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

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Revision as of 11:01, 26 January 2019 by Theresab (talk | contribs) (added gallstones)
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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 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 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:

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.

Coronary Heart Disease/Cardiovascular Disease (CHD/CVD)

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

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.]

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. [See link for referenced footnotes.]

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.]
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.]
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]
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, walking on dung, and other insults, this state of constantly having the body's immune resources ready to fight may make it less able to fight for long. 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.
  • 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. [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]
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