Biomarker-related phospho-tau217 appears in synapses around Aβ plaques prior to tau tangle in cerebral cortex of preclinical Alzheimer’s disease

Phospho-tau protein p-tau181 is a cerebrospinal fluid biomarker for Alzheimer's disease (AD), while p-tau217 is the most sensitive plasma biomarker for cerebral amyloid β (Aβ) load prior to tau pathology in preclinical AD. Diagnostic and prognostic use of these p-tau biomarkers requires neuropathological interpretation. Here, we analyzed the cellular localization of biomarker p-tau species in postmortem human brains harboring different extents of Aβ plaque and tau pathology. Signals for p-tau217 were absent in normal brains but present in pre- and post-synapses surrounding Aβ plaques in preclinical AD brains. p-Tau217 colocalized with tau pathology markers p-tau202/205, p-tau231, and p-tau262, while p-tau181 was normally present in glutamatergic and GABAergic axons, which were distorted around Aβ plaques, where p-tau217 and p-tau181 colocalized. p-tau217-containing pre-synapses were enriched with active tau kinases and were not preferentially engulfed by glial cells. Emergence of p-tau217 represents a neuronal/synaptic reaction to Aβ plaques in preclinical AD brains.