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

Ruth Chia^#¹, Ruin Moaddel^#², Justin Y Kwan³, Memoona Rasheed¹, Paola Ruffo¹, Natalie Landeck⁴, Paolo Reho^{4

5}, Rosario Vasta^{1

6}, Andrea Calvo^{6

7}, Cristina Moglia^{6

7}, Antonio Canosa^{6

7

8}, Umberto Manera^{6

7}, Allison Snyder³, Sara Saez-Atienzar⁹, Maurizio Grassano⁶, Maura Brunetti⁶, Federico Casale⁶, Anindita Ray⁴, Kumar Arvind⁴, Betul Comertpay¹, Min Zhu², J Raphael Gibbs¹⁰; American Genome Center; Camille Alba^{11

12

13}, Ted M Dawson¹⁴, Liana S Rosenthal¹⁵, Anna J Hall¹⁵, Alexander Y Pantelyat¹⁵, Derek P Narendra¹⁶, Debra J Ehrlich¹⁷, Keenan A Walker¹⁸, Peter Kosa¹⁹, Bibiana Bielekova¹⁹, Josephine M Egan², Julián Candia²⁰, Toshiko Tanaka²⁰, Luigi Ferrucci²⁰, Clifton L Dalgard^#^{11

12}, Sonja W Scholz^#^{4

15}, Adriano Chiò^#^{6

7

8}, Bryan J Traynor^#^{21

22

23

24}

Affiliations

¹ Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
² Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
³ Neurodegenerative Disorders Clinic, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁴ Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁵ Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.
⁶ 'Rita Levi Montalcini' Department of Neuroscience, Amyotrophic Lateral Sclerosis Center, University of Turin, Turin, Italy.
⁷ Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
⁸ Institute of Cognitive Sciences and Technologies, C.N.R, Rome, Italy.
⁹ Department of Neurology, The Ohio State University, Columbus, OH, USA.
¹⁰ Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
¹¹ Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
¹² The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
¹³ Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
¹⁴ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁶ Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
¹⁷ Parkinson's Disease Clinic, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
¹⁸ Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
¹⁹ Laboratory of Clinical Immunology and Microbiology, Neuroimmunological Diseases Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
²⁰ Longitudinal Studies Section, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
²¹ Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. bryan.traynor@nih.gov.
²² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. bryan.traynor@nih.gov.
²³ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. bryan.traynor@nih.gov.
²⁴ RNA Therapeutics Laboratory, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA. bryan.traynor@nih.gov.

^# Contributed equally.

PMID: 40830661
DOI: 10.1038/s41591-025-03890-6

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

Ruth Chia et al. Nat Med. 2025.

. 2025 Aug 19.

doi: 10.1038/s41591-025-03890-6. Online ahead of print.

Authors

Affiliations

¹ Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
² Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
³ Neurodegenerative Disorders Clinic, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁴ Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁵ Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.
⁶ 'Rita Levi Montalcini' Department of Neuroscience, Amyotrophic Lateral Sclerosis Center, University of Turin, Turin, Italy.
⁷ Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
⁸ Institute of Cognitive Sciences and Technologies, C.N.R, Rome, Italy.
⁹ Department of Neurology, The Ohio State University, Columbus, OH, USA.
¹⁰ Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
¹¹ Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
¹² The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
¹³ Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
¹⁴ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁶ Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
¹⁷ Parkinson's Disease Clinic, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
¹⁸ Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
¹⁹ Laboratory of Clinical Immunology and Microbiology, Neuroimmunological Diseases Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
²⁰ Longitudinal Studies Section, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
²¹ Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. bryan.traynor@nih.gov.
²² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. bryan.traynor@nih.gov.
²³ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. bryan.traynor@nih.gov.
²⁴ RNA Therapeutics Laboratory, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA. bryan.traynor@nih.gov.

^# Contributed equally.

PMID: 40830661
DOI: 10.1038/s41591-025-03890-6

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.

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Conflict of interest statement

Competing interests: R.C., R.M., J.Y.K., L.F., C.L.D., S.W.S. and B.J.T. have a patent pending (US Patent application no. 63/717,807) on the diagnostic testing for ALS based on the proteomic panel. B.J.T. holds patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. B.J.T. and S.W.S. receive research support from Cerevel Therapeutics. S.W.S. serves on the scientific advisory committees of the Lewy Body Dementia Association, Mission MSA and the GBA1 Canada Initiative. The other authors declare no competing interests.

References

1. Feldman, E. L. et al. Amyotrophic lateral sclerosis. Lancet 400, 1363–1380 (2022). - PubMed - PMC
1. Arthur, K. C. et al. Projected increase in amyotrophic lateral sclerosis from 2015 to 2040. Nat. Commun. 7, 12408 (2016). - PubMed - PMC
1. Fournier, C. N. Considerations for amyotrophic lateral sclerosis (ALS) clinical trial design. Neurotherapeutics 19, 1180–1192 (2022). - PubMed - PMC
1. Masrori, P. & Van Damme, P. Amyotrophic lateral sclerosis: a clinical review. Eur. J. Neurol. 27, 1918–1929 (2020). - PubMed
1. Turner, M. R. et al. Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol. 12, 310–322 (2013). - PubMed - PMC

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1ZIAAG000933/U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous