Three core criteria support the calcium hypothesis: (1) calcium imbalance occurs prior to AD neuropathology and clinical symptoms; (2) disrupted calcium signaling acts as a convergent pathway for diverse AD risk factors, and (3) bidirectional interactions between calcium dysregulation and Aβ and tau pathology create a self-perpetuating cycle of injury and degeneration [59,60]. This evidence concerns the gene MAPT and Alzheimer disease.