TDP-43–Associated Neurodegenerative Disease Conceptualization and Integrated Staging

Importance: Classifying disease based on underlying pathobiology rather than clinical phenotype has implications for the development of biomarkers and therapy development. Observations: Transactive response DNA-binding protein 43 kDa (TDP-43) pathology is observed across a range of clinically defined neurodegenerative disorders including limbic predominant age-related encephalopathy (LATE), most cases of amyotrophic lateral sclerosis (ALS), inclusion body myositis, multisystem proteinopathy, and approximately half the cases of frontotemporal dementia (FTD). Despite this shared biology, the current nosology for these neurodegenerative disorders is based on their distinct clinical phenotypes. An alternative approach recognizes the central role of TDP-43 pathology in disease pathogenesis, reserving the use of clinical terms like ALS, FTD, or LATE to describe phenotypic manifestations of underlying pathobiology. This approach also recognizes the converging biomarker and neuropathological data indicating that pathology begins presymptomatically, before the overt clinical manifestations of disease appear. Conclusions and Relevance: In proposing a pathobiological definition of disease, the goal is to provide a road map for developing biomarkers that accurately reflect the underlying pathobiology of disease and for advancing therapeutic candidates that effectively target fundamental disease mechanisms.

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Publication Details

Journal
JAMA Neurology
Published
2026-08-24
DOI
https://doi.org/10.1001/jamaneurol.2026.2812
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
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article

TDP-43–Associated Neurodegenerative Disease Conceptualization and Integrated Staging

Clifford R. Jack, Gregory A. Jicha, Joe Lewcock, Adam M. Staffaroni et al.
JAMA Neurology
Amyotrophic Lateral Sclerosis Research
article

TDP-43–Associated Neurodegenerative Disease Conceptualization and Integrated Staging

Clifford R. Jack, Gregory A. Jicha, Joe Lewcock, Adam M. Staffaroni, Lyle W. Ostrow, Stephanie Fradette, Corey T. McMillan, Martin R. Turner, Sami Barmada, Kuldip D. Dave, Samantha Budd Haeberlein, William W. Seeley, Clotilde Lagier‐Tourenne, Nicholas J. Maragakis, Adam Boxer, Penny Dacks, Jenna Gregory, Chiadi Onyike, Jonathan Rohrer, Adam Simmons, Collin Hovinga, Zane Zeier, Laura Mitic, Susan E. Browne, Michael Benatar, Bradley F. Boeve, Edward B. Lee, Paymaan Jafar-nejad, Ammar Al-Chalabi, Billy Dunn, Deb Scharper, Joanne Wuu, Olga Uspenskaya, Martina de Majo, Jacquelyn Shapiro, Tanya Simuni, Leonard Petrucelli
article en

Abstract

Importance: Classifying disease based on underlying pathobiology rather than clinical phenotype has implications for the development of biomarkers and therapy development. Observations: Transactive response DNA-binding protein 43 kDa (TDP-43) pathology is observed across a range of clinically defined neurodegenerative disorders including limbic predominant age-related encephalopathy (LATE), most cases of amyotrophic lateral sclerosis (ALS), inclusion body myositis, multisystem proteinopathy, and approximately half the cases of frontotemporal dementia (FTD). Despite this shared biology, the current nosology for these neurodegenerative disorders is based on their distinct clinical phenotypes. An alternative approach recognizes the central role of TDP-43 pathology in disease pathogenesis, reserving the use of clinical terms like ALS, FTD, or LATE to describe phenotypic manifestations of underlying pathobiology. This approach also recognizes the converging biomarker and neuropathological data indicating that pathology begins presymptomatically, before the overt clinical manifestations of disease appear. Conclusions and Relevance: In proposing a pathobiological definition of disease, the goal is to provide a road map for developing biomarkers that accurately reflect the underlying pathobiology of disease and for advancing therapeutic candidates that effectively target fundamental disease mechanisms.

JAMA Neurology
Northwestern University (US), Biogen (United States) (US), Mayo Clinic (US), University of Kentucky (US), Johns Hopkins University (US), University of Miami (US), King's College - North Carolina (US), University of California, San Francisco (US), King's College London (GB), University of Aberdeen (GB), University of Michigan (US), Johns Hopkins Medicine (US), Ionis Pharmaceuticals (United States) (US), Critical Path Institute (US), Amyotrophic Lateral Sclerosis Association (US), Michael J. Fox Foundation (US), Knoxville College (US), Bluefield College (US), University of Oxford (GB), Massachusetts General Hospital (US), AIMM Therapeutics (Netherlands) (NL), Denali Therapeutics (United States) (US), International Alliance of ALS/MND Associations (GB), CSL (United States) (US), Temple University Hospital (US), UK Dementia Research Institute (GB), Association for Frontotemporal Degeneration (US), NIHR Queen Square Dementia Biomedical Research Unit (GB), Pennsylvania Academy of Science (US), Alector (United States) (US), King's College Hospital (GB), University College London (GB), University of Pennsylvania (US), Blackburn College (US)
Partnerships for the goals
Openalex Percentile: Top 10%
Amyotrophic Lateral Sclerosis Research
DOISourceOpenAlex
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