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

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 a gene 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 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.

Hypercholesterolemia (High Cholesterol)

ApoE ϵ4s tend to run high cholesterol numbers. This may or may not be problematic for ApoE ϵ4s. The brain, while only 2% of body mass, contains ≈20% of the body’s cholesterol, it is the most cholesterol-rich organ in the body. Cholesterol is important for healthy cognition and low cholesterol is associated with brain atrophy. Since the ApoE4 protein transports less cholesterol to the brain than ApoE3 or ApoE2, perhaps ϵ4 carriers simply make more cholesterol to compensate for this and to accommodate needs of the brain/body.

Hypercholesterolemia 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

Studies supporting hypercholesterolemia in ApoE ϵ4s:

• Association of hypercholesterolemia and apolipoprotein E4 in school children (Hisako Yanagi, et al., Oct 1990):

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.

• Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders (Robert W. Mahley, 09 Jun 2016)

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).

• Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study (CarlosLahoz, et al., 15 February 2001):

The apo E4 (Arg112-Cys) polymorphism has been associated with dementia and hypercholesterolemia.

Coronary Heart Disease/Cardiovascular Disease (CHD/CVD)

There are a number of studies with a variety of findings:

• Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders, (Robert W. Mahley, 09 Jun 2016):

Atherosclerosis is the hardening and narrowing of the arteries.

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.]

• Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS (Robert W. Mahley, et al., Dec 22, 2008)

Atherogenesis is the process of forming plaques in the intima layer of arteries.

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.][See link for referenced footnotes.]

• A prospective study of the association between APOE genotype and the risk of myocardial infarction among apparently healthy men(Simin Liu, et al., Feb 2003):

A Myocardial infarction (MI) is more commonly known as a heart attack.

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.]

• The Significant Increase in Cardiovascular Disease Risk in APOEɛ4 Carriers is Evident Only in Men Who Smoke: Potential Relationship Between Reduced Antioxidant Status and ApoE4 (P. J. Talmud, et al., 26 Jul 2005):

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.]

• Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study (Carlos Lahoz, et al., 15 Feb 2001):

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]

• Is the apoE4 allele an independent predictor of coronary events?, (Angelo Scuteri, et al., Jan 2001):

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.]

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 primarily 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. There's still much to be learned in this area. Some findings:

This paper, Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS(Robert W. Mahley, et al, December 22, 2008) discusses the roles of ApoE beyond lipoprotein metabolism.

• 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][See link for referenced footnotes.]

And from this paper, APOE genotype-specific differences in the innate immune response (Michael P. Vitek, et al, Sep 2009):

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

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]

Issues of the Brain

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.]

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 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.] [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.] [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).

From this paper Vascular pathology in the aged human brain, (Grinberg, L.T. & Thal, D.R. Acta, Feb 2010):

Genetically, an association between SVD and the apoE ε4 allele has been reported [154].

The above 154 footnote refers to this paper: APOE, vascular pathology, and the AD brain (Yip AG, et al., Jul 2005), which says:

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.]

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.

From this paper Vascular pathology in the aged human brain (Grinberg, L.T. & Thal, D.R. Acta, Feb 2010):

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.]

Blood Brain Barrier (BBB) Leakage

The blood–brain barrier (BBB) separates the circulating blood from the brain, it protects the brain from pathogens. When the blood–brain barrier becomes leaky, bacteria and viruses are allowed to infiltrate thus producing a toxic effect. Alzheimer's disease is likely aggravated by a breakdown of the blood-brain barrier.

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.]

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

Interestingly, Apoe−/− and APOE4 mice also show a reduction of TJ [Tight Junction] 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)[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.”