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In this longitudinal Olink Explore high-throughput proteomic study, 516 serially collected plasma samples from 33 phenoconverters, 35 patients with ALS, 10 pre-symptomatic pathogenic variant carriers and 59 controls were included. We identified 81 proteins whose concentrations changed prior to phenoconversion; characterized the longitudinal trajectory of these proteins; and identified a core panel of 19 proteins that, collectively, predicted phenoconversion over the 0.5- to 5-year time horizons (areas under curve 0.80-0.89) and yielded estimates of time-to-phenoconversion with a mean absolute error of 1.6 years. These findings were replicated in UK Biobank data, confirming pre-symptomatic increases in several proteins (e.g. NEFL, EDA2R, CA3) and that a multi-protein panel outperformed NEFL alone in estimating time-to-phenoconversion. This work sheds light on the biology of pre-symptomatic ALS. Moreover, our identification of a panel of novel susceptibility\/risk biomarkers based on empirical longitudinal data furthers the ultimate goal of ALS prevention.<\/jats:p>","DOI":"10.64898\/2025.12.06.25341403","type":"posted-content","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T11:20:23Z","timestamp":1765279223000},"source":"Crossref","is-referenced-by-count":4,"title":["Predicting Phenoconversion to Clinically Manifest ALS: Results of a Large-Scale Proteomic Study"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5414-1885","authenticated-orcid":false,"given":"Ximing","family":"Ran","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9643-9855","authenticated-orcid":false,"given":"Joanne","family":"Wuu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1583-146X","authenticated-orcid":false,"given":"Zhaohui S.","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0873-8689","authenticated-orcid":false,"given":"Johnathan","family":"Cooper-Knock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6519-7225","authenticated-orcid":false,"given":"Volkan","family":"Granit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7167-5983","authenticated-orcid":false,"given":"Anne-Laure","family":"Grignon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yindi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliza","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Catalina","family":"Fernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Colato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9194-3247","authenticated-orcid":false,"given":"Nathan","family":"Carberry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2805-1307","authenticated-orcid":false,"given":"Christina M.","family":"Lill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3736-1841","authenticated-orcid":false,"given":"Paolo","family":"Piazza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8020-7567","authenticated-orcid":false,"given":"Andrea","family":"Malaspina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4241-5135","authenticated-orcid":false,"given":"Michael","family":"Benatar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025121004402222000_2025.12.06.25341403v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00405-2"},{"key":"2025121004402222000_2025.12.06.25341403v1.2","doi-asserted-by":"crossref","first-page":"5143","DOI":"10.1002\/alz.13859","article-title":"Revised criteria for diagnosis and staging of Alzheimer\u2019s disease: Alzheimer\u2019s Association Workgroup","volume":"20","year":"2024","journal-title":"Alzheimer\u2019s & dementia : the journal of the Alzheimer\u2019s Association"},{"key":"2025121004402222000_2025.12.06.25341403v1.3","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1038\/s41582-024-00961-z","article-title":"The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology","volume":"20","year":"2024","journal-title":"Nature reviews Neurology"},{"key":"2025121004402222000_2025.12.06.25341403v1.4","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.jalz.2016.07.005","article-title":"The DIAN-TU Next Generation Alzheimer\u2019s prevention trial: Adaptive design and disease progression model","volume":"13","year":"2017","journal-title":"Alzheimer\u2019s & dementia : the journal of the Alzheimer\u2019s Association"},{"key":"2025121004402222000_2025.12.06.25341403v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3007941"},{"key":"2025121004402222000_2025.12.06.25341403v1.6","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2022-330473"},{"key":"2025121004402222000_2025.12.06.25341403v1.7","unstructured":"Benatar M , Staffaroni AM , Wuu J , et al. 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