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APOE4 Community

From SNPedia

Note, November, 2013[edit]

Work on this (at least by me, Epsilon4, the person who started it) will be continued at apoe4.info. We at apoe4.info are extremely grateful to SNPedia for allowing us to begin the project here.


This is a space for organizing information about how to prevent and treat ApoE4-associated pathology. (See Notes for rationale.)

The ε4 variant of the APOE gene is famous for conferring a significantly higher risk for Alzheimer's disease, but numerous other diseases have been linked to it, including, to name a few, other forms of dementia, heart disease, and gallbladder stones. Much of the focus of this wiki space will nonetheless likely be on Alzheimer's disease and other forms of dementia, since dementia is what most ε4 carriers are concerned about, given the devastating consequences of dementia and the current lack of effective treatment for it.

See the discussion page for ideas about how we can organize these pages.

Encouraging ApoE4 research[edit]

Here are some ideas about what can be done to focus more research on the APOE-ε4 allele and the protein it produces, ApoE4.

  • Encourage researchers to pool existing data to get statistical significance. There are many researchers sitting on unpublished data looking at lifestyle and even drug interventions and their relation to outcomes based on ε4 status. The numbers of ε4 homozygotes in any particular study are in nearly all cases (I'd guess) too small to reach statistical significance, but if the data were pooled it would surely permit some at least tentative, if not solid conclusions.
  • Those ε4 homozygotes who are interested in participating in trials could contact researchers and say they are available to be studied (heterozygotes could of course also be studied). Some researchers would jump at the chance to research non-demented ε4 homozygotes, since the expense of finding ε4 homozygotes in younger populations is enormous.

Some research teams or organizations that could be contacted:

Status: 23andMe is not currently pursuing ApoE-related research.

ε4 carriers who feel comfortable sharing their data (anonymously) can upload their sequencing and health information to existing open genome projects:

Possible interventions/treatment[edit]

Note: No cure for Alzheimer’s disease nor any well-grounded prevention regimen is currently known. The following is a list of putative treatment and prevention measures, along with a rationale (be it research support or speculation based on a plausible mechanism of action), with links to research papers.

Additionally, research shows that the most effective deterrent to developing Alzheimer’s found to date is a healthy lifestyle including a well balanced diet and exercise [PMID 20182018] [PMID 24535714]. A cohort study following over 1800 Japanese immigrants found an inverse relationship between fruit and vegetable juice consumption and incidence of Alzheimer’s, with more pronounced results among those with the APOE-ε4 allele [PMID 16945610]. Another study, examining adherence to the Mediterranean diet (a diet rich in fruits, vegetables, legumes, cereals and healthy fats such as monounsaturated and omega 3 fatty acids [PMID 7754995]) followed a cohort of ~2000 elderly individuals in New York for 4 years; researchers found that higher adherence to the Mediterranean diet resulted in lower rates of Alzheimer’s, with an odds ratio of 0.76 (95% confidence interval, 0.67-0.87; P<0.001) [PMID 17030648]. The results were irregardless of APOE-ε4 allele status. Finally, a population-based study of 1500 people in Finland found that individuals who participated in physical activity at least twice a week through middle age carry a 60% lower risk of Alzheimer’s [PMID 18165854]. The protective effects were most pronounced in individuals with the APOE-ε4 allele.

Coffee (and caffeine)[edit]

Much evidence exists that coffee consumption, and caffeine in general (tea will be considered separately), seems to offer some protection against many forms of dementia, including Alzheimer's, regardless of ApoE status.


Possibly somewhat preventive (applies to both Alzheimer’s and Parkinson’s), especially in women; possibly even slightly effective as a treatment.


- Neuroprotective effects in several studies in mouse models of Alzheimer’s

[PMID 19581722]

[PMID 19581723]

[PMID 16938404]

[PMID 12711619] (free full text available)

- Epidemiological studies.

[PMID 20859800] (Review)

[PMID 20182036] (2010. Effect seen in women, not in men.)

[PMID 17679672] (2007. Effect seen in women, not in men.)

[PMID 20164564] (2010. No effect seen in men.)

But many studies note effects in both men and women. See issue dedicated to caffeine and neurological effects for more studies:

Journal of Alzheimer's Disease, Volume 20, Supplement 1/2010.

Preface has good summary: "Therapeutic Opportunities for Caffeine in Alzheimer's Disease and Other Neurodegenerative Disorders".

Men smoke more, and smoking lowers caffeine levels: less effect in men because smoking not controlled for? (See “Caffeine intake and dementia: systematic review and meta-analysis”, p. S202 [PMID 20182026]).

Large (4,809 subjects), recent (2011) analysis showed no consistent effects in men, but some (non-linear) effects in women. "Gender differences in tea, coffee, and cognitive decline in the elderly: the Cardiovascular Health Study". [PMID 21841254]

Proposed mechanism(s)[edit]

- Reduces presenilin 1 (PS1) and beta-secretase (BACE) activity. (www.ncbi.nlm.nih.gov/pmc/articles/PMC3205506/, “Caffeine”)

- Upregulation of adenosine A1 receptors which suppresses the synthesis of pro-inflammatory cytokines and reduced glutamate release and subsequent excitotoxic injury. (“Stuck at the bench: Potential natural neuroprotective compounds for concussion”, “Caffeine”; Caffeine may block inflammation linked to mild cognitive impairment)

- Adenosine associated decreases in blood brain barrier permeability may reduce the amount of amyloid passing into the brain? ("Caffeine, cognitive functioning, and white matter lesions in the elderly: establishing causality from epidemiological evidence", “Discussion”)

For more see “Midlife Coffee and Tea Drinking and the Risk of Late-Life Dementia: A Population-Based CAIDE Study”, p. 89, “Possible mechanisms”.

Might APOE status affect relevance of the research supporting this intervention?[edit]

- Has any research examined ApoE status?

Two studies:

1. “Midlife Coffee and Tea Drinking and the Risk of Late-Life Dementia: A Population-Based CAIDE Study” [PMID 19158424] concludes that carriers of APOE-ε4 (no differentiation here between hetero- and homozygotes) may receive more benefit in reduction in dementia risk (though not AD per se).

2. “Tea consumption and cognitive impairment and decline in older Chinese adults” [PMID 18614745] found no stratification of effect based on ε4 status.

Speculation about how it might or might not apply APOE-ε4 carriers[edit]

No reason to think the research wouldn’t apply to APOE-ε4 hetero- or homozygotes, though it might help ε4 carriers more than others, given that blood-brain barrier permeability seems to be greater in ε4 carriers, and reducing BBB permeability is one possible mechanism for caffeine’s effects.

Theoretical concerns?[edit]

- Caffeine raises homocysteine levels, and homocysteine is associated with greater risk of Alzheimer’s.

- Unfiltered coffee raises cholesterol levels somewhat.

Omega-3 (n-3) fatty acids[edit]

Several lines of reasoning led to the hypothesis that consumption of omega-3 fatty acids (DHA and EPA, found primarily in fish, and ALA, found in plants) will reduce the risk of dementia (and can even improve cognition in youth)[PMID 24228198]. However, recent evidence suggests that ApoE-ε4 carriers likely see no benefit from the supplementation.


Transgenic mice modelling the ApoE-ε4 homozygous status show 24% reduced uptake of DHA in the brain, as compared to ApoE-ε2 mice [PMID 24345162]. These results indicate that ApoE-ε4 likely do not benefit from DHA supplementation. Other omega-3 fatty acids are not as well researched.

Note, a few researchers suspect that the reason DHA has not been effective in ε4 carriers is that the negative consequences of DHA consumption (DHA oxidation) overwhelm potential benefits, and that consumption of sufficient antioxidants along with the DHA, or, alternatively, consuming it in a natural form, where it would be less subject to oxidation, would permit it to be beneficial for ε4 carriers. For a summary, see "Omega-3s, ApoE Genotype and Cognitive Decline". This theory has not been tested however, and the epidemiological evidence offered in support of the theory is mostly from societies that consume the omega-3 fatty acid found in plant-based diets, ALA (which, itself, may help ε4 carriers, but more research is needed).

Alcohol consumption[edit]

(This section is a stub. You can help SNPedia by expanding it.)

Correlative studies have shown that regular consumption of a small amount of alcohol is linked to a number of health benefits, especially cardiovascular benefits, which, themselves, are correlated with reduced risk of dementia.

But the studies are not all consistent, and many researchers speculate that there are too many confounding factors to be able to adequately isolate the effect of alcohol consumption.

The question for ε4-carriers is whether APOE status modifies the relation between alcohol consumption and health effects. The answer is a fairly clear "yes". The principal question is whether alcohol is harmful to ε4-carriers, or merely non-beneficial. The evidence is mixed. All reviews call for more studies.


Consumption of a small amount of alcohol (the equivalent of one drink for a typical woman, a bit more for a typical man) may reduce risk in non-ε4-carriers. In ε4-carriers (including ε3/ε4s; note though that ε2/ε4s have not been studied sufficiently), any amount of alcohol appears to be damaging according to some studies, neutral according to others, and slightly beneficial according to yet others.


- According to one often-cited study, ε4 teetotalers may have a lower risk than ε3s who never drink (but not lower than ε3s who drink a little).

[PMID 15304383] (free full text available):

Results. Participants who drank no alcohol at midlife and those who drank alcohol frequently were both twice as likely to have mild cognitive impairment in old age as those participants who drank alcohol infrequently. The risk of dementia related to alcohol drinking was modified by the presence of the apolipoprotein e4 allele. The carriers of apolipoprotein e4 had an increased risk of dementia with increasing alcohol consumption: compared with non-carriers who never drank [which, for them, is not as good as drinking a little bit], the odds ratio for carriers who never drank was 0.6 [emphasis added], for infrequent drinkers it was 2.3, and for frequent drinkers was 3.6 (the overall interaction term "drinking frequency*apolipoprotein e4" was significant (P = 0.04), as were the interactions "infrequent drinking*apolipoprotein e4" (P = 0.02) and "frequent drinking*apolipoprotein e4" (P = 0.03)). Non-carriers of apolipoprotein e4 had similar odds ratios for dementia irrespective of alcohol consumption.

Note, however, that the authors speculate that the infrequent drinkers may have been binge drinkers:

Concerning alcohol drinking, it might also be that it is the drinking pattern which together with apoE ɛ4 carrier status forms a hazardous combination. At the time of the midlife assessment of the current study, it was a common habit in Finland to drink reasonable (sic) seldom (most drinkers drank only once of twice per month in the current data), but still, a large quantity of alcohol per each drinking session (i.e. binge drinking). This binge drinking habit might specifically interact with apoE ɛ4 and therefore, the increase in the dementia risk might be more pronouncedly seen among those persons carrying the apoE ɛ4 allele and classified as frequent drinkers in our study. These issues need to be further clarified in large cohort studies with more detailed information about alcohol consumption.

- A different study also finds that ε4 carriers have an increased risk of AD when they drink infrequently, compared to when they don't drink at all (3.78 odds ratio, with a 95% confidence interval of 0.94–15.24). Most of the findings are very similar to the above study. (Note that the same research team conducted both analyses, and the populations examined were drawn from the same cohort in Scandinavia, where "infrequent drinking" is likely to mean infrequent binge drinking.)

[PMID 18318693] (I have the full text, not sure if available Mqrius (talk) 06:56, 9 October 2013 (UTC))

Compared with the ‘apoE ε4 non-carrier and never drinker’ group the ‘apoE ε4 carrier and never drinker’ group had an OR 0.67 (95% CI = 0.17–2.73), ‘apoE ε4 carrier and infrequent drinker’ group 2.36 (95% CI = 0.83–6.73) and ‘apoE ε4 carrier and frequent drinker’ group 3.82 (95% CI = 1.14–12.75) for dementia.

Proposed mechanism(s)[edit]

- Alcohol seems to block neurogenesis.


- ε4s have increased markers of inflammation (il-6 and SAP) with alcohol consumption.

[PMID 17684217] (free full text available)

Might APOE status affect relevance of the research supporting this intervention?[edit]

(See above. Answer: Yes.)

Recent reviews:

[PMID 22396679] (free full text available)

[PMID 22396249]

[PMID 21857787]

[PMID 20617045]

To Do[edit]

Find studies of infrequent or light (non-binge) drinking that examine outcomes for ε4-carriers!


It appears that the best strategy for ε4-carriers, in general, when it comes to alcohol consumption, might be to avoid alcohol entirely, especially if the putative beneficial effects of alcohol (improved cholesterol profiles -- which may be yet another benefit that accrues only to non-ε4s) can be achieved by other means. But there simply hasn't been enough research.

Turmeric and curcumin[edit]

(This section is a stub. You can help SNPedia by expanding it.)

There is evidence that turmeric, and in particular one of its components, curcumin, might protect against Alzheimer's and other forms of dementia.


[Finish later.]


Great summary of some differences between APOE-ε4s and others in the effects of various treatment/prevention modalities:


A mouse model of APOE4:



In response to https://www.23andme.com/you/community/thread/15952/. (You need an account at 23andMe to follow this link. Demo accounts, which are free, work fine.)