TDP-43-Associated Neurodegenerative Disease Conceptualization and Integrated Staging: A Review.

Authors

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

Published in

JAMA neurology. Aug 24, 2026. Epub Aug 24, 2026.

Abstract

Classifying disease based on underlying pathobiology rather than clinical phenotype has implications for the development of biomarkers and therapy development.
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.
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.

PMID:
42636000
Bibliographic data and abstract were imported from PubMed on 25 Aug 2026.

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