Plasma eMTBR-tau as a robust biomarker for Alzheimer's disease tangle pathology up to 10 years before death
- 1University of Pittsburgh
Abstract
Scalable and accessible biomarkers of neurofibrillary tangle pathology are needed for Alzheimers 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.
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BibTeX
@misc{shi2026plasma,
title = {{Plasma eMTBR-tau as a robust biomarker for Alzheimer's disease tangle pathology up to 10 years before death}},
author = {R. Shi and X. Zeng and M. F. Farinas and M. N. Nafash and D. S. Smirnov and M. I. Kamboh and B. Snitz and J. K. Kofler and A. D. Cohen and T. A. Pascoal and M. D. Ikonomovic and H. Zetterberg and O. Lopez and T. K. Karikari},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.29.26363951},
url = {https://www.medrxiv.org/content/10.64898/2026.09.29.26363951v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Plasma eMTBR-tau as a robust biomarker for Alzheimer's disease tangle pathology up to 10 years before death
AU - R. Shi
AU - X. Zeng
AU - M. F. Farinas
AU - M. N. Nafash
AU - D. S. Smirnov
AU - M. I. Kamboh
AU - B. Snitz
AU - J. K. Kofler
AU - A. D. Cohen
AU - T. A. Pascoal
AU - M. D. Ikonomovic
AU - H. Zetterberg
AU - O. Lopez
AU - T. K. Karikari
PY - 2026
DA - 2026/09/29
PB - medRxiv
DO - 10.64898/2026.09.29.26363951
UR - https://www.medrxiv.org/content/10.64898/2026.09.29.26363951v1
AB - Scalable and accessible biomarkers of neurofibrillary tangle pathology are needed for Alzheimers 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.
ER -