Background: The risk effect of APOE ε4 allele for Alzheimer’s disease is acknowledged, whereas the putative protective effect of ε2 allele remains in debate.

Objectives: To investigate whether those inconsistent findings may be attributable to differences in age and sex composition of the study populations.

Methods: A community dementia free cohort (n = 985) aged ⩾75 years was followed up to detect Alzheimer’s disease cases (DSM-III-R criteria). Data were analysed using Cox models with adjustment for major potential confounders.

Results: Over a median 5.6 year follow up, Alzheimer’s disease was diagnosed in 206 subjects. Compared with APOE ε3/ε3 genotype, the relative risk (RR) of Alzheimer’s disease was 1.4 (95% confidence interval (CI), 1.0 to 2.0; p = 0.03) for heterozygous ε4 allele and 3.1 (95% CI, 1.6 to 5.9) for homozygous ε4 allele. The association between ε4 allele and Alzheimer’s disease risk was stronger in men than in women (RR related to the interaction term ε4 allele by sex, 0.4; 95% CI, 0.2 to 0.9). The ε4 allele accounted for one third of Alzheimer’s disease cases among men, but only one tenth among women. The ε2 allele was related to a reduced Alzheimer’s disease risk mainly in people aged <85 years (RR, 0.4; 95% CI, 0.2 to 0.8). The RR of Alzheimer’s disease related to the interaction term of ε2 allele by age was 2.4 (95% CI, 1.0 to 6.0; p = 0.06).

Conclusions: The APOE genotype specific effects on Alzheimer’s disease vary by age and sex, in which the ε4 allele has a stronger risk effect in men, and the ε2 allele confers a protective effect only in younger-old people.