Cerebrospinal Fluid (CSF) Proteomic Signature in Preclinical and Clinical AD: Role of Adhesion Molecules.

Cerebrospinal Fluid (CSF) Proteomic Signature in Preclinical and Clinical AD: Role of Adhesion Molecules. | 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 Cerebrospinal Fluid (CSF) Proteomic Signature in Preclinical and Clinical AD: Role of Adhesion Molecules. Ihab Hajjar, Reem Neal, Zhiyi Yang, Malik Obideen, Melissa Peterson, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5404760/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 Background: Although Amyloid-beta and Tau are the hallmarks of Alzheimer’s Disease (AD), other protein pathways such as endothelial dysfunction may be involved and may precede cognitive symptoms. Our objective was to characterize the cerebrospinal fluid (CSF) proteomic profiles focusing on cardiometabolic-related protein pathways in individuals on the AD spectrum. Methods: We performed CSF and plasma-targeted proteomics (276 proteins) from 354 participants of the Brain Stress Hypertension and Aging Program (BSHARP), of which 8% had preclinical AD, and 24% had MCI due to AD. We instituted a bioinformatic pipeline to generate data-driven protein modules, used “Hub” and "Critical” proteins within each module to describe protein signatures for each AD stage and then assessed their associations with clinical and biological AD traits. Finally, we completed pathway enrichment analysis to get insight into pathways that might be implicated in AD pathogenesis. Results: The 276 measured proteins clustered into five modules that were associated with CSF Amyloid-β42, Tau, and pTau. (all p-value <0.05). A CSF protein AD signature was characterized by elevated levels of CSF Hepatocyte Growth Factor (HGF), Intercellular and Vascular Cell Adhesion Molecule 1 (ICAM-1, VCAM-1), Neuropilin 1 and 2 (NRP-1, NRP-2), Scavenger Receptor Class B Member 2(SCARB2), Plasminogen Activator, Urokinase (PLAU). (all <0.05) We also found a significant difference in the CSF/Plasma ratio for the proteins associated with Cognitive Status and the Tau/Aβ42 ratio (TAR) in the CSF. Pathway enrichment analysis revealed that cell adhesion and endothelial dysfuncton(all p-value <0.05) were key mechanisms involved in AD pathogenesis, especially in the preclinical stage. Conclusion: Our results suggest a proteomic signature in the CSF of individuals with preclinical AD that is driven by adhesion molecules and might be implicated in the pathogenesis of AD. Future studies investigating these pathways may provide insights into novel AD biomarkers and therapeutic targets. Health sciences/Diseases/Neurological disorders/Neurodegeneration Biological sciences/Molecular biology/Proteomics/Protein–protein interaction networks Health sciences/Medical research/Biomarkers Full Text Additional Declarations There is NO Competing Interest. Supplementary Files AdhesionpapersuppFinal11062024.docx 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-5404760","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":391416206,"identity":"143023ea-1d0c-442e-8b10-8d0c48996b1e","order_by":0,"name":"Ihab 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Our objective was to characterize the cerebrospinal fluid (CSF) proteomic profiles focusing on cardiometabolic-related protein pathways in individuals on the AD spectrum.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethods: We performed CSF and plasma-targeted proteomics (276 proteins) from 354 participants of the Brain Stress Hypertension and Aging Program (BSHARP), of which 8% had preclinical AD, and 24% had MCI due to AD. We instituted a bioinformatic pipeline to generate data-driven protein modules, used “Hub” and \"Critical” proteins within each module to describe protein signatures for each AD stage and then assessed their associations with clinical and biological AD traits. Finally, we completed pathway enrichment analysis to get insight into pathways that might be implicated in AD pathogenesis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults: The 276 measured proteins clustered into five modules that were associated with CSF Amyloid-β42, Tau, and pTau. (all p-value \u0026lt;0.05). A CSF protein AD signature was characterized by elevated levels of CSF Hepatocyte Growth Factor (HGF), Intercellular and Vascular Cell Adhesion Molecule 1 (ICAM-1, VCAM-1), Neuropilin 1 and 2 (NRP-1, NRP-2), Scavenger Receptor Class B Member 2(SCARB2), Plasminogen Activator, Urokinase (PLAU). (all \u0026lt;0.05) We also found a significant difference in the CSF/Plasma ratio for the proteins associated with Cognitive Status and the Tau/Aβ42 ratio (TAR) in the CSF. Pathway enrichment analysis revealed that cell adhesion and endothelial dysfuncton(all p-value \u0026lt;0.05) were key mechanisms involved in AD pathogenesis, especially in the preclinical stage.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusion: Our results suggest a proteomic signature in the CSF of individuals with preclinical AD that is driven by adhesion molecules and might be implicated in the pathogenesis of AD. Future studies investigating these pathways may provide insights into novel AD biomarkers and therapeutic targets.\u003c/p\u003e","manuscriptTitle":"Cerebrospinal Fluid (CSF) Proteomic Signature in Preclinical and Clinical AD: Role of Adhesion Molecules.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-16 05:29:38","doi":"10.21203/rs.3.rs-5404760/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsmed","sideBox":"Learn more about [Communications Medicine](http://www.nature.com/commsmed)","snPcode":"43856","submissionUrl":"https://mts-commsmed.nature.com/cgi-bin/main.plex","title":"Communications Medicine","twitterHandle":"@commsmedicine","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1fecf405-a216-48d3-bcc9-a52b33cea9f0","owner":[],"postedDate":"January 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":41718473,"name":"Health sciences/Diseases/Neurological disorders/Neurodegeneration"},{"id":41718474,"name":"Biological sciences/Molecular biology/Proteomics/Protein\u0026#x2013;protein interaction networks"},{"id":41718475,"name":"Health sciences/Medical research/Biomarkers"}],"tags":[],"updatedAt":"2025-01-16T05:29:38+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-16 05:29:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5404760","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5404760","identity":"rs-5404760","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}