Apolipoprotein E (ApoE) epsilon4 allele, a risk factor for the development of Alzheimer's disease (AD), is associated with increased amyloid deposition. We examined cerebral cortex in 68 AD cases using antibodies to beta-amyloid (Abeta) peptides of different length (Abeta1-40 and Abeta1-42) and found that the increased plaque frequency observed with epsilon4 genotypes may be largely attributed to an increase in Abeta1-40-positive plaques. Indeed, both the number of Abeta1-40-positive plaques, as well as the ratio of Abeta1-40/Abeta1-42-positive plaques, increased with epsilon4 dosage. In contrast, the frequency of Abeta1-42-immunoreactive plaques was similar for epsilon3/epsilon3, epsilon3/epsilon4, and epsilon4/epsilon4 genotypes. ApoE may influence Abeta1 length by facilitating Abeta1-40 deposition onto Abeta1-42-seeded plaques or by modulating the activity of a putative carboxypeptidase that forms Abeta1-40 from Abeta1-42 in situ.