The effect of the apolipoprotein E (apoE) genotype on the age at onset of Alzheimer's disease (AD) and the relative risk conferred by the apoE epsilon 4 allele were studied in 91 patients and 69 healthy age-matched controls. According to the age of presentation, which varied from 44 to 95 years, subjects were divided into four groups. The inheritance of at least one epsilon 4 allele was associated with a significant reduction of the age at onset by 7.7 years among patients who were 83 years or older when examined. A weaker inverse relationship between the epsilon 4 allele and the age at onset was also observed among patients who were aged 44-63 years at presentation. The effect of the epsilon 4 allele was minimal or absent in the two intermediate age categories. The relative risk of AD conferred by the inheritance of at least one epsilon 4 allele showed no consistent age-related pattern. The overall risk expressed as an odds ratio was 5.0 (95% CI 2.4-10.5). With respect to the limitations of the study, we tentatively conclude (1) that the effect of the apoE epsilon 4 allele on the age at onset is not restricted to AD patients of a particular age, in accordance with current hypotheses on the role of apoE gene products in the biology of AD; (2) that the relative risk of AD associated with the epsilon 4 allele is not significantly modulated by age. Although the apoE epsilon 4 allele is an important susceptibility factor for AD occurring in middle age as well as in later life, it is of limited value in routine clinical diagnosis and should not be used for predictive testing in asymptomatic individuals.