There is no unifying hypothesis to account for the anatomical distribution of neuropathology, the involvement of beta-amyloid precursor protein (beta APP) and the role of increasing age in triggering the Alzheimer disease process. We report here that layer II pre-alpha neurones in transentorhinal and entorhinal cortex contain more beta APP immunoreactivity than other cortical neurones in normal individuals. This immunoreactivity increased in the early stages of Alzheimer's disease and was lost as the disease progressed. These neurones are known to undergo genetically programmed re-sprouting and synaptogenesis during the fifth and sixth decades of life. We hypothesize that these phenomena are related and that the Alzheimer's disease process originates in entorhinal cortex neurones due to the enhancement of their normally high content of beta APP during age-related resprouting.