~65
Typical age at symptom onset in ε4/ε4 carriers, with a narrower range than in ε3/ε3. Almost all show Alzheimer’s pathology at autopsy.
Fortea et al., Nature Medicine 2024 (NACC brain donors and five biomarker cohorts)
The gene
One letter apart
Apolipoprotein E carries cholesterol and other lipids in the brain and blood. Everyone inherits two copies, one from each parent.
| Allele | Residue 112 | Residue 158 | Alzheimer’s risk |
|---|---|---|---|
| ε2 | CCys | CCys | Lower than ε3 |
| ε3 | CCys | RArg | Reference (most common) |
| ε4 | RArg | RArg | Highest; strongest with two copies |
A single amino-acid change at residue 112 separates ε4 from ε3. Carrying one ε4 copy raises risk; carrying two (ε4/ε4, homozygous) raises it much further and shifts symptoms to an earlier, more predictable age. Risk by genotype also differs by age, sex and ancestry.
What we know
Evidence so far
55
Age from which Alzheimer’s biomarkers are already higher than in ε3/ε3. By 65, nearly all have abnormal spinal-fluid amyloid and about 75% have a positive amyloid scan.
Fortea et al., Nature Medicine 2024
~13×
Higher odds of moderate to severe amyloid in brain blood vessel walls (cerebral amyloid angiopathy) at autopsy with two ε4 copies.
Greenberg et al., Annals of Neurology 1995
4.8×
Higher odds of accumulating two or more small brain bleeds over follow-up in ε4/ε4 adults without symptoms. This matters for the safety of anti-amyloid drugs.
A4 Study, Alzheimer’s & Dementia 2025
84 → 68
Mean age at onset fell from 84 to 68 as the number of ε4 copies rose, in 42 families with late-onset Alzheimer’s. Two copies were nearly sufficient to cause disease by age 80 in these families.
Corder et al., Science 1993
51–60%
Estimated lifetime risk of Alzheimer’s by age 85 for ε4/ε4 (about 51% in men and 60% in women), versus about 11–14% for the general population. Family studies give higher estimates.
Genin et al., Molecular Psychiatry 2011
Full references are on the Papers page.