The calcium ion (Ca²⁺) plays fundamental roles in orchestrating dynamic changes in the function and structure of nerve cell circuits in the brain. The endoplasmic reticulum (ER), an organelle that actively removes Ca²⁺ from the cytoplasm, can release stored Ca²⁺ through ER membrane receptor channels responsive either to the lipid messenger inositol trisphosphate(IP₃) or to cytosolic Ca²⁺. Emerging findings suggest that perturbed ER Ca²⁺ homeostasis contributes to the dysfunction and degeneration of neurons that occurs in Alzheimer’s disease (AD). Presenilin-1 (PS1) is an integral membrane protein in the ER; mutations in PS1 that cause early-onset inherited AD increase the pool of ER Ca²⁺ available for release and also enhance Ca²⁺ release through ER IP₃- and ryanodine-sensitive channels. By enhancing Ca²⁺ flux across the ER membrane, PS1 mutations may exaggerate Ca²⁺ signaling in synaptic terminals and thereby render them vulnerable to dysfunction and degeneration in the settings of aging and amyloid accumulation in AD.