Direct evidence for involvement of the MAM in AD comes from studies demonstrating that cleaved, active forms of the PSs and γ-secretase activity are localized predominantly in the MAM, where PS1 and PS2 interact directly with IP3R, and mutated PS1 and PS2 open IP3R channel flooding intracellular Ca2+ and also stimulate Aβ production [35,36,37,38]. This evidence concerns the gene PSEN1 and Alzheimer disease.