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Background The primary effect of the apolipoprotein E e4 ( APOE e4 ) allele is on the age at onset of Alzheimer disease (AD). Objective To investigate whether the presence of the APOE e4 allele can account for the earlier age at onset of familial AD (FAD) compared with sporadic AD (SAD). Design Population-based, case series ascertained in a prospective study of aging and dementia in Medicare recipients aged 65 years or older. Setting Clinics in northern Manhattan and in the Dominican Republic and Puerto Rico. Participants There were 680 Caribbean Hispanic subjects: 111 patients with FAD, with at least 1 family member with dementia; 163 patients with SAD; and 406 elderly persons without dementia or other illnesses. Main Outcome Measure Age at onset of dementia was examined in relation to frequency of APOE e4 . Sex, education, and medical risk factors for stroke, hypertension, diabetes, and heart disease were examined as effect modifiers. Results The mean age at onset of AD was significantly lower in FAD than in SAD, and a statistically significant dose effect of the APOE e4 allele was present for age at onset in FAD ( P = .001) but not in SAD. The age at onset in patients homozygous for the APOE e4 allele with FAD and SAD was similar. Compared with SAD, the major difference was younger age at onset in patients with FAD who were heterozygous for the APOE e4 allele and those without an APOE e4 allele. Conclusions Apolipoprotein E e4 had a consistent lowering effect on age at onset of FAD, but this was attenuated in SAD. This suggests that among individuals with a family history of AD and the APOE e4 allele, additional genetic or environmental factors may accelerate the onset of dementia.