Large numbers of neurofibrillary tangles (NFTs) and amyloid plaques are diagnostic markers for Alzheimer disease (AD), but lesser numbers of these lesions are also seen in nondemented elderly individuals. Much of the existing literature suggests that the NFTs of AD have a closer correlation with cognitive function than do amyloid plaques. Whether a similar relationship exists in normal aging and mild cognitive impairment (MCI), a condition that frequently reflects a preclinical stage of AD, remains unknown. To determine the distribution patterns of beta-amyloid plaques and NFTs and the association of these lesions with memory performance in nondemented individuals. We investigated regional distributions and neuropsychological correlates of NFTs and amyloid plaques in cognitively normal elderly persons and subjects with MCI who received neuropsychological testing before death. Subjects Eight nondemented subjects who volunteered to receive annual neuropsychological testing and agreed to brain donation were studied. Five subjects showed no cognitive impairment, and 3 were diagnosed with MCI. Distribution of NFTs followed a rigorous and hierarchical pattern, but distribution of amyloid plaques varied among individuals. Subjects with MCI displayed higher NFT densities than did nonimpaired subjects. In addition, NFT density in the temporal lobe correlated with memory scores, whereas density of amyloid plaques did not. Neurofibrillary tangles are more numerous in medial temporal lobe regions associated with memory function and show a relationship to performance on memory tests in nondemented individuals. These results suggest that NFTs may constitute a pathological substrate for memory loss not only in AD but also in normal aging and MCI.