MAPT and Alzheimer disease: Most research into therapeutics has been philosophically guided by the connection of the hallmark histopathology of AD, cortical amyloid plaques, and neurofibrillary tangles, with familial dementia-causing mutations associated with their most insoluble component proteins, the amyloid-β peptide (Aβ) (1, 2), and the microtubule-associated protein tau (3, 4).