AbstractAn increased frequency of the apolipoprotein E type 4 allele (APOE‐4) has previously been associated with both late‐onset sporadic and late‐onset familial Alzheimer disease (AD) [Strittmatter et al. (1993)Proc Natl Acad Sci USA90:1977–1981; Saunders et al. (1993a)Neurology43:1467–1472]. To further investigate this association we genotyped affected individuals from 92 separate AD pedigrees including both early‐ and late‐onset cases. An increased frequency of the APOE‐4 allele was found only among the late‐onset cases, both familial and sporadic, confirming the earlier reports. In addition, age at onset was significantly decreased in the APOE‐4 homozygotes (in late onset families) compared to either APOE‐4 heterozygotes or individuals not carrying an APOE‐4 allele. We also observed a significantly decreased frequency of the APOE‐2 allele in both the early‐and late‐onset familial cases. These results strengthen the argument for a direct role of APOE in susceptibi