The presence of senile plaques in the neocortex of apparently nondemented elderly persons often is accepted as part of "normal" aging. Alternatively, because cerebral deposition of beta-amyloid may be a key mechanism in the development of Alzheimer's disease (AD), the presence of beta-amyloid-containing plaques may represent very early AD. To examine the relationships of cognitively normal aging, very mild dementia of the Alzheimer type, and the presence of neocortical senile plaques, we performed clinicopathologic correlation in 21 longitudinally studied healthy elderly subjects (84.5 +/- 6.6 years old at death). Nine subjects had strikingly high plaque densities in the neocortex; two of these subjects died of head injury before which there was no evidence of cognitive impairment. The other seven subjects with high plaque densities had clinical evidence for very mild cognitive impairment (Clinical Dementia Rating score of 0.5) at some time during their course and mildly impaired psychometric performance at last assessment before death. The remaining 12 subjects had no clinical or psychometric impairment and had few or no neocortical AD lesions. These results suggest that senile plaques may not be part of normal aging but instead represent presymptomatic or unrecognized early symptomatic AD. The high density of senile plaques (predominately of the diffuse subtype) in the cortex of subjects just at the threshold of detectable dementia is consistent with the hypothesis that beta-amyloid deposition is an initial pathogenetic event in the development of AD.