Molecular features of human pathological tau distinguish tauopathy-associated dementias

Mukesh Kumar¹, Christoph N Schlaffner², Shaojun Tang³, Maaike A Beuvink¹, Arthur Viode⁴, Waltraud Mair¹, Meenakshi Jha⁴, Ceren Uncu¹, Hendrik Wesseling¹, Tian Wang¹, Derek H Oakley⁵, Pieter Beerepoot¹, Jie Xue¹, Theresa R Connors⁵, David A Davis⁶, Matthew P Frosch⁵, Melissa E Murray⁷, Salvatore E Spina⁸, Lea T Grinberg⁷, William W Seeley⁸, Bruce L Miller⁸, Adam L Boxer⁹, Daniel H Geschwind¹⁰, Kenneth S Kosik¹¹, Dennis W Dickson⁷, Bernhard Y Renard¹², Michael DeTure⁷, Ann C McKee¹³, Bradley T Hyman⁵, Hanno Steen¹⁴, Judith A Steen¹⁵

Affiliations

¹ F.M. Kirby Neurobiology Center, Department of Neurobiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
² F.M. Kirby Neurobiology Center, Department of Neurobiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Data Analytics and Computational Statistics, Hasso Plattner Institute, Digital Engineering Faculty, University of Potsdam, Potsdam, Germany.
³ F.M. Kirby Neurobiology Center, Department of Neurobiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Department of Biostatistics, Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
⁴ Departments of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
⁵ Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁶ UMMG Department of Neurology, Miller School of Medicine, Medical Campus, University of Miami, Miami, FL, USA.
⁷ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
⁸ Memory and Aging Center, Department of Neurology and Pathology, University of California, San Francisco, San Francisco, CA, USA.
⁹ Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
¹⁰ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹¹ Neuroscience Research Institute and Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, USA.
¹² Data Analytics and Computational Statistics, Hasso Plattner Institute, Digital Engineering Faculty, University of Potsdam, Potsdam, Germany.
¹³ Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, MA, USA.
¹⁴ F.M. Kirby Neurobiology Center, Department of Neurobiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Departments of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁵ F.M. Kirby Neurobiology Center, Department of Neurobiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: judith.steen@childrens.harvard.edu.

PMID: 41616780
DOI: 10.1016/j.cell.2025.12.036

Free article

Molecular features of human pathological tau distinguish tauopathy-associated dementias

Mukesh Kumar et al. Cell. 2026.

Free article

. 2026 Feb 5;189(3):956-968.e13.

doi: 10.1016/j.cell.2025.12.036. Epub 2026 Jan 29.

Authors

Affiliations

¹ F.M. Kirby Neurobiology Center, Department of Neurobiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
² F.M. Kirby Neurobiology Center, Department of Neurobiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Data Analytics and Computational Statistics, Hasso Plattner Institute, Digital Engineering Faculty, University of Potsdam, Potsdam, Germany.
³ F.M. Kirby Neurobiology Center, Department of Neurobiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Department of Biostatistics, Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
⁴ Departments of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
⁵ Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁶ UMMG Department of Neurology, Miller School of Medicine, Medical Campus, University of Miami, Miami, FL, USA.
⁷ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
⁸ Memory and Aging Center, Department of Neurology and Pathology, University of California, San Francisco, San Francisco, CA, USA.
⁹ Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
¹⁰ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹¹ Neuroscience Research Institute and Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, USA.
¹² Data Analytics and Computational Statistics, Hasso Plattner Institute, Digital Engineering Faculty, University of Potsdam, Potsdam, Germany.
¹³ Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, MA, USA.
¹⁴ F.M. Kirby Neurobiology Center, Department of Neurobiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Departments of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁵ F.M. Kirby Neurobiology Center, Department of Neurobiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: judith.steen@childrens.harvard.edu.

PMID: 41616780
DOI: 10.1016/j.cell.2025.12.036

Abstract

In Alzheimer's disease (AD), pathological tau protein shows a progressive accumulation of post-translational modifications (PTMs), reflecting disease severity, progression, and prion-like activity. Although many neurodegenerative diseases with dementia display tau aggregates, the pathological proteoforms of tau protein from each disease type remain unknown. Here, using a quantitative mass spectrometry-based proteomics platform, FLEXITau, deep characterization of pathological tau protein isolated from the brains of 203 human subjects with AD, familial AD (fAD), chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), Pick's disease (PiD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB)-a non-tauopathy symptomatic control-and healthy controls (CTR) is performed. Unsupervised data analyses and supervised machine learning identify distinct molecular features of pathological tau for each disease, enabling molecular disease stratification. This study identifies potential disease-specific biomarkers and therapeutic targets for tauopathies and provides critical quantitative information for pharmacokinetic modeling required for therapeutic and disease mechanism studies.

Keywords: MRM; PTMs; biomarkers; cleavage; machine learning; mass spectrometry; neurodegenerative diseases; proteomics; tau protein; therapeutics.

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Conflict of interest statement

Declaration of interests B.T.H. has a family member who works at Novartis and owns stock in Novartis; he serves on the SAB of Dewpoint and owns stock. He serves on a scientific advisory board or is a consultant for AbbVie, Aprinoia Therapeutics, Arvinas, Avrobio, Axial, Biogen, BMS, Cure Alz Fund, Cell Signaling, Eisai, Genentech, Ionis, Novartis, Sangamo, Sanofi, Takeda, the US Department of Justice, Vigil, and Voyager. His laboratory is supported by research grants from the National Institutes of Health, Cure Alzheimer’s Fund, Tau Consortium, and the JPB Foundation—and sponsored research agreements from AbbVie and BMS. A.L.D. is a co-founder of Neurovanda Therapeutics and has equity in Alector and Arvinas. He serves as a consultant for Alector, Arvinas, Alexion, Arrowhead, BMS, Eli Lilly, Janssen, Merck, Neurocrine, Novartis, Oligomerix, Ono, Oscotec, Switch, and Transposon. He receives research support from Biogen, Eisai, and Regeneron. His laboratory is supported by grants from the NIH, the Alzheimer’s Association, Association for Frontotemporal Degeneration, Bluefield Project, GHR Foundation, Gates Ventures, and Rainwater Charitable Foundation.

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Molecular features of human pathological tau distinguish tauopathy-associated dementias

Affiliations

Molecular features of human pathological tau distinguish tauopathy-associated dementias

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous