{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T10:33:51Z","timestamp":1793010831448,"version":"4.5.0"},"reference-count":39,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder for which reliable preclinical biomarkers to predict disease onset are currently lacking. Plasma proteomics offers a promising avenue for early detection. The identification of plasma proteins and pathways associated with incident ALS holds potential to improve early diagnosis, enable risk stratification and provide insights into disease mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Employing the Olink Explore platform, we quantified 2920 plasma proteins within a prospective cohort of UK Biobank participants. Multivariate Cox proportional hazards regression was utilized to identify proteins associated with incident generalized ALS, C9\u2010ALS (\n                      <jats:italic>C9orf72<\/jats:italic>\n                      \u2010associated ALS) and non\u2010C9\u2010ALS. Enrichment analysis was conducted to delineate the biological pathways implicated by the identified proteins. Associations between plasma protein levels and the age at onset (AAO) of ALS were assessed via linear regression, while a multivariate Cox model was employed to evaluate the relationships between protein levels and ALS survival. We subsequently assessed potential causal relationships using Mendelian randomization (MR) and colocalization and analysed protein cross\u2010sectional temporal patterns in ALS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In this prospective cohort study, we followed 52\u2009584 participants from the UK Biobank for a mean of 11.8\u2009years. During this period, 291 (0.55%) incident cases of ALS were identified, among whom 34 individuals carried the\n                      <jats:italic>C9orf72<\/jats:italic>\n                      hexanucleotide repeat expansion mutation. Nine proteins demonstrated associations with all\u2010type ALS risk (FDR &lt;\u20090.05): NEFL (HR: 2.897), CSRP3 (HR: 1.233), MYBPC1 (HR: 1.352), MEGF10 (HR: 1.744), MYOM3 (HR: 1.289) and THBS4 (HR: 1.570) were identified as risk factors, whereas EGFLAM (HR: 0.402), ITGAV (HR: 0.284) and CD248 (HR: 0.573) exhibited protective effects. NEFL (HR: 2.742) and three additional proteins were primarily associated with non\u2010C9\u2010ALS, while only NEFL (HR: 4.403) and COL5A1 (HR: 3.072) showed significant associations with C9\u2010ALS. When combined with age and sex, these proteins yielded area under the curve (AUC) values exceeding 0.750 for predicting ALS at 3, 5 and 10\u2009years. Furthermore, elevated NEFL levels were correlated with an earlier onset of non\u2010C9\u2010ALS and began to increase approximately 9.27\u2009years prior to diagnosis, reaching a peak 1\u20132\u2009years before clinical presentation in non\u2010C9ALS cases via cross\u2010sectional temporal analysis. Pathway analysis implicated muscle\u2010related, extracellular matrix, energy metabolism and inflammatory pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This investigation uncovers extensive alterations in plasma proteins associated with ALS risk, revealing potential novel biomarkers for both sporadic and\n                      <jats:italic>C9orf72<\/jats:italic>\n                      \u2010linked forms of the disease. These results enhance our comprehension of early ALS pathogenesis and provide a foundation for subsequent biomarker identification and the development of targeted therapeutic strategies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70405","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T01:56:27Z","timestamp":1792547787000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Plasma Proteomic Signatures Predict Incident Amyotrophic Lateral Sclerosis: A Prospective Study Stratified by\n                    <i>C9orf72<\/i>\n                    Expansion"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7935-4159","authenticated-orcid":false,"given":"Wei\u2010Ming","family":"Su","sequence":"first","affiliation":[{"name":"Department of Neurology and Institute of Neurology, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing\u2010Qing","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9708-5999","authenticated-orcid":false,"given":"Nan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng\u2010Yi","family":"He","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology, West China Hospital Sichuan University  Chengdu Sichuan 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