While the epsilon 4 allele of apolipoprotein E (ApoE) has been identified as a risk factor in Alzheimer's disease (AD), the mechanism by which this risk is conveyed is not understood. Immunohistochemical studies demonstrating ApoE-A beta colocalization in senile plaques, neurofibrillary tangles, and blood vessels and in vitro studies of ApoE-A beta interactions suggest that ApoE plays a role in amyloid processing and/or fibrillogenesis. We examined the ApoE-A beta association in diffuse and neuritic plaques in the neocortex, striatum, and cerebellum, and determined the ApoE genotype in 100 brains derived from dementia patients with neuropathologically confirmed AD. As expected, the epsilon 4 allele was overrepresented in AD patients compared with patients without neurological disease (p < 0.001). ApoE-positive plaque counts in neocortex were higher in epsilon 4/4 individuals than in individuals with other genotypes (p < 0.0005). Overall, in the 100 cases, ApoE-positive plaques were less frequent than A beta-positive plaques in contiguous sections (p < 0.0001). In all cases, A beta-positive diffuse plaques in the striatum failed to label with ApoE antibody, whereas the majority of cerebellar diffuse plaques showed A beta-ApoE colocalization. Possible explanations for these discrepancies include regional variation in amyloid processing and fibrillogenesis, varying stages of plaque evolution, and technical considerations.