Abstract : Alzheimer's disease is characterized by amyloid β‐peptide deposition, synapse loss, and neuronal death, which are correlated with cognitive impairments. Mutations in the presenilin‐1 gene on chromosome 14 are causally linked to many cases of early‐onset inherited Alzheimer's disease. We report that synaptosomes prepared from transgenic mice harboring presenilin‐1 mutations exhibit enhanced elevations of cytoplasmic calcium levels following exposure to depolarizing agents, amyloid β‐peptide, and a mitochondrial toxin compared with synaptosomes from nontransgenic mice and mice overexpressing wild‐type presenilin‐1. Mitochondrial dysfunction and caspase activation following exposures to amyloid β‐peptide and metabolic insults were exacerbated in synaptosomes from presenilin‐1 mutant mice. Agents that buffer cytoplasmic calcium or that prevent calcium release from the endoplasmic reticulum protected synaptosomes against the adverse effect of presenilin‐1 mutations on mitochondrial function. Abnormal synaptic calcium homeostasis and mitochondrial dysfunction may contribute to the pathogenic mechanism of presenilin‐1 mutations.