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Publication
medRxiv

Redefining ALS: Large-scale proteomic 1 profiling reveals a prolonged pre-diagnostic phase with immune, muscular, metabolic, and brain involvement

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  • August 28, 2025
  • Christina Lill, et al., University of Munster
Topic/Product:
CNS Disease Panel 120, Neurology
Disease Area:
ALS
Sample Type:
Plasma

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.

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Authors & Affiliations

Jan Homann¹²*, Roxanna Korologou-Linden²*, Vivian Viallon³*, Sarah Morgan⁴*, Valerija Dobricic⁵*, Laura Deecke¹, Julia P. Schessner⁶, Karl Smith-Byrne⁷, Daniel Birtles⁴, Yujia Zhao⁸, Joanne Wuu⁹, Fanny Artaud¹⁰, Fatema Hajizadah⁴, Jose Maria Huerta¹¹¹², Olena Ohlei¹, Mikhail Lebedev⁶, P. Martijn Kolijn⁸, Marcela Guevara¹²¹³¹⁴, Ana Jimenez-Zabala¹⁵¹⁶, María José Sánchez¹²¹⁷¹⁸, Camino Trobajo-Sanmartín¹²¹³¹⁴, Sandra M. Colorado-Yohar¹¹¹²¹⁹, Sonia Alonso-Martín¹⁵²⁰, Dafina Petrova¹²¹⁷¹⁸²¹, Sabina Sieri²², Klaus Berger¹, Susan Peters⁸, Nick Wareham²³, Rudolph Kaaks²⁴, Ruth C. Travis⁷, Roel C. H. Vermeulen⁸²⁵, The Global Neurodegeneration Proteomics Consortium (GNPC)$, Ioanna Tzoulaki²⁶²⁷, Alexis Elbaz¹⁰, Matthias Mann⁶²⁸, Carlotta Sacerdote²⁹, Giovanna Masala³⁰, Verena Katzke²⁴, Michael Benatar⁹, Lars Bertram⁵, Lefkos Middleton², Elio Riboli², Marc J. Gunter²⁶, Pietro Ferrari³, Oliver Robinson²²⁶, and Christina M. Lill¹²

¹ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
² Ageing and Epidemiology Unit (AGE), School of Public Health, Imperial College London, London, UK
³ International Agency for Research on Cancer (IARC/WHO), Nutrition and Metabolism Branch, Lyon, France
⁴ Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Queen Mary University of London, London, UK
⁵ Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany
⁶ Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
⁷ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
⁸ Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
⁹ Department of Neurology and the ALS Center, University of Miami, Miami, FL, USA
¹⁰ Université Paris-Saclay, UVSQ, Inserm, Gustave Roussy, CESP, Villejuif, France
¹¹ Department of Epidemiology, Murcia Regional Health Council, Biomedical Research Institute of Murcia-IMIB, Murcia, Spain
¹² Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
¹³ Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain
¹⁴ Navarre Institute for Health Research (IdiSNA), Pamplona, Spain
¹⁵ Biogipuzkoa Health Research Institute, San Sebastian, Gipuzkoa, Spain
¹⁶ Ministry of Health of the Basque Government, Sub-Directorate for Public Health and Addictions of Gipuzkoa, San Sebastián, Gipuzkoa, Spain
¹⁷ Escuela Andaluza de Salud Pública (EASP), Granada, Spain
¹⁸ Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain
¹⁹ Research Group on Demography and Health, National Faculty of Public Health, University of Antioquia, Medellín, Colombia
²⁰ CIBERNED, ISCIII (Carlos III Institute, Spanish Ministry of Sciences and Innovation), Madrid, Spain
²¹ Servicio de Oncología Médica, Hospital Universitario Virgen de las Nieves, Granada, Spain
²² Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
²³ Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK
²⁴ Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
²⁵ University Medical Centre Utrecht, Utrecht, The Netherlands
²⁶ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
²⁷ Centre for Systems Biology, Biomedical Research Foundation, Academy of Athens, Athens, Greece
²⁸ NNF Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
²⁹ Department of Health Sciences, University of Eastern Piedmont, Novara, Italy
³⁰ Clinical Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy

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Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

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Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition.  He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.