Risk and protective effects of the APOE gene towards Alzheimer's disease in the Kungsholmen project:: variation by age and sex

Background: The risk effect of APOE epsilon4 allele for Alzheimer's disease is acknowledged, whereas the putative protective effect of epsilon2 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 greater than or equal to75 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 epsilon3/epsilon3 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 epsilon4 allele and 3.1 (95% CI, 1.6 to 5.9) for homozygous epsilon4 allele. The association between epsilon4 allele and Alzheimer's disease risk was stronger in men than in women (RR related to the interaction term epsilon4 allele by sex, 0.4; 95% CI, 0.2 to 0.9). The epsilon4 allele accounted for one third of Alzheimer's disease cases among men, but only one tenth among women. The e2 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 epsilon2 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 e4 allele has a stronger risk effect in men, and the epsilon2 allele confers a protective effect only in younger-old people.