The perforant pathway is a large neuronal projection that arises from layers II and III of the entorhinal cortex of the parahippocampal gyrus. It is the principal source of cortical input to the hippocampal formation. In 11 cases of Alzheimer's disease, we have found that neurofibrillary tangles develop in the cells of origin of the perforant pathway. In addition, the termination zone of the perforant pathway, in the outer two thirds of the molecular layer of the dentate gyrus, contains a distinct layer of neuritic plaques. None of the 8 control subjects had such changes. These profound alterations effectively disconnect the hippocampal formation from the association and limbic cortices. Because of the central role of the hippocampus and parahippocampal gyrus in learning, it is likely that pathological changes in the perforant pathway, by precluding normal hippocampal operation, account for some aspects of the memory impairment in Alzheimer's disease.