Mutations in presenilins (PS) are the major cause of familial Alzheimer's disease (FAD) and have been associated with calcium (Ca²⁺) signaling abnormalities. Here, we demonstrate that FAD mutant PS1 (M146L) and PS2 (N141I) interact with the inositol 1,4,5-trisphosphate receptor (InsP₃R) Ca²⁺ release channel and exert profound stimulatory effects on its gating activity in response to saturating and suboptimal levels of InsP₃. These interactions result in exaggerated cellular Ca²⁺ signaling in response to agonist stimulation as well as enhanced low-level Ca²⁺ signaling in unstimulated cells. Parallel studies in InsP₃R-expressing and -deficient cells revealed that enhanced Ca²⁺ release from the endoplasmic reticulum as a result of the specific interaction of PS1-M146L with the InsP₃R stimulates amyloid beta processing, an important feature of AD pathology. These observations provide molecular insights into the "Ca²⁺ dysregulation" hypothesis of AD pathogenesis and suggest novel targets for therapeutic intervention.