APOE Genotype

What it is

APOE encodes apolipoprotein E, a lipoprotein component involved in cholesterol transport (peripherally and in the brain). Three common variants — ε2, ε3, ε4 — differ at two amino acid positions and substantially affect lifetime risk of cardiovascular and Alzheimer’s disease.

Genotype frequencies and effects

• ε3/ε3 (~60%) — reference risk.
• ε4 carriers: one copy ~25%, two copies ~2–5%. Each copy of ε4 raises Alzheimer’s risk ~3× (one copy) or ~10–15× (two copies) and shifts age at onset earlier.
• ε2 carriers (~10–15%) — protective against Alzheimer’s but associated with increased risk of type III hyperlipoproteinaemia.
• Over-represented in centenarian cohorts: ε2 enriched, ε4 depleted (because ε4 carriers die earlier).

What to do with knowledge

• Testing: widely available (23andMe, Galleri, etc.); some carriers prefer not to know.
• ε4 carriers appear to benefit more from lifestyle interventions for dementia prevention (FINGER subgroup analyses, observational data) — possibly the most actionable group for early cardiovascular risk-factor control, hearing-loss correction, sleep optimisation, and dietary changes.
• Anti-amyloid antibodies (lecanemab, donanemab) carry higher ARIA risk in ε4 carriers; treatment decisions should incorporate genotype.
• Avoid traumatic brain injury (heading in soccer, contact sports) given the interaction with ε4.

Caveats

Many ε4 carriers never develop Alzheimer’s; many non-carriers do. APOE is the largest single common risk factor but not deterministic.

Related entries

Alzheimer's disease, Cognitive decline, FINGER trial.