We sought to determine the pattern of ApoE immunoreactivity in mesial temporal lobe tissue from 12 Alzheimer patients, age 66-88, and to determine the distribution of this immunoreactivity among different plaque types representing hypothesized stages of plaque evolution. In these patients, the cortical area of ApoE immunoreactivity was 30% that of beta-amyloid. Only 6% of diffuse non-neuritic amyloid deposits were even weakly ApoE immunoreactive (ApoE+). This is in contrast to our previous demonstration that microglia overexpressing interleukin-1 (IL-1) are present in most diffuse non-neuritic deposits. Eighty-three per cent of diffuse neuritic plaques and 86% of dense-core neuritic plaques were highly ApoE+, consistent with IL-1-induced astrocyte activation and synthesis of ApoE resulting in the appearance of ApoE immunoreactivity in neuritic plaques. Dense-core non-neuritic ('burned out') plaques were only rarely (6%) ApoE+. These results, together with the known trophic and toxic effects of ApoE on neurites, suggest that plaque-associated ApoE contributes to the formation of overgrown degenerating (dystrophic) neurites in plaques. However, the fact that some neuritic plaques are not ApoE+ suggests contributions by additional trophic and toxic factors. Our results are also consistent with a role for ApoE in the condensation of diffuse amyloid deposits into a beta-pleated-sheet form that occurs concomitant with dystrophic neurite formation in the neuritic beta-amyloid plaques of Alzheimer's disease.