Redefining ALS: Large-scale proteomic profiling reveals a prolonged pre-diagnostic phase with immune, muscular, metabolic, and brain involvement
Year: 2025
Type: preprint
Abstract: Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form. Methods: We leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput proteomic profiling (7,285 protein markers, SomaScan). Cox proportional hazards models based on 4,567 participants (including 172 incident ALS cases) were used to identify protein biomarkers associated with future ALS diagnosis. Top results were indirectly validated in two independent case-control studies of prevalent ALS (n=417 ALS, 852 controls). Functional annotation included cross-disease comparisons, gene set and tissue enrichment testing, organ-specific proteomic clocks, and the application of large-language models (LLM). Findings: Five proteins (SECTM1, CA3, THAP4, KLHL41, SLC26A7) were identified as significant pre-diagnostic ALS biomarkers (FDR=0.05), detectable approximately two decades before diagnosis. Of these, all except SECTM1 were indirectly validated in independent cohorts of prevalent ALS cases, supporting their clinical significance. Additionally, 22 nominally significant (p<0.05) pre-diagnostic biomarkers were FDR-significant in prevalent ALS with consistent effect directions. Cross-disease comparisons with pre-diagnostic Parkinson’s and Alzheimer’s disease suggested a largely specific pre-diagnostic ALS biomarker signature. Gene ontology and tissue enrichment highlighted early involvement of immune, muscle, metabolic, and digestive processes. Furthermore, analyses of proteomic clocks revealed accelerated aging in brain-cognition, immune, and muscle tissues before clinical diagnosis. Druggability and LLM analyses revealed possible therapeutic targets and novel strategies, emphasizing translational relevance. Interpretation: Our study provides first evidence of ultra-early molecular changes in common ALS up to two decades prior to clinical onset, mainly affecting immune, muscle, metabolic, digestive, and cognitive systems. Our study nominates several compelling candidates for risk stratification studies and novel therapeutic targets for early intervention.
Source: medRxiv
Authors: Jan Homann, Roxanna Korologou-Linden, Vivian Viallon, Sarah Morgan, Valerija Dobricic, Laura Deecke, Julia P. Schessner, Karl Smith-Byrne, Daniel Birtles, Yujia Zhao, Joanne Wuu, Fanny Artaud, Fatema Hajizadah, Jose Maria Huerta, Olena Ohlei, Mikhail Lebedev, P. Martijn Kolijn, Marcela Guevara, Ana Jimenez-Zabala, María José Sánchez, Camino Trobajo-Sanmartín, Sandra M. Colorado-Yohar, Sonia Alonso-Martín, Dafina Petrova, Sabina Sieri, Klaus Berger, Susan Peters, Nick Wareham, Rudolph Kaaks, Ruth C. Travis, Roel C. H. Vermeulen, Ioanna Tzoulaki, Alexis Elbaz, Matthias Mann, Carlotta Sacerdote, Giovanna Masala, Verena Katzke, Michael Benatar, Lars Bertram, Lefkos Middleton, Elio Riboli, Marc J. Gunter, Pietro Ferrari, Oliver Robinson, Christina M. Lill
Institutions: University of Münster, Imperial College London, Centre international de recherche sur le cancer, Queen Mary University of London, Blizard Institute, University of Lübeck, Max Planck Institute of Biochemistry, University of Oxford, Utrecht University, University of Miami, Inserm, Université de Versailles Saint-Quentin-en-Yvelines, Université Paris-Saclay, Centre de recherche en Epidémiologie et Santé des Populations, Instituto Murciano de Investigación Biosanitaria, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Instituto de Salud Pública de Navarra, Navarre Institute of Health Research, Basque Government, Biogipuzkoa Health Research Institute, Instituto de Investigación Biosanitaria de Granada, Andalusian School of Public Health, Universidad de Antioquia, Instituto de Salud Carlos III, Biomedical Research Networking Center on Neurodegenerative Diseases, Hospital Universitario Virgen de las Nieves, Fondazione IRCCS Istituto Nazionale dei Tumori, University of Cambridge, MRC Epidemiology Unit, Medical Research Council, German Cancer Research Center, University Medical Center Utrecht, Academy of Athens, Biomedical Research Foundation of the Academy of Athens, University of Copenhagen, Università degli Studi del Piemonte Orientale “Amedeo Avogadro”, Azienda Ospedaliera Citta' della Salute e della Scienza di Torino
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: World Health Organization, Compagnia di San Paolo, Cure Alzheimer's Fund, Rare Diseases Clinical Research Network, Cancer Research UK, National Institute for Health and Care Research, Imperial College London, European Commission, Deutsche Forschungsgemeinschaft, ZonMw, Ministero della Salute, Westfälische Wilhelms-Universität Münster, Associazione Italiana per la Ricerca sul Cancro, Medical Research Council, World Cancer Research Fund, Instituto de Salud Carlos III, Rijksinstituut voor Volksgezondheid en Milieu, NIHR Imperial Biomedical Research Centre, School of Public Health, Imperial College London, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences
Awards: Aetiology of type 2 diabetes and related metabolic disorders, G1136667113, G2286363763, G261809072, G2714613917, G3328679326, Metabolomic and omic assessment of biological ageing across the life-course (METAGE), G4409035895, G4844208673, G4881195352, The EPIC-Norfolk prospective population study: biological and behavioural determinants of health and disease in an ageing population, G527520901, G5315906942, G5469230434, G574262416, G6274749655, G6636188017, G6896564351, G6923329853, G7112453972, EPIC-Oxford: benefits and risks of plant-based diets, Metabolomic and omic assessment of biological ageing across the life-course (METAGE), G899966268, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe)
OpenAlex ID: W4413800244