A plasma proteomics-based candidate biomarker panel predictive of amyotrophic lateral sclerosis.

Journal: Nature medicine
Published Date: Aug 19, 2025

Abstract

Identifying a reliable biomarker for amyotrophic lateral sclerosis (ALS) is crucial for clinical practice. Here, in this cross-sectional study, we used the Olink Explore 3072 platform to investigate plasma proteomics as a biomarker tool for this neurodegenerative condition. Thirty-three proteins were differentially abundant in the plasma of patients with ALS (n = 183) versus controls (n = 309). We replicated our findings in an independent cohort (n = 48 patients with ALS and n = 75 controls). We then applied machine learning to create a model that diagnosed ALS with high accuracy (area under the curve, 98.3%). By analyzing plasma samples from individuals before ALS symptoms emerged, we estimated the age of clinical onset and showed that the disease process-impacting skeletal muscle, nerves and energy metabolism-occurs years before symptoms appear. Our research suggests that plasma proteins can be a biomarker for this fatal disease and offers molecular insights into its prodromal phase.

Authors

  • Ruth Chia
    Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
  • Ruin Moaddel
    National Institute on Aging, Baltimore, MD, USA.
  • Justin Y Kwan
    Neurodegenerative Disorders Clinic, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Memoona Rasheed
    Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
  • Paola Ruffo
    Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
  • Natalie Landeck
    Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Paolo Reho
    Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Rosario Vasta
    Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
  • Andrea Calvo
    b ALS Center, 'Rita Levi Montalcini' Department of Neuroscience , University of Torino , Torino , Italy.
  • Cristina Moglia
    b ALS Center, 'Rita Levi Montalcini' Department of Neuroscience , University of Torino , Torino , Italy.
  • Antonio Canosa
    b ALS Center, 'Rita Levi Montalcini' Department of Neuroscience , University of Torino , Torino , Italy.
  • Umberto Manera
    ALS Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, 10126, Turin, Italy.
  • Allison Snyder
    Neurodegenerative Disorders Clinic, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Sara Saez-Atienzar
    Department of Neurology, The Ohio State University, Columbus, OH, USA.
  • Maurizio Grassano
    'Rita Levi Montalcini' Department of Neuroscience, Amyotrophic Lateral Sclerosis Center, University of Turin, Turin, Italy.
  • Maura Brunetti
    'Rita Levi Montalcini' Department of Neuroscience, Amyotrophic Lateral Sclerosis Center, University of Turin, Turin, Italy.
  • Federico Casale
    'Rita Levi Montalcini' Department of Neuroscience, Amyotrophic Lateral Sclerosis Center, University of Turin, Turin, Italy.
  • Anindita Ray
    Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Kumar Arvind
    Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Betul Comertpay
    Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
  • Min Zhu
    Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, No.50 Ximeng Road, Taizhou, 317000, China.
  • J Raphael Gibbs
    Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
  • Camille Alba
    Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
  • Ted M Dawson
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Liana S Rosenthal
    Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Anna J Hall
    Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Alexander Y Pantelyat
    Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Derek P Narendra
    Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Debra J Ehrlich
    Parkinson's Disease Clinic, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Keenan A Walker
    Laboratory of Behavioral Neuroscience, National Institute on Aging, Intramural Research Program, Baltimore, MD, USA.
  • Peter Kosa
    National Institutes of Health, National Institute of Allergy and Infectious Diseases, Laboratory of Clinical Immunology and Microbiology, Neuroimmunological Diseases Section, Bethesda, MD, United States.
  • Bibiana Bielekova
    National Institutes of Health, National Institute of Allergy and Infectious Diseases, Laboratory of Clinical Immunology and Microbiology, Neuroimmunological Diseases Section, Bethesda, MD, United States.
  • Josephine M Egan
    Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
  • Julián Candia
    Center for Human Immunology, Autoimmunity and Inflammation, National Institutes of Health, Bethesda, MD 20892, USA; Department of Physics, University of Maryland, College Park, MD 20742, USA; Center for Stem Cell Biology & Regenerative Medicine, Departments of Pediatrics and Physiology, University of Maryland School of Medicine, Baltimore MD 21201, USA.
  • Toshiko Tanaka
    Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
  • Luigi Ferrucci
    Translational Gerontology Branch, Longitudinal Studies Section, National Institute on Aging, National Institutes of Health, MedStar Harbor Hospital, 3001 S. Hanover Street, Baltimore, MD, USA.
  • Clifton L Dalgard
    Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
  • Sonja W Scholz
    Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Adriano Chiò
    b ALS Center, 'Rita Levi Montalcini' Department of Neuroscience , University of Torino , Torino , Italy.
  • Bryan J Traynor
    Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. bryan.traynor@nih.gov.

Keywords

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