Year: 2026
Type: article
Study design: Observational Study
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.
Source: Cell
Authors: 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
Institutions: Boston Children's Hospital, Harvard University, Hasso Plattner Institute, University of Potsdam, Virginia Commonwealth University, VCU Massey Comprehensive Cancer Center, Massachusetts General Hospital, University of Miami, Mayo Clinic in Florida, University of California, San Francisco, University of California, Los Angeles, University of California, Santa Barbara, Boston University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,400
Funders: Mayo Clinic, Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Eli Lilly and Company, Biogen, Alexion Pharmaceuticals, University of Miami, McLean Hospital, Cure Alzheimer's Fund, University of Maryland, Regeneron Pharmaceuticals, GHR Foundation, Larry Ellison Foundation, Rainwater Charitable Foundation, Eisai, National Institutes of Health, University of California, San Francisco, Tau Consortium, European Research Council, National Institute on Aging, National Institute of Mental Health, National Institute on Drug Abuse, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: Traumatic Brain Injury and Repetitive Head Impacts: Contributions to AD/ADRD and CTE Neuropathology and Resulting Clinical Syndromes, Early Onset AD Consortium - the LEAD Study (LEADS), Impact of coding and non-coding variation in progressive supranuclear palsy, G4497698608, Early Onset Alzheimer's Disease Consortium, Proteogenomics to characterize novel non-coding and extragenic translation, G5846511141, G5959518096, G6086078501, Complexity and Heterogeneity of Alzheimer disease, G7026053751, Regulation of SMN and Identification of its Downstream Target, G776654204, Quantifying post-translational modifications and protein expression by HTP-MS, Are multiple tau species toxic in Alzheimer's Disease?, Drivers of Pathological Tau Aggregation, G9000150898, ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration, Cycle 2 (ALLFTD2), Boston University Alzheimer's Disease Research Center, Frontotemporal Dementia: Genes, Images, and Emotions, Integrated Platform to study Neurodegeneration in Alzheimer’s Disease, New Approaches to Dementia Heterogeneity, Massachusetts Alzheimer's Disease Research Center (MADRC)
OpenAlex ID: W7126091256