Neurofibrillary tangles and senile plaques are common neuropathological features in both normal brain aging and Alzheimer's disease. In order to examine the patterns of lesion distribution in cerebral aging, we review the clinicopathological analysis of 1144 nondemented cases comparing their neuropathologic features to that reported in cases with mild cognitive impairment and cases with Alzheimer's disease. Regardless of cognitive status, layer II of the entorhinal cortex is involved with neurofibrillary tangle formation in all of the cases, while the CA1 field of the hippocampus and the subiculum are less consistently affected. Neocortical area 20 is particularly prone to develop neurofibrillary tangles in intellectually preserved elders, whereas other neocortical areas are relatively spared. Substantial senile plaque formation is seen in the neocortex of non-demented cases. Quantitatively, mild cognitive impairment is correlated with neurofibrillary tangle densities in layer II of the entorhinal cortex, and clinically overt Alzheimer's disease with neurofibrillary tangle densities in area 20. In non-demented centenarians, there is an early development of neurofibrillary tangles in areas usually spared in the course of the degenerative process in younger individuals. These observations demonstrate that mesial and inferior temporal lobe structures are affected more frequently than originally thought in normal brain aging. In this respect, neurofibrillary tangle formation in area 20 may represent a crucial step of the degenerative process, because it may precede the emergence of the neuropsychological deficits characteristic of Alzheimer's disease. In addition, this study reveals age-related heterogeneity in the regional vulnerability of the cerebral cortex during normal brain aging.