{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:49:14Z","timestamp":1792784954295,"version":"4.5.0"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS105479, U54 NS092091"],"award-info":[{"award-number":["R01 NS105479, U54 NS092091"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS105479, U54 NS092091"],"award-info":[{"award-number":["R01 NS105479, U54 NS092091"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS105479"],"award-info":[{"award-number":["R01 NS105479"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS105479"],"award-info":[{"award-number":["R01 NS105479"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS105479, U54 NS092091"],"award-info":[{"award-number":["R01 NS105479, U54 NS092091"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["4365, 172123"],"award-info":[{"award-number":["4365, 172123"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["4365, 172123"],"award-info":[{"award-number":["4365, 172123"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["4365, 172123"],"award-info":[{"award-number":["4365, 172123"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000971","name":"Amyotrophic Lateral Sclerosis Association","doi-asserted-by":"publisher","award":["2015, 16-TACL-242"],"award-info":[{"award-number":["2015, 16-TACL-242"]}],"id":[{"id":"10.13039\/100000971","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000971","name":"Amyotrophic Lateral Sclerosis Association","doi-asserted-by":"publisher","award":["2015, 16-TACL-242"],"award-info":[{"award-number":["2015, 16-TACL-242"]}],"id":[{"id":"10.13039\/100000971","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000971","name":"Amyotrophic Lateral Sclerosis Association","doi-asserted-by":"publisher","award":["2015, 16-TACL-242"],"award-info":[{"award-number":["2015, 16-TACL-242"]}],"id":[{"id":"10.13039\/100000971","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ALS Recovery Fund and Kimmelman Estate","id":[{"id":"https:\/\/ror.org\/01zza8h42","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The study of pre-symptomatic amyotrophic lateral sclerosis (ALS) and the design of disease prevention trials are greatly hampered by our inability to predict which unaffected carriers of ALS-associated pathogenic variants will phenoconvert to clinically manifest disease and when. 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. Here we identified 92 proteins with concentrations that changed before phenoconversion; characterized the longitudinal trajectory of these proteins and identified a core panel of 19 proteins which, collectively, predicted phenoconversion over the 0.5-year to 5-year time horizons (crossvalidated areas under the curve 0.80\u20130.89) and yielded estimates of time to phenoconversion with a mean absolute error of 1.6\u2009years. These findings were partially replicated in UK Biobank data, confirming pre-symptomatic increases in several proteins (for example, NEFL, EDA2R and 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 new susceptibility\/risk biomarkers based on empirical longitudinal data furthers the ultimate goal of ALS prevention.<\/jats:p>","DOI":"10.1038\/s41591-026-04528-x","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:02:32Z","timestamp":1785142952000},"page":"3417-3429","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS"],"prefix":"10.1038","volume":"32","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"}]},{"given":"Michael P.","family":"McDermott","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"}]},{"given":"Yindi","family":"Li","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"}]},{"given":"Anne-Laure","family":"Grignon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7739-8714","authenticated-orcid":false,"given":"Elizabeth","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0408-151X","authenticated-orcid":false,"given":"Maria Catalina","family":"Fernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4068-1629","authenticated-orcid":false,"given":"Danielle","family":"Colato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":"297","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"4528_CR1","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/S1474-4422(23)00405-2","volume":"23","author":"T Simuni","year":"2024","unstructured":"Simuni, T. et al. A biological definition of neuronal alpha-synuclein disease: towards an integrated staging system for research. Lancet Neurol. 23, 178\u2013190 (2024).","journal-title":"Lancet Neurol."},{"key":"4528_CR2","doi-asserted-by":"publisher","first-page":"5143","DOI":"10.1002\/alz.13859","volume":"20","author":"CR Jack Jr.","year":"2024","unstructured":"Jack, C. R. Jr. et al. Revised criteria for diagnosis and staging of Alzheimer\u2019s disease: Alzheimer\u2019s Association Workgroup. Alzheimer\u2019s Dement. 20, 5143\u20135169 (2024).","journal-title":"Alzheimer\u2019s Dement."},{"key":"4528_CR3","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1038\/s41582-024-00961-z","volume":"20","author":"M Benatar","year":"2024","unstructured":"Benatar, M. et al. The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology. Nat. Rev. Neurol. 20, 364\u2013376 (2024).","journal-title":"Nat. Rev. Neurol."},{"key":"4528_CR4","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.jalz.2016.07.005","volume":"13","author":"RJ Bateman","year":"2017","unstructured":"Bateman, R. J. et al. The DIAN-TU next generation Alzheimer\u2019s prevention trial: adaptive design and disease progression model. Alzheimer\u2019s Dementia 13, 8\u201319 (2017).","journal-title":"Alzheimer\u2019s Dementia"},{"key":"4528_CR5","doi-asserted-by":"publisher","first-page":"228fs213","DOI":"10.1126\/scitranslmed.3007941","volume":"6","author":"RA Sperling","year":"2014","unstructured":"Sperling, R. A. et al. The A4 study: stopping AD before symptoms begin?. Sci. Transl. Med. 6, 228fs213 (2014).","journal-title":"Sci. Transl. Med."},{"key":"4528_CR6","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1136\/jnnp-2022-330473","volume":"94","author":"M Benatar","year":"2023","unstructured":"Benatar, M. et al. A roadmap to ALS prevention: strategies and priorities. J. Neurol. Neurosurg. Psychiatry 94, 399\u2013402 (2023).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"4528_CR7","doi-asserted-by":"crossref","unstructured":"Benatar, M. et al. Design considerations for C9orf72 disease prevention trials. Brain 148, 3844\u20133855 (2025).","DOI":"10.1093\/brain\/awaf290"},{"key":"4528_CR8","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1097\/WCO.0000000000001168","volume":"36","author":"M Benatar","year":"2023","unstructured":"Benatar, M., Turner, M. R. & Wuu, J. Presymptomatic amyotrophic lateral sclerosis: from characterization to prevention. Curr. Opin. Neurol. 36, 360\u2013364 (2023).","journal-title":"Curr. Opin. Neurol."},{"key":"4528_CR9","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/brain\/awab404","volume":"145","author":"M Benatar","year":"2022","unstructured":"Benatar, M. et al. Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases. Brain 145, 27\u201344 (2022).","journal-title":"Brain"},{"key":"4528_CR10","unstructured":"Bouhadoun, S., Delva, A., Schwarzschild, M. A., Postuma, R. B. Preparing for Parkinson\u2019s disease prevention trials: current progress and future directions. J. Parkinsons Dis. https:\/\/doi.org\/1877718X251334050 (2025)."},{"key":"4528_CR11","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1002\/ana.25276","volume":"84","author":"M Benatar","year":"2018","unstructured":"Benatar, M., Wuu, J., Andersen, P. M., Lombardi, V. & Malaspina, A. Neurofilament light: a candidate biomarker of pre-symptomatic ALS and phenoconversion. Ann. Neurol. 84, 130\u2013139 (2018).","journal-title":"Ann. Neurol."},{"key":"4528_CR12","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1080\/21678421.2019.1646769","volume":"20","author":"M Benatar","year":"2019","unstructured":"Benatar, M. et al. Neurofilaments in pre-symptomatic ALS and the impact of genotype. Amyotroph. Lateral Scler. Frontotemporal Degener. 20, 538\u2013548 (2019).","journal-title":"Amyotroph. Lateral Scler. Frontotemporal Degener."},{"key":"4528_CR13","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1007\/s13311-022-01237-4","volume":"19","author":"M Benatar","year":"2022","unstructured":"Benatar, M. et al. Design of a randomized, placebo-controlled, phase 3 trial of tofersen initiated in clinically presymptomatic SOD1 variant carriers: the ATLAS study. Neurotherapeutics 19, 1248\u20131258 (2022).","journal-title":"Neurotherapeutics"},{"key":"4528_CR14","unstructured":"FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource (FDA & National Institutes of Health, 2016); https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK326791\/"},{"key":"4528_CR15","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1002\/mus.24979","volume":"53","author":"M Benatar","year":"2016","unstructured":"Benatar, M. et al. ALS biomarkers for therapy development: State of the field and future directions. Muscle Nerve 53, 169\u2013182 (2016).","journal-title":"Muscle Nerve"},{"key":"4528_CR16","doi-asserted-by":"publisher","first-page":"2711","DOI":"10.1093\/brain\/awac394","volume":"146","author":"M Benatar","year":"2023","unstructured":"Benatar, M., Wuu, J. & Turner, M. R. Neurofilament light chain in drug development for amyotrophic lateral sclerosis: a critical appraisal. Brain 146, 2711\u20132716 (2023).","journal-title":"Brain"},{"key":"4528_CR17","doi-asserted-by":"publisher","first-page":"2194","DOI":"10.1038\/s41591-022-01942-9","volume":"28","author":"AM Staffaroni","year":"2022","unstructured":"Staffaroni, A. M. et al. Temporal order of clinical and biomarker changes in familial frontotemporal dementia. Nat. Med. 28, 2194\u20132206 (2022).","journal-title":"Nat. Med."},{"key":"4528_CR18","doi-asserted-by":"publisher","first-page":"1732","DOI":"10.1212\/WNL.0b013e31826e9b1d","volume":"79","author":"M Benatar","year":"2012","unstructured":"Benatar, M. & Wuu, J. Presymptomatic studies in ALS: rationale, challenges, and approach. Neurology 79, 1732\u20131739 (2012).","journal-title":"Neurology"},{"key":"4528_CR19","doi-asserted-by":"publisher","first-page":"e1001779","DOI":"10.1371\/journal.pmed.1001779","volume":"12","author":"C Sudlow","year":"2015","unstructured":"Sudlow, C. et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015).","journal-title":"PLoS Med."},{"key":"4528_CR20","doi-asserted-by":"publisher","first-page":"2295","DOI":"10.1212\/WNL.0000000000002773","volume":"86","author":"M Benatar","year":"2016","unstructured":"Benatar, M. et al. Presymptomatic ALS genetic counseling and testing: experience and recommendations. Neurology 86, 2295\u20132302 (2016).","journal-title":"Neurology"},{"key":"4528_CR21","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000213917","volume":"105","author":"M Benatar","year":"2025","unstructured":"Benatar, M. et al. Proposed research criteria for mild motor impairment as a prodromal syndrome in amyotrophic lateral sclerosis. Neurology 105, e213917 (2025).","journal-title":"Neurology"},{"key":"4528_CR22","doi-asserted-by":"crossref","unstructured":"Ashburner, M. & The Gene Ontology Consortium. Gene ontology: tool for the unification of biology. Nat. Genet. 25, 25\u201329 (2000).","DOI":"10.1038\/75556"},{"key":"4528_CR23","doi-asserted-by":"publisher","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","volume":"51","author":"D Szklarczyk","year":"2023","unstructured":"Szklarczyk, D. et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 51, D638\u2013D646 (2023).","journal-title":"Nucleic Acids Res."},{"key":"4528_CR24","unstructured":"World Health Organization. ICD-10: International Statistical Classification of Diseases and Related Health Problems: Tenth revision 2nd edn https:\/\/iris.who.int\/handle\/10665\/42980 (2004)."},{"key":"4528_CR25","doi-asserted-by":"crossref","unstructured":"Chia, R. et al. A plasma proteomics-based candidate biomarker panel predictive of amyotrophic lateral sclerosis. Nat. Med. 31, 3440\u20133450 (2025).","DOI":"10.1038\/s41591-025-03890-6"},{"key":"4528_CR26","doi-asserted-by":"publisher","unstructured":"Homann, J. et al. Redefining ALS: Large-scale proteomic profiling reveals a prolonged pre-diagnostic phase with immune, muscular, metabolic, and brain involvement. Preprint at medRxiv https:\/\/doi.org\/10.1101\/2025.08.20.25334061 (2025).","DOI":"10.1101\/2025.08.20.25334061"},{"key":"4528_CR27","doi-asserted-by":"crossref","unstructured":"Cheng, T.-H., Wei, C.-P., Tseng, V. Feature selection for medical data mining: comparisons of expert judgment and automatic approaches. In 19th IEEE Symposium on Computer-Based Medical Systems (CBMS\u201906) 165\u2013170 (2006).","DOI":"10.1109\/CBMS.2006.87"},{"key":"4528_CR28","doi-asserted-by":"publisher","first-page":"2952","DOI":"10.1007\/s00415-019-09507-6","volume":"266","author":"D Ito","year":"2019","unstructured":"Ito, D. et al. Elevated serum creatine kinase in the early stage of sporadic amyotrophic lateral sclerosis. J. Neurol. 266, 2952\u20132961 (2019).","journal-title":"J. Neurol."},{"key":"4528_CR29","doi-asserted-by":"publisher","first-page":"C441","DOI":"10.1152\/ajpcell.00200.2020","volume":"319","author":"LM Cooper","year":"2020","unstructured":"Cooper, L. M., West, R. C., Hayes, C. S. & Waddell, D. S. Dual-specificity phosphatase 29 is induced during neurogenic skeletal muscle atrophy and attenuates glucocorticoid receptor activity in muscle cell culture. Am. J. Physiol. Cell Physiol. 319, C441\u2013C454 (2020).","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"4528_CR30","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.molmed.2024.02.002","volume":"30","author":"SD Ozen","year":"2024","unstructured":"Ozen, S. D. & Kir, S. Ectodysplasin A2 receptor signaling in skeletal muscle pathophysiology. Trends Mol. Med. 30, 471\u2013483 (2024).","journal-title":"Trends Mol. Med."},{"key":"4528_CR31","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1002\/path.5149","volume":"246","author":"ITA Lechado","year":"2018","unstructured":"Lechado, I. T. A. et al. Sarcolemmal loss of active nNOS (Nos1) is an oxidative stress-dependent, early event driving disuse atrophy. J. Pathol. 246, 433\u2013446 (2018).","journal-title":"J. Pathol."},{"key":"4528_CR32","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1002\/2211-5463.13031","volume":"11","author":"C Li","year":"2021","unstructured":"Li, C. et al. Megf10 deficiency impairs skeletal muscle stem cell migration and muscle regeneration. FEBS Open Bio. 11, 114\u2013123 (2021).","journal-title":"FEBS Open Bio."},{"key":"4528_CR33","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1016\/j.nbd.2011.09.011","volume":"45","author":"C Ringer","year":"2012","unstructured":"Ringer, C., Weihe, E. & Schutz, B. Calcitonin gene-related peptide expression levels predict motor neuron vulnerability in the superoxide dismutase 1-G93A mouse model of amyotrophic lateral sclerosis. Neurobiol. Dis. 45, 547\u2013554 (2012).","journal-title":"Neurobiol. Dis."},{"key":"4528_CR34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104521","volume":"90","author":"J Dorst","year":"2023","unstructured":"Dorst, J. et al. Metabolic alterations precede neurofilament changes in presymptomatic ALS gene carriers. eBioMedicine 90, 104521 (2023).","journal-title":"eBioMedicine"},{"key":"4528_CR35","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1136\/jnnp-2020-323671","volume":"91","author":"DE Lule","year":"2020","unstructured":"Lule, D. E. et al. Deficits in verbal fluency in presymptomatic C9orf72 mutation gene carriers-a developmental disorder. J. Neurol. Neurosurg. Psychiatry 91, 1195\u20131200 (2020).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"4528_CR36","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/s42466-025-00417-9","volume":"7","author":"L Tzeplaeff","year":"2025","unstructured":"Tzeplaeff, L. et al. Identification of a presymptomatic and early disease signature for amyotrophic lateral sclerosis (ALS): protocol of the premodiALS study. Neurol. Res. Pract. 7, 56 (2025).","journal-title":"Neurol. Res. Pract."},{"key":"4528_CR37","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1080\/21678421.2024.2396831","volume":"25","author":"I Lee","year":"2024","unstructured":"Lee, I. et al. Body mass index is lower in asymptomatic C9orf72 expansion carriers but not in SOD1 pathogenic variant carriers compared to gene negatives. Amyotroph. Lateral Scler. Frontotemporal Degener. 25, 672\u2013679 (2024).","journal-title":"Amyotroph. Lateral Scler. Frontotemporal Degener."},{"key":"4528_CR38","doi-asserted-by":"publisher","first-page":"3500","DOI":"10.1093\/brain\/awac185","volume":"145","author":"M Benatar","year":"2022","unstructured":"Benatar, M. et al. Mild motor impairment as prodromal state in amyotrophic lateral sclerosis: a new diagnostic entity. Brain 145, 3500\u20133508 (2022).","journal-title":"Brain"},{"key":"4528_CR39","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1080\/21678421.2019.1587634","volume":"20","author":"M Benatar","year":"2019","unstructured":"Benatar, M., Turner, M. R. & Wuu, J. Defining pre-symptomatic amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Frontotemporal Degener. 20, 303\u2013309 (2019).","journal-title":"Amyotroph. Lateral Scler. Frontotemporal Degener."},{"key":"4528_CR40","doi-asserted-by":"publisher","first-page":"100168","DOI":"10.1016\/j.mcpro.2021.100168","volume":"20","author":"L Wik","year":"2021","unstructured":"Wik, L. et al. Proximity extension assay in combination with next-generation sequencing for high-throughput proteome-wide analysis. Mol. Cell Proteom. 20, 100168 (2021).","journal-title":"Mol. Cell Proteom."},{"key":"4528_CR41","unstructured":"PEA: Exceptional Specificity in a High Multiplex Format (Olink, 2023); https:\/\/7074596.fs1.hubspotusercontent-na1.net\/hubfs\/7074596\/000-documents\/05-white%20paper\/1337-olink-pea-exceptional-specificity-white-paper.pdf"},{"key":"4528_CR42","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","volume":"57","author":"Y Benjamini","year":"1995","unstructured":"Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Statist. Soc. Ser. B57, 289\u2013300 (1995).","journal-title":"J. R. Statist. Soc. Ser. B"},{"key":"4528_CR43","doi-asserted-by":"publisher","first-page":"W191","DOI":"10.1093\/nar\/gkz369","volume":"47","author":"U Raudvere","year":"2019","unstructured":"Raudvere, U. et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 47, W191\u2013W198 (2019).","journal-title":"Nucleic Acids Res."},{"key":"4528_CR44","doi-asserted-by":"crossref","unstructured":"Wood, S. Generalized Additive Models: An Introduction with R 2nd edn (Chapman & Hall\/CRC, 2017).","DOI":"10.1201\/9781315370279"},{"key":"4528_CR45","doi-asserted-by":"publisher","unstructured":"Marra, G, Wood, S. Coverage properties of confidence intervals for generalized additive model components. Scand. J. Stat. https:\/\/doi.org\/10.1111\/j.1467-9469.2011.00760.x (2012).","DOI":"10.1111\/j.1467-9469.2011.00760.x"},{"key":"4528_CR46","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","volume":"562","author":"C Bycroft","year":"2018","unstructured":"Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203\u2013209 (2018).","journal-title":"Nature"},{"key":"4528_CR47","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/s41586-023-06592-6","volume":"622","author":"BB Sun","year":"2023","unstructured":"Sun, B. B. et al. Plasma proteomic associations with genetics and health in the UK Biobank. Nature 622, 329\u2013338 (2023).","journal-title":"Nature"}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04528-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04528-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04528-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T14:02:18Z","timestamp":1789480938000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04528-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":47,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["4528"],"URL":"https:\/\/doi.org\/10.1038\/s41591-026-04528-x","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]},"assertion":[{"value":"1 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 August 2026","order":5,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":6,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"In the version of the article initially published, the editor recognition statement was incorrect and has been amended to \u201cPrimary Handling Editor: Jerome Staal, in collaboration with the <i>Nature Medicine<\/i> team.\u201d in the HTML and PDF versions of the article.","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"M.P.M. reports consulting fees from Abcuro, Inc. and for serving on data safety monitoring or advisory boards for the NIH, Eli Lilly & Company, Neurocrine Biosciences, Inc., ReveraGen BioPharma, Inc., NS Pharma, Inc., Prilenia Therapeutics Development, Ltd., Seelos Therapeutics, Inc., Amgen, Inc., Entrada Therapeutics, Inc. and Appello Pharmaceuticals. V.G. was an employee at Biohaven Pharmaceuticals and holds stocks and\/or stock options in the company. He is currently an employee at Cartesian where he holds stock options. P.P. heads an academic, nonprofit facility that provides fee-for-service Olink proteomics analyses to academic and industry users. A.M. reports contracts from My Name\u20195 Doddie Foundation, Target ALS, National Institute for Health and Care Research, University College London Biomedical Research Centre, LifeArc, Medical Research Council, the NIH and Motor Neurone Disease Association, Alan Davidson Foundation, Weston Family Foundation and the EU H2020 program; consulting fees from Pfizer, Novartis, LifeArc, Accure, Trace and Neuroscience; and licenses to Biogen and ILTOO and patent nos. WO2021176044 A1 and WO2024121173A1. M.B. reports consulting fees from Alaunos, Alector, Alexion, Amgen, Annexon, Arrowhead, Biogen, Bristol Myers Squibb, Canopy, Cartesian, CorEvitas, Denali, Eli Lilly, Immunovant, Janssen, Merck, Novartis, Prilenia, Roche, Sanofi, Takeda, UCB, uniQure, Voyager and Woolsey; and is an unpaid member of the Board of Trustees of the ALS Association. The University of Miami has licensed intellectual property to Biogen to support design of the ATLAS study. No support for this study was received from Olink and Olink had no role in study design, data analysis, interpretation or manuscript preparation. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}