Abstract
Scalable and accessible biomarkers of neurofibrillary tangle pathology are needed for Alzheimer′s disease prognosis, diagnosis and monitoring. Here, we show that a blood-based immunoassay for an endogenously-cleaved eMTBR-tau fragment of tau protein is strongly associated with autopsy-diagnosed Alzheimer neuropathologic change (ADNC) and predominantly reflects the burden and anatomical progression of tangle pathology but not amyloid plaque load despite being most elevated in amyloid-positive symptomatic individuals. Plasma eMTBR-tau was significantly more accurate than plasma p-tau217 in classifying Braak staging and ADNC statuses at autopsy. Importantly, neuropathologic classification by plasma eMTBR-tau remained high (AUC=0.91-0.95) even when increasing intervals between blood collection and death up to a decade, while maintaining superior sensitivity and specificity over p-tau217. Higher baseline plasma eMTBR-tau was associated with worse cognition cross-sectionally and longitudinally predicted faster worsening. These results were replicated in a living cohort with in vivo tangle and plaque neuroimaging. Plasma eMTBR-tau concordance with tau neuroimaging was up to 94%, suggesting surrogacy. Together, plasma eMTBR-tau captures biological signatures of Braak staging and ADNC over a prolonged pre-mortem window, highlighting potential for early disease detection, biological staging, prognosis and therapeutic development.