The apolipoprotein Eepsilon4 allele (ApoEepsilon4) is associated with a selective increase in deposition of the 40-amino acid form of the beta-amyloid peptide (Abeta40) in endstage Alzheimer's disease. To determine how apoE genotype affects the early events in beta-amyloid pathogenesis, we analyzed the medial temporal lobes of 244 elderly persons who were not clinically demented using antibodies selective for the C termini of Abeta40 and Abeta42. We found that: (1) the number of both Abeta42- and Abeta40-positive senile plaques increase with age; (2) Abeta42 appears at younger ages, and in more amyloid deposits, than does Abeta40 in all ApoE groups; (3) when compared at similar ages, older persons with ApoEepsilon4 are more likely to have Abeta42- and Abeta40-immunoreactive deposits than are persons without ApoEepsilon4; (4) Abeta40-containing plaques arise at least a decade later than do Abeta42 plaques, and are seldom found in the medial temporal lobe of older persons lacking ApoEepsilon4; and (5) in the absence of overt Alzheimer's disease, cerebral amyloid angiopathy is rare in the elderly, but in our sample was significantly augmented in ApoEepsilon4 homozygotes. We conclude that ApoEepsilon4 hastens the onset of Abeta42 deposition in the senescent brain, which in turn fosters the earlier evolution of fibrillar, Abeta40-positive plaques, thereby increasing the risk of Alzheimer's disease.