Cerebrospinal fluid proteomic signatures reveal APOE genotype-dependent lipid and immune profiles in cognitively unimpaired elderly

Cerebrospinal fluid proteomic signatures reveal APOE genotype-dependent lipid and immune profiles in cognitively unimpaired elderly | 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 proteomic signatures reveal APOE genotype-dependent lipid and immune profiles in cognitively unimpaired elderly Guojun Bu, Zhiyuan Ning, Jeff Y.L. Lam, Zonghua Li, Yuka Martens, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8605807/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 Cerebrospinal fluid (CSF) proteomics offers insights into molecular changes in aging and Alzheimer’s disease (AD). Key AD biomarkers, in particular amyloid-β (Aβ) and tau, in CSF are strongly associated with APOE genotype, the strongest genetic risk determinant of AD. To investigate how APOE genotype influences CSF proteome across AD pathology and age, we analyzed 362 neurology-related proteins and established AD biomarkers in CSF from 145 cognitively unimpaired participants in the Mayo Clinic Study of Aging. Importantly, our cohort is uniquely balanced across APOE genotypes, with similar representation of APOE2 carriers, APOE3/3 genotype, and APOE4 carriers. We identified several proteins, including lipid metabolism-related Lp-PLA2 and immune-related ITGAM, with strong APOE genotype-specific association. Notably, meta-analysis confirmed that ITGAM levels were consistently higher in APOE4 compared to APOE2 carriers across multiple cohorts and proteomic platforms. In addition, with increasing amyloid deposition, APOE4 carriers exhibited stronger immune responses, reflected by elevated ITGAM, TNF-α receptors, and IL-6, whereas APOE2 carriers showed attenuated responses. We further observed sex-specific effects among APOE2 carriers, characterized by distinct patterns in amyloid and CXCL11 levels. These findings suggest distinct mechanisms underlying APOE2’s protective and APOE4’s detrimental effects in brain aging and AD, paving for personalized diagnostics and interventions. Biological sciences/Neuroscience/Diseases of the nervous system/Alzheimer's disease Biological sciences/Neuroscience/Cognitive ageing APOE CSF proteomics Alzheimer’s disease lipid metabolism neuroinflammation Full Text Additional Declarations Yes there is potential Competing Interest. G.B. consults for SciNeuro Pharmaceuticals. R.C.P. is a consultant for Roche Inc., Genentech Inc., Eli Lilly and Co., Eisai Inc., and Nestle Inc, and receives royalties from Oxford University Press and UpToDate and educational materials for Medscape. MV receives research support from the NIH; she currently has equity ownership in Amgen, Johnson and Johnson, Medtronic and Merck. C.-C.L. is currently an employee of Simcere of America. All other authors declare no competing interests. Supplementary Files Ning2026SICSFproteomicsignaturesrevealAPOEgenotypedependentlipidandimmuneprofilesincognitivelyunimpairedelderly.xlsx Table S1-S15 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-8605807","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":580657675,"identity":"4c86481f-bc4f-4653-9723-4aec2eadfaf8","order_by":0,"name":"Guojun Bu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAkUlEQVRIiWNgGAWjYDACCQbGByDagIcELcwGQA2kaWGTIE2LfHSPWTXPnz8M5jwHiNRieOeM2W3eNgMGy94GYrXMyAFqaQA67DyxDgNpKeb5Q4oWeYkcM2YeNqCWs8Q6zEDmWLHk3DZjHoMzB4i1ZXbzxg9v/sjJGZxJINYWqNnERySDfAPxakfBKBgFo2CkAgDgKCOn/FeIcAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-3491-1016","institution":"Mayo Clinic","correspondingAuthor":true,"prefix":"","firstName":"Guojun","middleName":"","lastName":"Bu","suffix":""},{"id":580657676,"identity":"4b3ec33a-de59-4932-b59a-e924fb738c43","order_by":1,"name":"Zhiyuan Ning","email":"","orcid":"","institution":"The Hong Kong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Zhiyuan","middleName":"","lastName":"Ning","suffix":""},{"id":580657677,"identity":"53d30054-eb29-41f2-83db-09d6878642b0","order_by":2,"name":"Jeff Y.L. 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Key AD biomarkers, in particular amyloid-β (Aβ) and tau, in CSF are strongly associated with APOE genotype, the strongest genetic risk determinant of AD. To investigate how APOE genotype influences CSF proteome across AD pathology and age, we analyzed 362 neurology-related proteins and established AD biomarkers in CSF from 145 cognitively unimpaired participants in the Mayo Clinic Study of Aging. Importantly, our cohort is uniquely balanced across APOE genotypes, with similar representation of APOE2 carriers, APOE3/3 genotype, and APOE4 carriers. We identified several proteins, including lipid metabolism-related Lp-PLA2 and immune-related ITGAM, with strong APOE genotype-specific association. Notably, meta-analysis confirmed that ITGAM levels were consistently higher in APOE4 compared to APOE2 carriers across multiple cohorts and proteomic platforms. In addition, with increasing amyloid deposition, APOE4 carriers exhibited stronger immune responses, reflected by elevated ITGAM, TNF-α receptors, and IL-6, whereas APOE2 carriers showed attenuated responses. We further observed sex-specific effects among APOE2 carriers, characterized by distinct patterns in amyloid and CXCL11 levels. 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