Alzheimer disease (AD) is a neurodegenerative disorder characterized by a progressive cognitive decline that typically affects first memory and later executive functions, language, and visuospatial skills. This sequence of cognitive deterioration is thought to reflect the progressive invasion of the cerebral cortex by the two major pathological hallmarks of AD, neurofibrillary tangles (NFT) and senile plaques (SP) as well as degree of neuronal and synaptic loss. In order to explore the relationships between the involvement of specific neuronal populations and cognitive deterioration, and to compare the hierarchical patterns of cortical involvement in normal brain aging and Alzheimer disease, over 1200 brains from elderly subjects without cognitive deficits, as well as from patients with age-associated memory impairment and Alzheimer disease were examined. Our results suggest that the neuropathological changes associated with normal brain aging and Alzheimer disease affect select cortical circuits at different points in time. Extensive hippocampal alterations are correlated with age-associated memory impairment, whereas substantial neurofibrillary tangle formation in neocortical association areas of the temporal lobe is a prerequisite for the development of Alzheimer disease. In atypical AD, prominent and early deficits are found in language, musical skills and prosody, motor abilities, frontal and executive capacities, or visuospatial skills. These atypical clinical features are associated with an unusual pattern of NFT or SP formation that predominantly involves cortical areas usually spared in the course of the degenerative process. In an attempt to classify this highly heterogeneous subgroup, we will summarize clinicopathological analyses in patients with atypical progression of AD symptomatology with special reference to the relationship between specific cognitive and behavioral deficits and hierarchical patterns of AD lesion distribution within the cerebral cortex.