To test whether the hypothesis that the Alzheimer's Aβ peptide is neurotoxic, we introduced a transgene into mice to direct expression of this peptide to neurons. We show that the transgene is expressed in brain regions which are severely affected in Alzheimer's disease resulting in extensive neuronal degeneration. Morphological and biochemical evidence indicates that the eventual death of these cells occurs by apoptosis. Coincident with the cell degeneration and cell death is the presence of a striking reactive gliosis. Over 50% of the transgenic mice die by 12 months of age, half the normal life span of control mice. These data show that Aβ is neurotoxic in vivo and suggest that apoptosis may be responsible for the accompanying neuronal loss, the principal underlying cellular feature of Alzheimer's disease.