Overexpression of the familial Alzheimer’s disease gene Presenilin 2 (PS2) in nerve growth factor-differentiated PC12 cells increased apoptosis induced by trophic factor withdrawal or beta-amyloid. Transfection of antisense PS2 conferred protection against apoptosis induced by trophic withdrawal in nerve growth factor-differentiated or amyloid precursor protein-expressing PC12 cells, The apoptotic cell death induced by PS2 protein was sensitive to pertussis toxin, suggesting that heterotrimeric GTP-binding proteins are involved, A PS2 mutation associated with familial Alzheimer’s disease was found to generate a molecule with enhanced basal apoptotic activity, This gain of function might accelerate the process of neurodegeneration that occurs in Alzheimer’s disease, leading to the earlier age of onset characteristic a familial Alzheimer’s disease.