Familial Alzheimer’s disease (FAD) is caused by mutations in amyloid precursor protein or presenilins (PS1 and PS2). Many FAD-linked PS mutations affect intracellular calcium (Ca²⁺) homeostasis by mechanisms proximal to and independent of amyloid production, although the molecular details are controversial. We found that several FAD-causing PS mutants enhance gating of the inositol trisphosphate receptor (IP₃R) Ca²⁺ release channel by a gain-of-function effect that mirrored the genetics of FAD and was independent of secretase activity. In contrast, wild-type PS or PS mutants that cause frontotemporal dementia had no such effect. FAD-causing PS mutants altered the modes in which the IP₃R channel gated. Recordings of endogenous IP₃R in lymphoblasts derived from individuals with FAD or cortical neurons of asymptomatic PS1-AD mice revealed that they were more likely than IP₃R in cells with wild-type PS to dwell in a high open-probability burst mode, resulting in enhanced Ca²⁺ signaling. These results indicate that exaggerated Ca²⁺ signaling through IP₃R-PS interaction is a disease-specific and robust proximal mechanism in FAD.