The hypothalamus was examined in 3 cases of Alzheimer's disease and 3 control brains, using combined acetylcholinesterase (AChE) and thioflavin-S staining. Neurons undergoing neurofibrillary degeneration were restricted to 3 AChE-positive cell populations (lateral tuberal, lateral posterior and tuberomammillary) that have been found in the rat and monkey to project to the cerebral cortex. Our results suggest that the neurofibrillary degeneration in the hypothalamus involves primarily neurons that innervate cortical areas involved by Alzheimer's disease. This finding is consistent with the hypothesis that Alzheimer's disease is transmitted from neuron to neuron via normal neuronal connections.