APOE
APOE is the strongest common genetic risk factor for late-onset Alzheimer's disease and a major modulator of cardiovascular disease. The three classical alleles — ε2, ε3, ε4 — are defined by combinations of just two missense SNPs (rs429358 and rs7412). APOE is the rare consumer-genomics result that genuinely changes lifetime risk estimates, which is exactly why it is also the rare result that should not be received casually.
Lipid transport in plasma and the brain.
Apolipoprotein E (ApoE) is a 299-amino-acid protein that binds lipids to form lipoprotein particles. In plasma, it is a major component of VLDL, IDL, and a subset of HDL; it is the ligand recognized by the LDL receptor and the LDL receptor-related protein, and it drives clearance of triglyceride-rich lipoproteins from the bloodstream. In the brain — where ApoE is produced primarily by astrocytes — it shuttles cholesterol and phospholipids between cells and contributes to clearance of amyloid-β peptide from the interstitium.
The three classical alleles differ at two positions: residue 112 (rs429358) and residue 158 (rs7412). The ε3 allele (the ancestral combination Cys112/Arg158) is the most common worldwide. The ε4 allele (Arg112/Arg158) binds preferred lipid substrates differently and is less efficient at promoting amyloid-β clearance. The ε2 allele (Cys112/Cys158) binds the LDL receptor poorly, which can cause type III hyperlipoproteinemia in homozygotes — but it is also associated with a lower lifetime risk of Alzheimer's disease.
Effect direction and magnitude are not subtle. Lifetime risk of Alzheimer's disease is roughly 3× higher in ε3/ε4 heterozygotes and 8–12× higher in ε4/ε4 homozygotes compared with ε3/ε3 — and the age of onset shifts earlier. ε2 carriers have roughly half the ε3/ε3 risk. These are some of the largest common-variant effect sizes in complex-disease genetics.
Two SNPs, three alleles, six genotypes.
The classical APOE allele system is built from two SNPs that segregate together as a haplotype:
The two SNPs combine to produce three alleles and six diploid genotypes:
- ε3/ε3 — the most common genotype (~60% of Europeans). Reference risk.
- ε3/ε4 — ~21% of Europeans. ~3× increased Alzheimer's risk, modestly elevated cardiovascular risk.
- ε4/ε4 — ~2% of Europeans. ~8–12× increased Alzheimer's risk, earlier onset.
- ε2/ε3 — ~12% of Europeans. Roughly half the reference Alzheimer's risk.
- ε2/ε4 — ~2% of Europeans. Effects of ε2 and ε4 partially cancel; net Alzheimer's risk close to baseline.
- ε2/ε2 — ~0.5% of Europeans. Lowest Alzheimer's risk, but small risk of type III hyperlipoproteinemia (often requires a second hit).
The most important common risk allele in complex-disease genetics.
ClinVar lists rs429358 and rs7412 as risk factors for Alzheimer's disease and as variants associated with familial dysbetalipoproteinemia (type III hyperlipoproteinemia). APOE is one of the few common variants where the effect on lifetime risk is large enough to be clinically meaningful in isolation.
However, several caveats matter as much as the genotype itself:
- ε4 is a risk factor, not a verdict. Many ε4/ε4 homozygotes never develop dementia. Many non-ε4 carriers do. Modifiable factors — hypertension control, sleep, exercise, hearing protection, education, vascular risk management — substantially alter the absolute risk.
- There is currently no proven preventive treatment specific to APOE ε4 carriers. Lecanemab and donanemab show modest disease-modifying effects in symptomatic patients but are not preventive drugs, and they carry an ε4-dose-dependent risk of ARIA (amyloid-related imaging abnormalities).
- Pre-test counselling is recommended. Learning you carry ε4/ε4 cannot be unlearned and may affect insurance access in some jurisdictions (in the EU, GDPR plus national rules apply; in the US, GINA covers health insurance but not life or long-term-care).
- ε2/ε2 carriers have a ~5% lifetime risk of type III hyperlipoproteinemia, typically requiring a second metabolic insult (obesity, hypothyroidism, diabetes) to manifest.
"APOE is the variant where 'know thyself' meets 'be careful what you ask for.' If you would not change anything based on the answer, consider whether you want the answer."
Primary sources: ClinVar — APOE entries; OMIM 107741 — APOE; Corder et al., Science 1993 (original ε4 / Alzheimer's association); Genin et al., Mol Psychiatry 2011 (lifetime risk estimates by genotype); Fortea et al., Nat Med 2024 (ε4/ε4 as a near-deterministic form of Alzheimer's).
How to read your APOE genotype — carefully.
Both rs429358 and rs7412 are usually present on consumer SNP arrays. 23andMe historically gated APOE behind an explicit opt-in precisely because of the weight of the result. If you choose to look it up in raw data, find both:
- rs429358: T = ancestral, C = ε4-defining.
- rs7412: C = ancestral, T = ε2-defining.
Translate the two SNPs into haplotypes:
- rs429358 = T/T and rs7412 = C/C → ε3/ε3
- rs429358 = T/C and rs7412 = C/C → ε3/ε4
- rs429358 = C/C and rs7412 = C/C → ε4/ε4
- rs429358 = T/T and rs7412 = C/T → ε2/ε3
- rs429358 = T/T and rs7412 = T/T → ε2/ε2
- rs429358 = T/C and rs7412 = C/T → ε2/ε4 (phase ambiguous but conventionally assigned)
Before you look: consider whether you want this result, who else in your family it implicates (it is heritable), and whether you have access to genetic counselling. If you have a family history of early-onset dementia, a clinical geneticist — not a consumer report — is the right starting point.