MAPT and Alzheimer disease: The three key pathological hallmarks of AD include: (i) extracellular β-amyloid (Aβ) plaques, primarily composed of the peptide, Aβ, which is liberated from the amyloid precursor protein (APP) via serial cleavage by β- and γ-secretase, (ii) intracellular neurofibrillary tangles (NFTs), comprised of hyperphosphorylated tau (p-tau), and (iii) neuroinflammation including microglial activation and astrogliosis (Hardy and Higgins, 1992; Bertram and Tanzi, 2008).