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

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.

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).

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 (R² = 0.68) and best predicted Clinical Dementia Rating Sum of Boxes (CDR-SB decline) (R² = 0.26).

BD p-tau217 and BD-based ratios enhance dynamic range and prognostic performance while maintaining diagnostic accuracy, supporting further clinical evaluation.