Brain‐derived plasma p‐tau217 shows enhanced dynamic range for Alzheimer's disease neuropathological change

INTRODUCTION Plasma phosphorylated tau (p‐tau), particularly p‐tau217, is a highly specific biomarker of Alzheimer's disease (AD) pathology. However, plasma p‐tau217 can be elevated in rare non‐AD conditions. Brain‐derived (BD) p‐tau217 may reduce these off‐target effects, but its performance against neuropathology has not been evaluated. METHODS We compared p‐tau217, BD p‐tau217, their amyloid beta 42 (Aβ42) ratios, BD p‐tau217/p‐tau217, and BD p‐tau217/BD tau in end‐of‐life plasma from 288 neuropathologically characterized participants using a fully automated immunoassay. Biomarkers were assessed against National Institute on Aging–Alzheimer's Association (NIA‐AA) classification, Thal phase, Braak stage, cognitive decline, and tau‐PET (positron emission tomography). RESULTS All markers tracked neuropathological severity, with BD p‐tau217 having larger fold‐changes than p‐tau217 but BD p‐tau217/Aβ42 enhancing this further. BD p‐tau217/BD tau achieved the highest area under the curve (AUC) for distinguishing Intermediate/High from Not/Low AD neuropathological change (ADNC) (0.89 vs 0.82 for p‐tau217). Although BD p‐tau217/p‐tau217 showed smaller fold‐changes, it had the strongest association with continuous tangle burden in AD ( R 2 = 0.68) and best predicted Clinical Dementia Rating Sum of Boxes (CDR‐SB decline) ( R 2 = 0.26). DISCUSSION BD p‐tau217 and BD‐based ratios enhance dynamic range and prognostic performance while maintaining diagnostic accuracy, supporting further clinical evaluation.