MAPT and Alzheimer disease: According to the modified Ca2+ hypothesis of AD and recent evidence from our group and others that NMDAR overactivation and chronic Ca2+ dyshomeostasis are upstream events of AD pathology, including Aβ/tau alterations [127], it can be reasonably assumed that the marginal results of current MEM treatment in advanced AD patients are largely due to improper timing of the delayed treatment, which misses the pathogenic phase of neuronal hyperactivity ongoing for years during the prodromal/preclinical period of disease progression.