysfunctional uptake of LDLs may, thereby, lead to the accumulation of oxidized LDLs in the atherosclerotic vessel wall [9]. Thus, oxidized LDLs may be candidates to trigger the development of atherosclerotic plaques. ApoE and LDL receptors [e.g. LDLR and A2M receptor/LDL receptor-related protein (LRP = CD91)] were found in AS plaques (Fig. 1c) [8, 43]. The apoE ε4 allele is controversially discussed as a possible genetic risk factor for AS [64, 75, 116]. [Bold font added to quote for emphasis.] [See link for referenced footnotes.]

Small Vessel Disease (SVD)

Small Vessel Disease (SVD) is a condition found in older adults which can contribute to cognitive decline and vascular dementia. SVD encompasses degenerative alterations in the vessel wall of the small arteries and arterioles (a small branch of an artery leading into capillaries).

APOE gene polymorphisms have been associated with amyloidogenic CSVD [Cerebral Small Vessel Disease] and serve as the strongest genetic factor for the disease including AD. Two main types of APOE genes are involved in CVSD: APOE ε4 and APOE ε2
Genetically, an association between SVD and the apoE ε4 allele has been reported [154].
Conclusion: APOE-epsilon4 is associated with small vessel arteriolosclerosis, microinfarcts of the deep nuclei, neuritic senile plaque density, and amyloid angiopathy in patients with autopsy-proven Alzheimer disease (AD). These results suggest a role for epsilon4 in some of the microvascular changes commonly found in AD and are consistent with a potential amyloidogenic role for epsilon4. [Bold font added to quote for emphasis.]

Cerebral amyloid angiopathy (CAA)

Cerebral amyloid angiopathy (CAA) is a condition in which proteins (amyloid) build up on the walls of the arteries in the brain. CAA increases the risk for stroke caused by bleeding and dementia.

CAA, especially capillary CAA, is associated with the apoE ε4 allele [37, 100, 103, 126, 130, 132]. This finding points to an important role of apoE for the development of CAA because apoE4 is less effective in the receptor-mediated clearance of Aβ [Amyloid Beta] when compared to apoE3 [19]. This property of apoE4 presumably results in capillary Aβ deposition in apoE ε4 carriers as soon as alterations in the perivascular drainage occur. In addition, the apoE ε4-genotype promotes Aβ aggregation in vascular smooth muscle cell cultures [85]. Finally, CAA-related hemorrhage is reported to be associated with the apoE ε2 and ε4 allele [37, 88, 95, 97]. [See link for referenced footnotes.]
Conclusions: There is convincing evidence for a dose dependent association between APOE ε4 and sporadic CAA. Further work is needed to better understand the mechanism of this association and to further investigate other genetic associations with CAA. (Bold font added to quote for emphasis.)

Blood Brain Barrier (BBB) Breakdown/Leakage

The blood–brain barrier (BBB) separates the circulating blood from the brain, it protects the brain from pathogens the blood may carry. When the blood–brain barrier becomes leaky, bacteria and viruses are allowed to infiltrate the brain thus producing a toxic, neuroinflammatory effect. Breakdown of the BBB likely contributes to APOE4-associated cognitive decline independently of Alzheimer’s disease pathology.

From APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease(Hussein N. Yassine and Caleb E. Finch, 10 June 2020):

There is evidence supporting BBB breakdown in older APOE4 carriers. In APOE-TR [transgenic mice] models, activation of the cyclophilin A (CypA)–matrix metalloproteinase 9 (MMP-9) pathway leads to enzymatic degradation of the BBB tight junction and 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, and microvascular and cerebral blood flow reductions. The vascular defects in APOE4-TR mice appear to precede neuronal dysfunction and may initiate neurodegenerative changes. Also, this study showed that the astrocyte secreted apoE3 and apoE2, but not apoE4, suppressed the CypA–MMP-9 pathway in pericytes via low-density lipoprotein receptor-related protein 1 (LRP1; Bell et al., 2012). In humans, postmortem brain tissue analysis support BBB breakdown in patients with AD, which is more pronounced in APOE4 carriers compared with APOE3 or APOE2 (Zipser et al., 2007). The CSF plasma albumin quotient, a marker of BBB breakdown, is greater in older (above 65) cognitively normal APOE4 carriers compared to persons carrying the other genotypes (Halliday et al., 2013). Ongoing studies are examining whether more subtle vascular changes at the BBB appear in younger cognitively normal APOE4 carriers.

Axel Montagne has researched the blood brain barrier for years. He is the lead author of the paper APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline(Axel Montagne et al, 29 Apr 2020). From the abstract:

Recent studies have suggested that breakdown of the blood–brain barrier (BBB) is an early biomarker of human cognitive dysfunction[7], including the early clinical stages of Alzheimer’s disease[5,8,9,10]. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer’s disease[11,12,13,14], leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes[15,16,17,18,19], which maintain BBB integrity[20,21,22]. ...Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer’s disease pathology, and might be a therapeutic target in APOE4 carriers.

A comprehensive interview with Dr Montagne as conducted by Dr Rhonda Patrick and posted on Feb 28, 2023 can be found here Axel Montagne, PhD, on Solving Alzheimer’s and Dementia with Blood-Brain Barrier Repair. ApoE4 is addressed multiple times in this interview.


From this paper, The blood-brain barrier in Alzheimer's disease(Elena Zenaro, et al., Nov 2017):

Previous studies have shown that lack of murine Apoe and expression of APOE4 gene, a major genetic risk factor for AD, but not APOE2 and APOE3, leads to BBB dysfunction by activating a proinflammatory cyclophilin A (CypA)–nuclear factor-κ B–matrix-metalloproteinase-9 pathway in mouse pericytes (Bell et al., 2012). Interestingly, Apoe−/− and APOE4 mice also show a reduction of TJ proteins and develop vascular defects before neuronal and synaptic changes occur (Bell et al., 2012). In support of these data, recent studies using postmortem human brain tissues have shown that APOE4 compared with APOE3 accelerates pericyte loss in AD, which correlates with the magnitude of BBB breakdown to plasma proteins immunoglobulin G and fibrin (Halliday et al., 2016). APOE4 compared with APOE3 leads to a higher accumulation of CypA and MMP-9 in pericytes and endothelial cells in AD suggesting a role for LRP1-dependent CypA–MMP-9 BBB degrading pathway in accelerated BBB breakdown in AD APOE4 compared with AD APOE3 carriers (Halliday et al., 2016).


The abstract of the paper cited above Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease(Matthew R Halliday et al, Jan 2016) says:

The blood–brain barrier (BBB) limits the entry of neurotoxic blood-derived products and cells into the brain that is required for normal neuronal functioning and information processing. Pericytes maintain the integrity of the BBB and degenerate in Alzheimer’s disease (AD). The BBB is damaged in AD, particularly in individuals carrying apolipoprotein E4 (APOE4) gene, which is a major genetic risk factor for late-onset AD. The mechanisms underlying the BBB breakdown in AD remain, however, elusive. Here, we show accelerated pericyte degeneration in AD APOE4 carriers >AD APOE3 carriers >non-AD controls, which correlates with the magnitude of BBB breakdown to immunoglobulin G and fibrin. We also show accumulation of the proinflammatory cytokine cyclophilin A (CypA) and matrix metalloproteinase-9 (MMP-9) in pericytes and endothelial cells in AD (APOE4 >APOE3), previously shown to lead to BBB breakdown in transgenic APOE4 mice. The levels of the apoE lipoprotein receptor, low-density lipoprotein receptor-related protein-1 (LRP1), were similarly reduced in AD APOE4 and APOE3 carriers. Our data suggest that APOE4 leads to accelerated pericyte loss and enhanced activation of LRP1-dependent CypA–MMP-9 BBB-degrading pathway in pericytes and endothelial cells, which can mediate a greater BBB damage in AD APOE4 compared with AD APOE3 carriers.


From this paper The blood-brain barrier in Alzheimer's disease(B.D.Zipser, et al., Jul 2007):

These studies provide evidence that in advanced AD (Braak stage V–VI), plasma proteins like prothrombin can be found within the microvessel wall and surrounding neuropil, and that leakage of the blood–brain barrier may be more common in patients with at least one APOE4 allele. [Bold font added to quote.]

Mitochondrial dysfunction susceptibility

Mitochondria produce energy for our bodies. The energy they produce is called ATP (adenosine triphosphate). Mitochondrial dysfunction is a major determinant in how we age. It is a key factor in a myriad of diseases, and in particular is one of the earliest and most prominent features of Alzheimer’s Disease. Neurons, the fundamental units of the brain and nervous system, require massive amounts of energy to function and can die if they don’t have a constant supply of ATP. Anything that disrupts or impairs the brain’s ability to fuel itself has implications on cognition. The first priority of the mitochondria is to keep your cells oxygenized and blood pumping, other functions such as cognitive thinking, is a secondary task, so cognition will suffer in order for mitochondria to keep up with all their demands.

Studies indicate that the E4 allele is more susceptible to mitochondrial dysfunction, that ApoE4 is more sensitive than E3s or E2s to damaging free radicals. (Sources: Oxidative stress and Alzheimer disease (Yves Christen, Feb 2000) see below and APOE alters glucose flux through central carbon pathways in astrocytes(Holden C. Williams et al, Mar 2020)).

For more information on mitochondria and factors that degrade or can improve mitochondrial function see Mitochondria.

Some findings: Intertwined-relationship-among-ROS-mitochondria Intertwined relationship among ROS, mitochondria and APOE4 during the onset of Alzheimer's disease(Sihan Wang, 19 Dec 2022). From the link you can download the PDF paper.

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 [Reactive Oxygen Species], 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.

Regular proton pump inhibitor use and incident dementia: population-based cohort study(Peidong Zhang et al, 1 Sep 2022) Proton Pump Inhibitors (Prilosec, Prevacid, Nexium, Losec) are often used with conditions caused by excess stomach acid. But proton pumps aren’t limited to the stomach; they are present in every cell that has mitochondria, in other words every cell in the body except red blood cells.

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.

Neurons are extremely sensitive to attacks by destructive free radicals and according to this paper, Oxidative stress and Alzheimer disease(Yves Christen, Feb 2000) APOE is also sensitive to attacks by free radicals, with E4 being more sensitive than E3s or E2s. As stated in this paper:

Poirier (80) maintains that apo E has a beneficial effect for neuronal protection but that the apo E4 isoform is less effective than are the apo E2 and E3 isoforms. (In other words, apo E4 may not be toxic, but simply capable of producing a less-favorable effect.) Miyata and Smith (81) showed that apo E has a beneficial effect against free radicals.

Impaired Autophagy

Autophagy is the body's way of cleaning out damaged cells, in order to regenerate newer, healthier cells.

Some findings:

Effects of APOE4 expression on autophagy and mitochondrial dynamics and activity of astrocytes(14 May 2023)

These results point to a possible link between autophagy and β-amyloid clearance. Importantly, previous studies have shown that the expression of APOE4 may be related to impaired autophagy, especially in astrocytes.

A Review of ApoE4 Interference Targeting Mitophagy Molecular Pathways for Alzheimer's Disease(Huiyi Chen et al, 20 May 2022)

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.

ApoE4 attenuates autophagy via FoxO3a repression in the brain(Hee-Young Sohn et al, 02 Sep 2021)

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.


Gut Microbiota Differences

Gut microbiota, sometimes called gut flora or gut bugs refers to the microorganisms found in the gut (large and small intestines). The microbiome can contain both beneficial microbes as well as undesirable pathogens. Ideally, the bad bugs don't dominate the microbiome and the good and bad bugs are in balance.

The gut contains 500 million neurons and the gut and brain are strongly connected via the “gut-brain axis”. Communication between the gut and brain is facilitated by biochemical communication from neurotransmitters through the vagus nerve. The gut and its microbial inhabitants send signals via the axis to the brain and the brain also sends signals to the gut in two-way communication. The digestive tract also contains the largest component of the body’s immune system so the gut-brain axis is also connected through the body’s immune system.

Research shows that there is a difference in microbiota diversity and abundance between ApoE genotypes. The deficiencies ApoE4s hold could be a driver in our greater association with Alzheimer’s. [Source: APOE genotype influences the gut microbiome structure and function in humans and mice: relevance for Alzheimer's disease pathophysiology(Tam T. T. Tran et al, 8 Apr 2019)]

For more understanding of the gut-brain axis, its importance, and how to improve the gut microbiome see '''Gut-Brain Connection: Leaky Gut/Leaky Brain, Microbiome (gut bugs)'''

Some findings:

Genetic correlations between Alzheimer’s disease and gut microbiome genera(Davis Cammann et al, 31 Mar 2023)

This 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. [Bold font added to quote for emphasis.]

Genetic correlations between Alzheimer’s disease and gut microbiome genera(Min Hou et al, 24 Feb 2021)

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. [Bold font added to quote for emphasis.]

APOE-ε4 Carrier Status and Gut Microbiota Dysbiosis in Patients With Alzheimer Disease(Tam T. T. Tran et al, 8 Apr 2019)

Together, these findings indicate that APOE genotype is associated with specific gut microbiome profiles in both humans and APOE‐TR mice. This suggests that the gut microbiome is worth further investigation as a potential target to mitigate the deleterious impact of the APOE4 allele on cognitive decline and the prevention of AD.


Sleep Apnea

In 2019, Dr Rhonda Patrick interviewed Matthew Walker, Phd Dr. Matthew Walker on Sleep for Enhancing Learning, Creativity, Immunity, and Glymphatic System Dr Walker is a professor of neuroscience and psychology at the University of California, Berkeley, and serves as the Director of the Center for Human Sleep Science. Formerly, Dr. Walker served as a professor of psychiatry at the Harvard Medical School. From the transcript of the interview, Dr Walker said:

What I would also say that's important for people, if you know your ApoE status, and if you are apoe-4, be mindful of snoring as well. Because people who are apoe-4-positive, they also have a significantly elevated risk of a sleep disorder that we call sleep apnea, which is sleep disordered breathing, which is heavy snoring and a cessation of breathing entirely. And then you gasp when you wake up again.
But one of the other problems with sleep apnea is that you don't get the amount of deep sleep that you need. And you have hypoxic damage. Because you stopped breathing, your oxygen saturation goes down. You get hypoxia damage particularly in a region that is most sensitive to it in the brain, which is, drumroll, the hippocampus, the very same memory structure that is attacked in Alzheimer's disease.

So now you can see why I appeal for this sensitivity in this danger to sleep apnea. Because if you are apoe-4, you're already at high risk of Alzheimer's disease, you need to pay attention to your sleep. If you start snoring, and you have sleep apnea untreated, you will get less deep sleep. So you're compromising the thing that you need to try and lower your amyloid risk to begin with, because you're going to build up that amyloid, because you're not going to get the amyloid clearance elsewhere in the body, for example, in the liver. And then worse still, the part of the brain that is attacked severely by Alzheimer's disease and atrophies, which is the hippocampus, which is why memory fades, is a part of the brain that is damaged when you stop breathing because of oxygen desaturation.


Gallstones

Two papers from 1996 (the first two cited below) indicate a strong correlation between ApoE ε4 and gallstone formation/recurrence. However, more recent papers (also below) have cited no ApoE ε4 genetic susceptibility.

From this paper, Apolipoprotein E polymorphism and gallstones , (Bertomeu A, et al., Dec 1996)

...apo E4 increases hepatic lipoprotein uptake; hence, apo E4 could promote gallstone formation by increasing hepatic and biliary cholesterol concentrations. This study was designed to evaluate whether apo E polymorphism is related to gallstone risk....
Conclusions: Carrying the apo E4 isoform is a genetic risk factor for cholelithiasis [the formation of gallstones] in humans.[Bold font added to quote.]

Also from this study, Apolipoprotein E polymorphism and gallstones, (Portincasa P, et al., Sep 1996):

Apolipoprotein E (apoE) genotyping and gallbladder motility (sonography) were studied in a representative subgroup of patients (n = 50).
Recurrence rate [of gallstones] was higher (flog rank test, P = .037) in those patients who were homozygous and heterozygous for the E4 allele compared with the individuals who were not expressing the apoE4 allele.
The present study indicates that apoE4 genotype is associated with increased speed of gallstone clearance as well as a high risk of recurrence after ESWL [Extracorporeal shock‐wave lithotripsy – a gallstone treatment]. [Bold font added to quote.]

However, subsequent findings present a lack of correlation between ApoE ε4 and gallstones. From this study Apolipoprotein E Genotype and the Risk of Gallbladder Disease in Pregnancy, (Cynthia W. Ko, et al., Oct 1999):

In contrast to previous studies,10,11 [the above cited studies] we found that apoE4 was not a risk factor for gallbladder sludge and stones in pregnancy, even after adjusting for other known risk factors such as body mass index. Women who were heterozygous or homozygous for apoE4 were not at higher risk than women who did not carry any apoE4 allele. [Bold font added to quote.]

From this study, Genetic evidence that apolipoprotein E4 is not a relevant susceptibility factor for cholelithiasis in two high-risk populations, (Mella JG, et al., Jun 2007)

In this study analyzing the largest sample set available, apoE4 genotype was not associated with an increased frequency of GD [cholesterol gallstone disease (GD)] in either population. Moreover, in the Chilean population after adjusting for risk factors such as gender, age, body mass index, serum lipids, and glucose, the odds ratio for the association of the apoE4 allele and GD was significantly (P < 0.05) <1. Also, genotypes were not correlated with cholesterol crystal formation time, CSI, or gallstone cholesterol content. In contrast to previous smaller studies, apoE polymorphisms were not associated with susceptibility to cholesterol GD in high-risk populations.[Bold font added to quote.]

Additionally, from this study, Effect of apolipoprotein E polymorphism on bile lipid composition and the formation of cholesterol gallstone (Hasegawa K, et al., Jul 2003):

OBJECTIVE: It remains a matter of controversy whether possession of the apolipoprotein E4 (apoE4) allele is a genetic risk factor for the formation of cholesterol gallstones. The aim of the present study was to test this hypothesis by investigating the effect of apoE4 on bile lipid composition in normal subjects and in patients with cholesterol gallstones and to evaluate the distributions of apoE alleles in these two groups.
CONCLUSIONS: The apoE4 allele is not a contributory factor to cholesterol gallstone formation, at least in the Japanese population. [Bold font added to quote]


Decreased Longevity

As discussed in this paper, A meta-analysis of genome-wide association studies identifies multiple longevity genes, (Joris Deelen, et al., Aug 2019) for over two decades there have been studies associating genetic variation in APOE with longevity and lifespan identifying ApoE ε4 at increased risk for several age-related diseases, such as cardiovascular disease and Alzheimer’s disease therefore decreased longevity. The researchers in this paper took studies from all over the world to perform a genome-wide association (GWA) meta-analysis of over 13,000 long-lived individuals of diverse ethnic background, including European, East Asian and African American ancestry, to characterize the genetic architecture of human longevity and found:

“Consistent with previous reports, rs429358, defining ApoE ε4, was associated with decreased odds of becoming long-lived.”