Proteomic Profiling of Cerebrospinal Fluid Identifies Immune and Synapto-Axonal ALS Subtypes

Proteomic Profiling of Cerebrospinal Fluid Identifies Immune and Synapto-Axonal ALS Subtypes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Proteomic Profiling of Cerebrospinal Fluid Identifies Immune and Synapto-Axonal ALS Subtypes Laura Tzeplaeff, Xuan Liu, Clara Meijs, Lucas Caldi Gomes, Ana Galhoz, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8731842/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease, yet therapeutic progress remains slow due to pronounced biological heterogeneity. Here, we present a high-resolution proteomic map of cerebrospinal fluid (CSF) in a clinically well-characterized cohort of 93 individuals with ALS and 101 controls, defining molecular differences. Building on this landscape, unsupervised analysis revealed two reproducible ALS subtypes: an immune-enriched alpha subtype and a synapto-axonal beta subtype, further validated in an independent cohort (n=43 ALS). The alpha subtype was associated with higher neurofilament concentrations, whereas the beta subtype showed slower disease progression, indicating distinct pathological trajectories. We further derived a five-protein classifier (PARK7, PTPRS, ATRN, CNTN1, PCSK1N) that robustly discriminated subtypes across cohorts (AUC 0.951 ± 0.007). Together, this work defines the CSF proteomic landscape of ALS and establishes a foundation for molecular stratification in precision therapy and clinical trial design. Biological sciences/Neuroscience/Diseases of the nervous system/Amyotrophic lateral sclerosis Biological sciences/Computational biology and bioinformatics/Machine learning Full Text Additional Declarations There is NO Competing Interest. Supplementary Files InventoryofSupportingInformation.pdf Inventory of Supporting Information Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8731842","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":583331595,"identity":"9a645e6e-826d-4a5e-97cf-1003a06a6c40","order_by":0,"name":"Laura 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