MAPT and Alzheimer disease: In the last 25 years, translational studies—including experimental animal and human neuropathological, genetic, and in vivo biomarker-based evidence—support a descriptive hypothetical model of AD pathophysiology characterized by the upstream brain accumulation of Aβ species and plaques, which precedes spreading of tau, neuronal loss and ultimately clinical manifestations by up to 20–30 years [6].