Apolipoproein E (APO‐E) binds to the β‐amyloid peptide and is present in senile neuritic plaques in Alzheimer's disease (AD). The ε4 isoform of APO‐E has been associated with both sporadic and familial late‐onset AD, implying a causal role. Among patients and control subjects similar in age, gender, and ethnic group from the New York City community of Washington Heights‐Inwood, we found that the odds ratio (OR) for AD associated with homozygosity for APO‐ε4 was 17.9 (95% confidence interval [CI], 4.6–69.8) and that associated with heterozygosity for APO‐ε4 was 4.2 (95% CI, 1.8–9.5), compared with persons with other APO‐E genotypes. The association was stronger among patients with sporadic disease (OR = 10.3; 95% CI, 3.4–31.1) than among those with a family history of dementia in a first‐degree relative (OR = 0.9; 95% CI, 0.1–13.5). The association between APO‐ε4 and AD did not differ according to age at onset (<65 vs ≥65), but appeared to vary across the 3 ethnic groups investigated (black, Hispanic, and white). Our data confirm the association between AD and APO‐ε4 and support the hypothesis that the APO‐ε4 allele either confers genetic susceptibility to AD or may be in linkage disequilibrium with another susceptibility locus. Ethnic variability in the allelic frequency of APO‐ε4 in the elderly warrants further investigation.