Cerebrospinal fluid YWHAG:NPTX2 ratio predicts clinical severity and future phenoconversion in frontotemporal lobar degeneration
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: ABSTRACT Frontotemporal lobar degeneration (FTLD) is a common cause of early-onset dementias marked by progressive declines in behavior, cognition, and/or movement. FTLD neuropathologies, including TDP-43 proteinopathies and primary tauopathies, do not have reliable fluid biomarkers for in-vivo diagnosis nor biomarkers that directly correspond to FTLD clinical features. Fluid biomarkers that forecast and track FTLD clinical progression, irrespective of pathology or clinical syndrome, are urgently needed to improve clinical trial designs. We previously identified the ratio between two cerebrospinal fluid (CSF) synaptic proteins, YWHAG and NPTX2, as a prognostic biomarker of cognitive decline in Alzheimer’s disease (AD), independent of core AD pathologies, amyloid and tau. Here, we evaluate its utility in sporadic and familial FTLD compared to other neurodegenerative diseases. Using CSF assays from four independent cohorts (UCSF-MAC, ALLFTD, GENFI, PDBP), we find CSF YWHAG:NPTX2 is substantially elevated across all sporadic and familial FTLD syndromes, AD, and dementia with Lewy bodies. CSF YWHAG:NPTX2 robustly correlates with clinical severity across sporadic and familial FTLD ( C9orf72 , GRN , or MAPT mutations), independent of current gold-standard neurodegeneration biomarker neurofilament light (NfL). In presymptomatic familial FTLD, CSF YWHAG:NPTX2 is estimated to rise roughly a decade before symptom onset and improves prediction of imminent symptomatic conversion by 1.7-fold compared to plasma NfL alone, more than halving the estimated sample size required for an FTLD prevention clinical trial. These findings underscore CSF YWHAG:NPTX2 as a cross-dementia synaptic biomarker of cognitive decline and a promising biomarker for disease staging and prognosis across the clinico-pathological continuum of FTLD.
Authors: Hamilton Se-Hwee Oh, Joshua D. Downer, Connor D. Dietz, Claire Yballa, Edoardo Marcora, Argentina Lario-Lago, Hilary W. Heuer, Leah K. Forsberg, Jennifer Hsiao-Nakamoto, Chi-Lu Chiu, Paul Auger, Casey Powers, Gil Di Paolo, Fen Huang, Brian Appleby, Sami Barmada, Ece Bayram, Andrea Bozoki, David Clark, R. Ryan Darby, Bradford Dickerson, Kimiko Domoto-Reilly, Kelley Faber, Anne Fagan, Tatiana Foroud, Douglas R. Galasko, Daniel Geschwind, Nupur Ghoshal, Neill Graff-Radford, Ian M. Grant, Chadwick M Hales, Lawrence S. Honig, Ging-Yuek Hsiung, Edward D. Huey, David Irwin, David Knopman, John Kornak, Justin Kwan, Gabriel C. Léger, Irene Litvan, Ian R. Mackenzie, Mario F. Mendez, Chiadi Onyike, Belen Pascual, Peter Pressman, Rosa Rademakers, Eliana Marisa Ramos, Erik D. Roberson, Allison Snyder, Carmela Tartaglia, Dylan Wint, Arabella Bouzigues, Lucy L. Russell, Phoebe H. Foster, Eve Ferry-Bolder, John C. van Swieten, Lize C. Jiskoot, Harro Seelaar, Raquel Sanchez-Valle, Robert Laforce, Caroline Graff, Daniela Galimberti, Rik Vanderberghe, Alexandre de Mendonça, Giuseppe di Fede, Isabel Santana, Alexander Gerhard, Johannes Levin, Benedetta Nacmias, Markus Otto, Maxime Bertoux, Thibaud Lebouvier, Simon Ducharme, Chris R. Butler, Isabelle Le Ber, Elizabeth Finger, Mario Masellis, James B. Rowe, Matthis Synofzik, Fermin Moreno, Barbara Borroni, Aitana Sogorb-Esteve, Sophia Weiner, Johan Gobom, Henrik Zetterberg, Jonathan D. Rohrer, Emily W. Paolillo, Lawren VandeVrede, Peter J. Ljubenkov, Renaud La Joie, Gil D. Rabinovici, Joel H. Kramer, Bruce L. Miller, Maria Luisa Gorno-Tempini, Tania Gendron, Leonard Petrucelli, Bradley F. Boeve, Howard J. Rosen, Jennifer S. Yokoyama, Scott J. Russo, William W. Seeley, Julio C. Rojas, Kaitlin B. Casaletto, Adam M. Staffaroni, Alison Goate, Adam L. Boxer, Rowan Saloner
Institutions: Icahn School of Medicine at Mount Sinai, University of California, San Francisco, Mayo Clinic, Denali Therapeutics (United States), Case Western Reserve University, University of Michigan, University of Colorado Anschutz, University of North Carolina at Chapel Hill, Indiana University Indianapolis, Vanderbilt University, University of Washington, Indiana University School of Medicine, Washington University in St. Louis, University of California San Diego, University of California, Los Angeles, Mayo Clinic in Florida, Northwestern University, Emory University, Columbia University, University of British Columbia, University of Pennsylvania, National Institute of Neurological Disorders and Stroke, Johns Hopkins University, Houston Methodist, University of Antwerp, VIB-UAntwerp Center for Molecular Neurology, University of Alabama at Birmingham, University of Toronto, Cleveland Clinic, Lou Ruvo Brain Institute, UCL Queen Square Institute of Neurology, University College London, Erasmus MC, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, Université Laval, Karolinska University Hospital, Karolinska Institutet, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, KU Leuven, University of Lisbon, Fondazione IRCCS Istituto Neurologico Carlo Besta, Unidade Local de Saúde de Coimbra, Centro de Neurociências e Biologia Celular, University of Coimbra, University of Manchester, University of Duisburg-Essen, German Center for Neurodegenerative Diseases, Munich Cluster for Systems Neurology, Ludwig-Maximilians-Universität München, Don Carlo Gnocchi Foundation, Universität Ulm, Inserm, Université de Lille, Centre Hospitalier Universitaire de Lille, Lille Neurosciences & Cognition, Montreal Neurological Institute and Hospital, McGill University Health Centre, McGill University, University of Oxford, Imperial College London, Centre National de la Recherche Scientifique, Sorbonne Université, Institut des Sciences Moléculaires, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Institut du Cerveau, Western University, Sunnybrook Health Science Centre, Sunnybrook Research Institute, University of Cambridge, Hertie Institute for Clinical Brain Research, University of Tübingen, Instituto de Salud Carlos III, Biomedical Research Networking Center on Neurodegenerative Diseases, Biogipuzkoa Health Research Institute, Donostiako Unibertsitate Ospitalea, Centro San Giovanni di Dio Fatebenefratelli, University of Brescia, UK Dementia Research Institute, University of Gothenburg, Sahlgrenska University Hospital, University of Wisconsin–Madison
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7204846472
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