CNS-selective plasma p-tau217 accurately captures Alzheimer's disease pathology and progression
- 1University of Pittsburgh
Abstract
Blood-based biomarkers have expanded access to biologically supported diagnosis of Alzheimer's disease (AD), particularly through measurement of amyloid-beta (Abeta) and phosphorylated tau species. Among these, plasma tau phosphorylated at threonine 217 (p-tau217) is currently the leading biomarker recommended by clinical guidelines. However, circulating p-tau217 originates from both central nervous system (CNS) and peripheral tissues, potentially limiting specificity, particularly in individuals with common age-related comorbidities. Here we report a next-generation biomarker, brain-derived p-tau217%, which quantifies the proportion of circulating tau that is CNS-derived and phosphorylated at threonine 217. Across neuropathologically defined, Abeta- and tau-neuroimaging-characterized, and memory clinic cohorts, brain-derived p-tau217% consistently identified AD pathology and clinical AD with larger effect sizes, higher discriminative accuracy, and improved sensitivity and specificity, outperforming conventional non-CNS-selective plasma p-tau217, p-tau217/Abeta1-42 and p-tau217% alternatives as well as brain-derived-p-tau217 alone. Furthermore, the CNS-selective biomarker demonstrated more robust prediction of future clinical progression in individuals followed for up to two decades. Importantly, diagnostic performance remained high in older adults with diabetes and cardiovascular disease, populations in which standard p-tau217 showed reduced specificity. Moreover, superiority extended to comparisons against multiple CNS disease-related proteins in targeted proteomic analyses. These findings establish plasma brain-derived p-tau217% as a biologically grounded and clinically robust biomarker that advances molecular definition, detection, and prognosis of Alzheimer's disease.
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BibTeX
@misc{zeng2026cnsselective,
title = {{CNS-selective plasma p-tau217 accurately captures Alzheimer's disease pathology and progression}},
author = {X. Zeng and M. F. Farinas and M. N. Nafash and D. S. Smirnov and R. Shi and B. Lopresti and C. Matan and D. L. Tudorascu and S. B. Berman and R. Sweet and C. E. Shaaban and B. E. Snitz and J. K. Kofler and N. K. Nadkarni and H. J. Aizenstein and M. D. Ikonomovic and T. A. Pascoal and V. L. Villemagne and M. I. Kamboh and H. Zetterberg and A. D. Cohen and O. L. Lopez and T. K. Karikari},
howpublished = {medRxiv},
year = {2026},
month = may,
doi = {10.64898/2026.05.18.26353208},
url = {https://www.medrxiv.org/content/10.64898/2026.05.18.26353208v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - CNS-selective plasma p-tau217 accurately captures Alzheimer's disease pathology and progression
AU - X. Zeng
AU - M. F. Farinas
AU - M. N. Nafash
AU - D. S. Smirnov
AU - R. Shi
AU - B. Lopresti
AU - C. Matan
AU - D. L. Tudorascu
AU - S. B. Berman
AU - R. Sweet
AU - C. E. Shaaban
AU - B. E. Snitz
AU - J. K. Kofler
AU - N. K. Nadkarni
AU - H. J. Aizenstein
AU - M. D. Ikonomovic
AU - T. A. Pascoal
AU - V. L. Villemagne
AU - M. I. Kamboh
AU - H. Zetterberg
AU - A. D. Cohen
AU - O. L. Lopez
AU - T. K. Karikari
PY - 2026
DA - 2026/05/18
PB - medRxiv
DO - 10.64898/2026.05.18.26353208
UR - https://www.medrxiv.org/content/10.64898/2026.05.18.26353208v2
AB - Blood-based biomarkers have expanded access to biologically supported diagnosis of Alzheimer's disease (AD), particularly through measurement of amyloid-beta (Abeta) and phosphorylated tau species. Among these, plasma tau phosphorylated at threonine 217 (p-tau217) is currently the leading biomarker recommended by clinical guidelines. However, circulating p-tau217 originates from both central nervous system (CNS) and peripheral tissues, potentially limiting specificity, particularly in individuals with common age-related comorbidities. Here we report a next-generation biomarker, brain-derived p-tau217%, which quantifies the proportion of circulating tau that is CNS-derived and phosphorylated at threonine 217. Across neuropathologically defined, Abeta- and tau-neuroimaging-characterized, and memory clinic cohorts, brain-derived p-tau217% consistently identified AD pathology and clinical AD with larger effect sizes, higher discriminative accuracy, and improved sensitivity and specificity, outperforming conventional non-CNS-selective plasma p-tau217, p-tau217/Abeta1-42 and p-tau217% alternatives as well as brain-derived-p-tau217 alone. Furthermore, the CNS-selective biomarker demonstrated more robust prediction of future clinical progression in individuals followed for up to two decades. Importantly, diagnostic performance remained high in older adults with diabetes and cardiovascular disease, populations in which standard p-tau217 showed reduced specificity. Moreover, superiority extended to comparisons against multiple CNS disease-related proteins in targeted proteomic analyses. These findings establish plasma brain-derived p-tau217% as a biologically grounded and clinically robust biomarker that advances molecular definition, detection, and prognosis of Alzheimer's disease.
ER -