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Publication
medRxiv

CNS-selective plasma p-tau217 accurately captures Alzheimer’s disease pathology and progression

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Topic/Product:
Alzheimer's, CNS Disease Panel 120
  • May 21, 2026
  • List Item
Disease Area:
Alzheimer's Disease
Sample Type:
Plasma

Abstract

Abstract
Blood-based biomarkers have expanded access to biologically supported diagnosis of Alzheimer’s disease (AD), particularly through measurement of amyloid-beta (Aβ) and phosphorylated tau species1-3. Among these, plasma tau phosphorylated at threonine 217 (p-tau217) is currently the leading biomarker recommended by clinical guidelines4-6. However, circulating p-tau217 originates from both central nervous system (CNS) and peripheral tissues7, potentially limiting specificity, particularly in individuals with common age-related comorbidities8. 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, Aβ- 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/Aβ1-42 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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Authors & Affiliations

Xuemei Zeng1,2,3, Marissa F. Farinas1,2,3, Michel N. Nafash1,2,3, Denis S. Smirnov1,2,4, Brian J.
Lopresti5, Cristy Matan5, Dana L. Tudorascu1,3, Sarah B. Berman3,6, Robert A. Sweet1,3, C. Elizabeth
Shaaban3,7,8, Beth E. Snitz3,6, Julia K. Kofler3,9, Neelesh K. Nadkarni3,10, Howard J. Aizenstein1,3,
Milos D. Ikonomovic1,3,6,11, Tharick A. Pascoal1,3,5, Victor L. Villemagne1,3, M. Ilyas Kamboh3,12, Ann
D. Cohen1,3*, Oscar L. Lopez3,6*, Thomas K. Karikari1,2,3*#


1Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
2Biofluid Biomarker Laboratory, Western Psychiatric Hospital, University of Pittsburgh Medical
Center, Pittsburgh, PA 15213, USA
3Alzheimer’s Disease Research Center, University of Pittsburgh, Pittsburgh PA 15213, USA
4Department of Pathology, Mass General Brigham, Boston, MA 02114
5Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
6Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
7Department of Health Promotion and Development, School of Nursing, University of Pittsburgh,
Pittsburgh, PA, 15213, USA
8Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA
15213, USA
9Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
10Division of Geriatric Medicine, Department of Medicine, School of Medicine, University of
Pittsburgh, Pittsburgh, PA 15213, USA
11Geriatric Research Education and Clinical Center, VA Pittsburgh HS, Pittsburgh, PA, USA
12Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA,
15261, USA

*Joint senior authors
#Corresponding author: Thomas K. Karikari, Department of Psychiatry, School of Medicine,
University of Pittsburgh, Pittsburgh, PA, USA. 3811 O’Hara St., Pittsburgh, PA, 15213, USA.

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Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

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Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition.  He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.