APOE

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 in experimental models. 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. Compared with ε3/ε3, the odds of Alzheimer's disease are about 3× higher in ε3/ε4 heterozygotes and about 15× higher in ε4/ε4 homozygotes in people of European ancestry — and the age of onset shifts earlier. ε2/ε3 carriers have about 40% lower odds. 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 (~61% of Europeans). Reference risk.
• ε3/ε4 — ~24% of Europeans. ~3× the odds of Alzheimer's disease (OR 3.2), slightly higher LDL cholesterol.
• ε4/ε4 — ~2% of Europeans. ~15× the odds of Alzheimer's disease (OR 14.9), earlier onset.
• ε2/ε3 — ~10% of Europeans. ~40% lower odds of Alzheimer's disease (OR 0.6).
• ε2/ε4 — ~2% of Europeans. ~2.6× the odds of Alzheimer's disease (OR 2.6), between ε3/ε3 and ε3/ε4.
• ε2/ε2 — ~0.4% of Europeans. Alzheimer's odds estimate imprecise (OR 0.6, 95% CI 0.2–2.0); a minority develop type III hyperlipoproteinemia, usually with an additional metabolic factor.

The most important common risk allele in complex-disease genetics.

ClinVar lists rs429358 (the ε4-defining variant) as a risk factor for Alzheimer's disease, among conflicting submissions; its single-variant record for rs7412 (ε2-defining) is classified as drug response (atorvastatin efficacy), and the ε2 link to familial dysbetalipoproteinemia (type III hyperlipoproteinemia) comes from the lipid literature. 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 are indicated at the mild cognitive impairment or mild dementia stage of Alzheimer's disease and are not preventive drugs. Their FDA labels carry a boxed warning that ε4 homozygotes have a higher incidence of ARIA (amyloid-related imaging abnormalities), and state that ApoE ε4 testing should be performed before treatment.
• 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 and employment but not life, disability or long-term-care insurance).
• ε2/ε2 carriers: only a minority develop type III hyperlipoproteinemia, typically when an additional metabolic factor (obesity, hypothyroidism, diabetes) is present.

Primary sources: ClinVar — APOE entries; OMIM 107741 — APOE; Farrer et al., JAMA 1997 (APOE genotype and Alzheimer's disease odds ratios, meta-analysis); Corder et al., Science 1993 (ε4 gene dose, risk and earlier onset); Genin et al., Mol Psychiatry 2011 (lifetime risk estimates by genotype); Fortea et al., Nat Med 2024 (APOE4 homozygosity as a distinct genetic form of Alzheimer's); Castellano et al., Sci Transl Med 2011 (apoE isoforms and amyloid-β clearance in mouse models); Bennet et al., JAMA 2007 (APOE genotypes, LDL cholesterol and coronary risk); Khovidhunkit, Endotext 2025 (dysbetalipoproteinemia); FDA labels for LEQEMBI and KISUNLA (boxed warning on ARIA); allele frequencies from 1000 Genomes phase 3 via Ensembl.

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 → most often ε2/ε4, but without phasing two positions cannot tell it from ε1/ε3; a validated test is needed

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.