Hirota et al. report that phospho-tau 217, phospho-tau 231 and phospho-tau 181, cerebrospinal fluid and plasma biomarkers for preclinical Alzheimer’s disease, are associated with postsynaptic pathology around amyloid-β plaques, while phospho-tau 181 also represents axonal abnormality in the absence of neurofibrillary tangle pathology in App knock-in mouse models of amyloid-β amyloidosis. Here, MAPT is linked to early-onset autosomal dominant Alzheimer disease.