Molecular features of human pathological tau distinguish tauopathy-associated dementias

Mukesh Kumar; Christoph N Schlaffner; Shaojun Tang; Maaike A Beuvink; Arthur Viode; Waltraud Mair; Meenakshi Jha; Ceren Uncu; Hendrik Wesseling; Tian Wang; Derek H Oakley; Pieter Beerepoot; Jie Xue; Theresa R Connors; David A Davis; Matthew P Frosch; Melissa E Murray; Salvatore E Spina; Lea T Grinberg; William W Seeley; Bruce L Miller; Adam L Boxer; Daniel H Geschwind; Kenneth S Kosik; Dennis W Dickson; Bernhard Y Renard; Michael DeTure; Ann C McKee; Bradley T Hyman; Hanno Steen; Judith A Steen

doi:10.1016/j.cell.2025.12.036

Molecular features of human pathological tau distinguish tauopathy-associated dementias

Cell. 2026 Feb 5;189(3):956-968.e13. doi: 10.1016/j.cell.2025.12.036. Epub 2026 Jan 29.

Authors

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.

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.

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease / metabolism
Alzheimer Disease / pathology
Biomarkers / metabolism
Brain / metabolism
Brain / pathology
Chronic Traumatic Encephalopathy / metabolism
Chronic Traumatic Encephalopathy / pathology
Corticobasal Degeneration / metabolism
Corticobasal Degeneration / pathology
Dementia* / diagnosis
Dementia* / metabolism
Dementia* / pathology
Female
Humans
Lewy Body Disease / metabolism
Lewy Body Disease / pathology
Male
Middle Aged
Pick Disease of the Brain / metabolism
Pick Disease of the Brain / pathology
Protein Processing, Post-Translational
Proteomics / methods
Supranuclear Palsy, Progressive / metabolism
Supranuclear Palsy, Progressive / pathology
Tauopathies* / metabolism
Tauopathies* / pathology
tau Proteins* / metabolism

Substances

tau Proteins
Biomarkers
MAPT protein, human

Grants and funding

R01 AG056058/AG/NIA NIH HHS/United States