What does an ApoE test imply?

blog genetics health math

In my previous post I worked out how a negative carrier test for an autosomal recessive disorder updates a sibling's risk. Not much, as it turns out, unless the background rate is already quite high. ApoE is more interesting because it involves three common alleles.

ApoE in a nutshell

The APOE gene codes for a protein involved in lipid transport and cholesterol metabolism. It's the principal cholesterol carrier in the brain and interacts with the low-density lipoprotein receptor to clear lipoprotein particles from circulation. It comes in three common variants, called ε2, ε3, and ε4. Since you inherit one copy from each parent, there are six possible genotypes: ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4, and ε4/ε4.

There are a few reasons to care about this genotype: Alzheimer's risk, cardiovascular disease, and immunity.

Alzheimer's risk

ε4 is the strongest common genetic risk factor for late-onset Alzheimer's disease. The table below gives odds ratios for AD relative to ε3/ε3 in European-ancestry populations drawing data from a modern 337,484-person UK Biobank analysis (Lumsden et al. 2020, white British participants; per-genotype values from appendix table S4)1 alongside the classic Farrer et al. (1997) meta-analysis2 (Caucasian; 5,930 AD patients, 8,607 controls across 40 research groups).

Genotype UK Biobank, Lumsden 20201 (95% CI) Farrer 19972 (95% CI)
ε2/ε2 0.46 (0.06–3.27) 0.6 (0.2–2.0)
ε2/ε3 0.77 (0.53–1.11) 0.6 (0.5–0.8)
ε2/ε4 1.83 (1.10–3.05) 2.6 (1.6–4.0)
ε3/ε3 1.00 (reference) 1.0 (reference)
ε3/ε4 3.69 (3.08–4.40) 3.2 (2.8–3.8)
ε4/ε4 13.5 (10.6–17.2) 14.9 (10.8–20.6)

The two sources concord closely. Only the ε3/ε4 and ε4/ε4 associations cleared the phenome-wide–corrected significance threshold of this UK Biobank study; the protective ε2 genotypes are too sparse in a healthy middle-aged cohort, leaving the wide confidence intervals seen above.

AD effect sizes vary substantially by ancestry: Farrer reports the ε4/ε4 odds ratio ranging from 33.1 in Japanese and 14.9 in Caucasian cohorts down to 5.7 in African Americans and just 2.2 in Hispanics2.

ε4/ε4 individuals are 88% AD-biomarker-positive by age 803. Taking ε2/ε2 as the reference genotype, Williams et al. (2026) estimate that ε3 and ε4 together account for the vast majority of AD with attributable fractions ranging from ~72% (FinnGen) to ~93% (ADGC) across cohorts4. That is, the ε3/ε3 "baseline" is neutral only by convention, not in absolute terms.

Belloy et al. (2019)5 has another synthesis.

Cardiovascular risk

ApoE also has an impact on cardiovascular health via LDL cholesterol. ε2 is also favorable here: the ε2 isoform lowers circulating LDL while ε4 raises it. LDL-C, and coronary risk it associates with, climbs approximately linearly across the genotypes from ε2/ε2 to ε4/ε4. In the Bennet et al. (2007) meta-analysis (86,067 people for lipids; 37,850 coronary cases), the coronary heart disease (CHD) odds ratios relative to ε3/ε3 are6:

Genotype CHD OR (95% CI)
ε2/ε2 0.83 (0.55–1.25)
ε2/ε3 0.82 (0.72–0.92)
ε2/ε4 0.93 (0.81–1.07)
ε3/ε3 1.00 (reference)
ε3/ε4 1.05 (0.99–1.12)
ε4/ε4 1.22 (1.08–1.38)

Pooled by carrier status, ε2 carriers had roughly 20% lower coronary risk than ε3/ε3 (OR 0.80, 95% CI 0.70–0.90), while ε4 carriers were not significantly different (OR 1.06, 0.98–1.15)6. Coronary disease is not the whole cardiovascular story, though: independent of its modest coronary effect, the ε4 allele raises susceptibility to stroke and cerebrovascular disease (an allele-level effect, so it applies to both ε3/ε4 and ε4/ε4)5.

Modern direct-imaging data reinforce ε2's benefit: in the PESA cohort of 3,887 asymptomatic midlife adults, ε2 carriers had markedly less subclinical atherosclerosis across the carotid, femoral, and coronary beds (coronary odds ratio 0.53), largely independent of their lower LDL7. In Haffner et al.'s biethnic population study, LDL peak particle size decreased stepwise from ε2/ε3 → ε3/ε3 → ε3/ε4, leaving ε2 carriers prone to pattern-A LDL (large and buoyant), while ε4 carriers had smaller, denser pattern-B particles8. This is a well-established feature of the APOE–LDL-subclass relationship9.

The above looks good for ε2, but there's a problem. The same mechanism that causes it to lower LDL also makes it clear chylomicron and VLDL remnants poorly, so ε2 tends to raise triglycerides. In particular, ~5% of ε2/ε2 individuals develop type III hyperlipoproteinemia10, and even then usually only with a second insult like insulin resistance or hypothyroidism11. Elevated triglycerides drive pattern-B LDL, which is atherogenic and bad.

How can we reconcile ε2 being prone to both pattern A and pattern B? Preexisting factors. In an ε2 carrier who is already hypertriglyceridemic or has established coronary disease, the balance flips toward pattern B12. In the PESA cohort, ε2's atheroprotection vanished in carriers with triglycerides ≥150 mg/dL7. So ε2's cardiovascular benefit is real but triglyceride-contingent: it holds as long as triglycerides stay in range.

ApoE and immunity

ApoE also has immune effects. ApoE-null mice are markedly more susceptible to Listeria and Klebsiella infection10. In contrast, apoE facilitates herpes simplex (HSV), HIV, and dengue entering cells, and ε4 facilitates this the most.13. ApoE binds cell-surface glycosaminoglycans in the rank order E4 > E3 > E2, and that ordering tracks how readily each isoform helps HSV-1 attach to and enter cells13. Clinically, ε4 carriers get more cold sores: one study linked the ε4 allele to oral herpetic lesions (relative risk ≈4.6) while finding no effect on how often the virus reactivated or shed14. The same pattern holds for HIV: apoE4 is a weaker inhibitor of viral membrane fusion than apoE3, so it enhances HIV cell entry. In a 1,267-patient cohort, ε4/ε4 homozygotes progressed faster and carried higher steady-state viral loads in a dose-dependent way (ε4/ε4 > ε4/non-ε4 > non-ε4), and a separate cohort found ε4 carriers reaching HIV disease in 8.3 versus 10.5 years even though APOE genotype did not change the risk of acquiring HIV in the first place (ε2 = ε3 = ε4)15.

This ties back to Alzheimer's. ε4 is over-represented among AD patients who carry HSV-1 but not among those who don't. This suggests some of ε4's Alzheimer's risk may run through viral susceptibility10. For an ε2/ε3 result like mine, the E4 > E3 > E2 gradient means my genotype is among the least facilitating on this infectious-disease axis15.

Miscellaneous facts

  • Nearly all other mammals, and all the great apes, carry an ε4-like apoE. ε3 and ε2 arose more recently in human evolution, each by a single-nucleotide change10.
  • In a study of 40-year-old Danish men, ε3/ε3 men averaged 1.93 children with only 6% childless, versus 1.50 children (26% childless) for ε4 carriers and 1.66 (19% childless) for ε2 carriers. This is a statistically significant fertility edge for ε3/ε3 (P = 0.003)16.
  • The frequency of ε4 is lowest around the historical cradles of agriculture. These are thought to be among the first places dense enough to sustain epidemic viral disease and reinforce ApoE's role in immunity10.

Sibling update

Function Health offers an ApoE add-on test. I took it and found I have a ε2/ε3 genotype.

Given my result, how does the posterior probability that a sibling of mine has an ε4 allele change?

In European populations, typical allele frequencies17 are approximately:

  • ε2: $f_2 \approx 0.08$
  • ε3: $f_3 \approx 0.78$
  • ε4: $f_4 \approx 0.14$

ε4 is more common in Northern Europe (up to ~22%) and less common in Southern Europe (as low as ~6%). Kolbe et al. (2023)17 attribute the current European distribution mainly to ancient admixture rather than recent selection, while Egert, Rimbach & Huebbe (2012)18 review latitude correlations and dietary-response implications of the polymorphism.

I received one allele from each of my parents: ε2 from one, ε3 from the other. Each of my parents had a "hidden" allele that I didn't inherit. We model these hidden alleles as being drawn independently from the population averages.

A sibling of mine also gets one allele from each parent. For each parent, there's a 50% chance my sibling inherits the same allele I did (the "known" one) and a 50% chance they get the hidden allele. Thus, my sibling's genotype falls into four equally likely cases:

Probability From parent who gave me ε2 From parent who gave me ε3
1/4 ε2 (known) ε3 (known)
1/4 ε2 (known) hidden ~ $(f_2, f_3, f_4)$
1/4 hidden ~ $(f_2, f_3, f_4)$ ε3 (known)
1/4 hidden ~ $(f_2, f_3, f_4)$ hidden ~ $(f_2, f_3, f_4)$

The probability of my sibling receiving ε4 from any given parent is $\frac{1}{2}\cdot 0 + \frac{1}{2}\cdot f_4 = f_4/2$ since we know that each parent must have one non-ε4 allele. Therefore, the probability my sibling has no ε4 alleles is:

$$ P(\textrm{no ε4}) = \left(1 - \frac{f_4}{2}\right)^2 $$

The probability they are ε4 homozygous is:

$$ P(\textrm{ε4/ε4}) = \left(\frac{f_4}{2}\right)^2 $$

And the probability they carry at least one ε4 is:

$$ P(\textrm{any ε4}) = 1 - \left(1 - \frac{f_4}{2}\right)^2 $$

Plugging in numbers

Using $f_4 = 0.14$:

Population (no info) Sibling of ε2/ε3
No ε4 alleles $(1-0.14)^2 = 74.0$% $(1-0.07)^2 = 86.5$%
At least one ε4 26.0% 13.5%
Homozygous ε4/ε4 $0.14^2 = 2.0$% $0.07^2 = 0.5$%

My ε2/ε3 result roughly halves my siblings' probability of carrying any ε4 and quarters their probability of the high-risk ε4/ε4 genotype from 2% to 0.5%.

For completeness, we can compute the full sibling genotype distribution. The effective allele frequency from each parent is a 50/50 mix of the known allele and a population draw:

ε2 ε3 ε4
From ε2 parent $(1+f_2)/2 = 0.54$ $f_3/2 = 0.39$ $f_4/2 = 0.07$
From ε3 parent $f_2/2 = 0.04$ $(1+f_3)/2 = 0.89$ $f_4/2 = 0.07$

The sibling draws one allele from each parent independently, so each genotype's probability is a product of one entry from each row summed over both ways a heterozygote can be assembled. For ε2/ε3, a sibling can get it two ways: ε2 from the ε2-parent and ε3 from the ε3-parent ($0.54 \times 0.89$), or ε3 from the ε2-parent and ε2 from the ε3-parent ($0.39 \times 0.04$). These sum to $0.481 + 0.016 = 0.496$. A homozygous genotype like ε2/ε2 has only one route, ε2 from each parent: $0.54 \times 0.04 = 0.022$. Repeating for all six genotypes gives the full sibling distribution:

Genotype Population Sibling of ε2/ε3
ε2/ε2 0.6% 2.2%
ε2/ε3 12.5% 49.6%
ε2/ε4 2.2% 4.1%
ε3/ε3 60.8% 34.7%
ε3/ε4 21.8% 9.0%
ε4/ε4 2.0% 0.5%

The sibling distribution is dramatically shifted toward genotypes containing ε2 and ε3 — unsurprising, since those are the alleles I'm known to carry. The ε3/ε4 and ε4/ε4 probabilities are both roughly halved.

So the net effect here is that my siblings should worry less about Alzheimer's and more about pattern B LDL.

References

  1. Lumsden AL, Mulugeta A, Zhou A, Hyppönen E. Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank (doi:10.1016/j.ebiom.2020.102954). EBioMedicine. 2020 Sep;59:102954. PMID: 32818802. — Abstract: A hypothesis-free phenome-wide association study screened 337,484 white British UK Biobank participants (aged 37–73) for associations between APOE genotype and >950 disease outcomes, using ε3/ε3 as reference. The strongest association was with Alzheimer's disease: relative to ε3/ε3, the odds ratio was 3.69 (95% CI 3.08–4.40) for ε3/ε4 and 13.52 (10.64–17.18) for ε4/ε4 — closely reproducing the Farrer et al. (1997) estimates in a modern population cohort. APOE genotype was also associated with lipid disorders, ischaemic heart disease, and other outcomes, consistent with its dual role in neurodegeneration and cardiovascular disease. The full per-genotype AD odds ratios used here (phecode 290.11, including the ε2 genotypes) are from the supplementary appendix, table S4.↩

  2. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM (APOE and Alzheimer Disease Meta Analysis Consortium). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis (PubMed). JAMA. 1997 Oct 22–29;278(16):1349–1356. — Abstract: 40 research teams contributed APOE genotype, sex, age-at-onset, and ethnic data for 5,930 patients with probable or definite AD and 8,607 controls without dementia. In Caucasian clinic- and autopsy-based studies, odds ratios (95% CI) relative to ε3/ε3 were: ε2/ε2, 0.6 (0.2–2.0); ε2/ε3, 0.6 (0.5–0.8); ε2/ε4, 2.6 (1.6–4.0); ε3/ε4, 3.2 (2.8–3.8); ε4/ε4, 14.9 (10.8–20.6). In Japanese subjects the ε4 associations were stronger (ε3/ε4 OR 5.6, ε4/ε4 OR 33.1); in African Americans and Hispanics they were weaker. The ε4 allele is "a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women," with effects diminishing after age 70.↩

  3. Fortea J, Pegueroles J, Alcolea D, Belbin O, Dols-Icardo O, Vaqué-Alcázar L, Videla L, Gispert JD, Suárez-Calvet M, Johnson SC, Sperling R, Bejanin A, Lleó A, et al. APOE4 homozygosity represents a distinct genetic form of Alzheimer's disease (Nature Medicine). Nature Medicine. 2024 May;30(5):1284–1291. — Abstract: Drawing on postmortem data from more than 3,200 brains in the National Alzheimer's Coordinating Center plus clinical and biomarker data from over 10,000 individuals across five cohorts, the authors show that APOE ε4 homozygotes exhibit near-complete penetrance of Alzheimer's pathology: nearly all had abnormal CSF amyloid-β42 by age 65, and 88% were positive across amyloid-PET and CSF measures by age 80, following a predictable biomarker sequence and symptom-onset age. They argue ε4/ε4 constitutes a distinct genetic form of AD — with the important caveat that this near-full penetrance is biological (pathology/biomarkers); clinical dementia penetrance is lower.↩

  4. Williams DM, Heikkinen S, Hiltunen M, FinnGen, Davies NM, Anderson EL. The proportion of Alzheimer's disease attributable to apolipoprotein E (npj Dementia). npj Dementia. 2026;2:1. — Abstract: The authors estimated the fraction of clinically diagnosed AD, AD neuropathology, and all-cause dementia attributable to the common APOE alleles in four large cohorts (UK Biobank n = 171,105; FinnGen n = 289,150; plus ADGC and ROSMAP data), using ε2/ε2 as the reference genotype. Attributable fractions for AD ranged from 71.5% (95% CI: 54.9–81.7%) in FinnGen to 92.7% (82.4–96.5%) in ADGC. The proportions of all-cause dementia attributable to ε3 and ε4 were 44.4% (18.2–62.2%) in UKB and 45.6% (30.6–56.9%) in FinnGen.↩

  5. Belloy ME, Napolioni V, Greicius MD. A Quarter Century of APOE and Alzheimer's Disease: Progress to Date and the Path Forward (PubMed). Neuron. 2019 Mar 6;101(5):820–838. — Abstract: Alzheimer's disease is polygenic, yet uncertainty persists about how to characterize the nearly monogenic contribution of APOE. The APOE4 allele is the most significant genetic risk factor for AD while also increasing susceptibility to cardiovascular disease, stroke, and additional neurodegenerative conditions. This review synthesizes human data across APOE-related pathologies, including evolutionary genetics and risk stratification by ethnicity and sex, and examines whether APOE4 increases AD risk via a loss or gain of function.↩

  6. Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, Keavney B, Collins R, Wiman B, de Faire U, Danesh J. Association of apolipoprotein E genotypes with lipid levels and coronary risk (doi:10.1001/jama.298.11.1300). JAMA. 2007 Sep 19;298(11):1300–1311. — Abstract: A meta-analysis of 82 studies of lipid levels (86,067 participants) and 121 studies of coronary outcomes (37,850 cases, 82,727 controls) found approximately linear relationships of APOE genotype with both LDL cholesterol and coronary risk. Compared with ε3/ε3, the odds ratio for coronary disease was 0.80 (95% CI 0.70–0.90) in ε2 carriers and 1.06 (0.98–1.15) in ε4 carriers, tracking a stepwise gradient in LDL-C that spanned about 31% between the ε2/ε2 and ε4/ε4 genotypes.↩

  7. Toribio-Fernández R, Tristão-Pereira C, Silla-Castro JC, Callejas S, Oliva B, Fernandez-Nueda I, Garcia-Lunar I, Perez-Herreras C, Ordovás JM, Martin P, et al.; Cortes-Canteli M, Fuster V. Apolipoprotein E-ε2 and Resistance to Atherosclerosis in Midlife: The PESA Observational Study (doi:10.1161/CIRCRESAHA.123.323921). Circulation Research. 2024 Feb 16;134(4):411–424. — Abstract: In a subcohort of 3,887 asymptomatic middle-aged adults (mean age 45.8, 62% male) from the PESA study, APOE-ε2 carriers were at the lowest cardiovascular risk and had significantly lower odds of subclinical atherosclerosis by imaging across multiple territories (carotids 0.62 [95% CI 0.47–0.81]; femorals 0.60 [0.47–0.78]; coronaries 0.53 [0.39–0.74]; overall PESA score 0.58 [0.48–0.71]). This atheroprotection was mostly independent of the ε2-associated lower LDL cholesterol and other risk factors; however, ε2 carriers with triglycerides ≥150 mg/dL did not show the protection, suggesting the effect is triglyceride-dependent.↩

  8. Haffner SM, Stern MP, Miettinen H, Robbins D, Howard BV. Apolipoprotein E Polymorphism and LDL Size in a Biethnic Population (doi:10.1161/01.atv.16.9.1184). Arteriosclerosis, Thrombosis, and Vascular Biology. 1996 Sep;16(9):1184–1188. PMID: 8792773. — Abstract: In a population-based biethnic sample (Mexican Americans and non-Hispanic whites), LDL peak particle size varied significantly by APOE genotype, decreasing in the order ε2/3 > ε3/3 > ε3/4 > ε4/4. The ε4 allele was associated with both higher LDL cholesterol and smaller LDL size, so that ε2 carriers had the largest LDL particles and ε4 carriers the smallest — establishing APOE genotype as a determinant of LDL subclass distribution independent of ethnicity.↩

  9. Berneis KK, Krauss RM. Metabolic origins and clinical significance of LDL heterogeneity (doi:10.1194/jlr.r200004-jlr200). Journal of Lipid Research. 2002 Sep;43(9):1363–1379. PMID: 12235168. — Abstract: This review (from the group that defined the LDL subclass pattern A/B classification) synthesizes the metabolic and genetic origins of LDL particle heterogeneity. Small, dense LDL (pattern B) arises chiefly through triglyceride enrichment of LDL followed by hepatic-lipase remodeling, and clusters with elevated triglycerides and reduced HDL as part of the atherogenic lipoprotein phenotype; major gene effects on LDL diameter are described at the LDL-receptor, apoA-I/C-III/A-IV, CETP, and other loci.↩

  10. Mahley RW, Rall SC Jr. Apolipoprotein E: far more than a lipid transport protein (doi:10.1146/annurev.genom.1.1.507). Annual Review of Genomics and Human Genetics. 2000;1:507–537. PMID: 11701639. — The authoritative review Bennet et al. cite for the estimate that about 5% of ε2/ε2 homozygotes develop type III hyperlipoproteinemia (dysbetalipoproteinemia). The ε2 isoform binds LDL receptors poorly, impairing hepatic clearance of triglyceride-rich remnants; overt disease, however, requires a second precipitating factor (e.g. obesity, diabetes, hypothyroidism, or estrogen deficiency), so most ε2/ε2 homozygotes remain normolipidemic.↩

  11. Breslow JL, Zannis VI, SanGiacomo TR, Third JL, Tracy T, Glueck CJ. Studies of familial type III hyperlipoproteinemia using as a genetic marker the apoE phenotype E2/2 (PubMed). Journal of Lipid Research. 1982 Nov;23(8):1224–1235. — Abstract: Clinical presentations, lipoprotein characteristics, and apoE variants were examined in 17 individuals with type III hyperlipoproteinemia and their relatives. The apoE phenotype E2/2 appeared in 88% of the patients diagnosed with the disorder, with E4/2 in the rest. Among 69 relatives, those carrying E2/2 who had not themselves been diagnosed showed "a tendency to express type III HLP," but "genetic or environmental factors other than the apoE phenotype E2/2 are required" for full disease expression.↩

  12. Akanji AO, Suresh CG, Fatania HR, Al-Radwan R, Zubaid M. Associations of apolipoprotein E polymorphism with low-density lipoprotein size and subfraction profiles in Arab patients with coronary heart disease (doi:10.1016/j.metabol.2006.11.006). Metabolism. 2007 Apr;56(4):484–490. — Abstract: In Arab coronary heart disease patients, E2 carriers had smaller LDL particle size and a higher prevalence of LDL subclass pattern B than non-E2 patients — the reverse of the relationship seen in the study's non-CHD controls, where E2 was associated with lower pattern B. The authors attribute the inversion to the ε2-linked elevation in triglycerides, illustrating that the APOE–LDL-subfraction relationship is population- and triglyceride-dependent.↩

  13. Liu L, Bano F, Conca DV, et al. Recruitment of apolipoprotein E facilitates Herpes simplex virus 1 attachment and release (doi:10.1038/s44298-025-00099-9). npj Viruses. 2025;3:38. — A mechanistic study showing HSV-1 recruits host apoE to promote attachment, entry, and release, and that the isoforms differ: apoE4 binds the heparan- and dermatan-sulfate glycosaminoglycans used for viral attachment more strongly than apoE3 or apoE2 (rank order E4 > E3 > E2), giving a molecular basis for ε4's greater HSV susceptibility.↩

  14. Koelle DM, et al. APOE genotype is associated with oral herpetic lesions but not genital or oral herpes simplex virus shedding (doi:10.1136/sti.2009.039735). Sexually Transmitted Infections. 2010;86(3):202–206. PMID: 20410080. — In a cohort study, the APOE-ε4 allele was associated with a markedly higher rate of oral herpetic lesions (cold sores; relative risk ≈4.6), but APOE genotype was not associated with the frequency of oral or genital HSV reactivation or viral shedding — i.e. ε4 affects whether infection becomes symptomatic rather than how much virus is present.↩

  15. Kuhlmann I, Minihane AM, Huebbe P, Nebel A, Rimbach G. Apolipoprotein E genotype and hepatitis C, HIV and herpes simplex disease risk: a literature review (doi:10.1186/1476-511X-9-8). Lipids in Health and Disease. 2010;9:8. PMID: 20109174. — A review of isoform-specific APOE effects across three chronic viral infections. The ε4 allele tends to worsen susceptibility or outcome — e.g. apoE4 enhances HIV-1 cell entry and ε4 carriers show faster HIV progression — consistent with apoE4's stronger binding to the cell-surface heparan-sulfate proteoglycans several viruses exploit for entry. ε2 and ε3 sit at the lower-risk end, though the isoform data are sparse and sometimes inconsistent.↩

  16. Gerdes LU, Gerdes C, Hansen PS, Klausen IC, Færgeman O. Are men carrying the apolipoprotein ε4- or ε2 allele less fertile than ε3ε3 genotypes? (doi:10.1007/s004390050200) Human Genetics. 1996;98(2):239–242. PMID: 8698352. — The primary study behind the reproductive-advantage observation (Mahley & Rall's ref 30): among 40-year-old Danish men of known APOE genotype, ε3/ε3 men had fathered more children than carriers of the ε4 or ε2 allele, suggesting selection could act on ε3 through fertility even though APOE's disease effects appear only later in life.↩

  17. Kolbe D, da Silva NA, Dose J, Torres GG, Caliebe A, Krause-Kyora B, Nebel A. Current allele distribution of the human longevity gene APOE in Europe can mainly be explained by ancient admixture (PMC). Aging Cell. 2023 May;22(5):e13819. — Abstract: The authors investigated the evolutionary history of the three major APOE alleles in Europe using ancient DNA spanning 12,000 years. Selection produced large frequency differences between early European populations (hunter-gatherers versus early farmers), "possibly due to changes in diet/lifestyle," but allele distributions in populations from ~4000 BCE onward are "mainly [to] be explained by admixture" rather than ongoing selection.↩

  18. Egert S, Rimbach G, Huebbe P. ApoE genotype: from geographic distribution to function and responsiveness to dietary factors (Cambridge). Proceedings of the Nutrition Society. 2012 Aug;71(3):410–424. — Abstract: The three major APOE variants are distributed non-randomly across global populations: ε4 is enriched in Northern Europe, while ε3 is more prevalent in Mediterranean regions. ε4 is a major genetic risk factor for age-dependent chronic conditions including cardiovascular disease and Alzheimer's. The ε3 allele shows greater responsiveness to dietary flavonoids (quercetin) and marine n-3 fatty acids than ε4, while ε4 shows better vitamin D metabolism and dietary fat clearance — suggesting apoE genotype is a significant determinant of individual response to dietary interventions.↩