Plasma proteomics link menopause timing to brain aging and dementia risk

Plasma proteomics link menopause timing to brain aging and dementia risk | 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 Plasma proteomics link menopause timing to brain aging and dementia risk Madeline Wood Alexander, Brendan Wood, Hamilton Oh, Veronica Bot, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9499814/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 Earlier menopause is a risk factor for several age-related diseases, including dementia. The biological pathways linking menopause timing to later-life brain aging are not understood. Leveraging large-scale plasma proteomics in postmenopausal women from the UK Biobank (N=15,012), earlier menopause was associated with upregulation of pro-inflammatory and extracellular matrix degradation pathways, plus accelerated aging across proteomic clocks of organ and cellular aging, including brain and oligodendrocyte aging. Elevated GDF15, a canonical aging marker, was the top protein correlate of earlier menopause. We observed robust replication of menopause timing proteomic shifts in the Women’s Health Initiative Long Life Study (N=1,210). In UKB, proteins associated with earlier menopause, including GDF15, exhibited concordant associations with incident dementia risk and brain atrophy, cerebral small vessel disease burden, and white matter microstructural integrity. Collectively, our findings identify proteomic signatures linking ovarian aging to brain aging, providing a framework to inform interventions to reduce dementia risk. Biological sciences/Neuroscience/Cognitive ageing Biological sciences/Molecular biology/Proteomics Health sciences/Neurology/Neurological disorders/Dementia Health sciences/Risk factors Full Text Additional Declarations Yes there is potential Competing Interest. Competing interests: K.A.W. is an Associate Editor for Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, Alzheimer’s & Dementia: Translational Research and Clinical Interventions (TRCI), and on the Editorial Board of Annals of Clinical and Translational Neurology. K.A.W. is on the Board of Directors of the National Academy of Neuropsychology. K.A.W. has given unpaid presentations and seminars on behalf of SomaLogic. K.A.W. is the founder of Centia Bio. The work presented in this manuscript was conducted independently of Centia Bio and without financial support from the company. All efforts were performed in the government research settings. FG reports participation to an advisory board for Crinetics. Supplementary Files ageatmenopauseproteomicsExtendedData042226.xlsx Extended Data Tables ageatmenopauseproteomicsExtendedData042226.docx Extended Data Methods and Figures 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. 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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-9499814","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":631964728,"identity":"55af2675-e279-4687-8996-3128eab98e02","order_by":0,"name":"Madeline Wood 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Annals of Clinical and Translational Neurology. 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The biological pathways linking menopause timing to later-life brain aging are not understood. Leveraging large-scale plasma proteomics in postmenopausal women from the UK Biobank (N=15,012), earlier menopause was associated with upregulation of pro-inflammatory and extracellular matrix degradation pathways, plus accelerated aging across proteomic clocks of organ and cellular aging, including brain and oligodendrocyte aging. Elevated GDF15, a canonical aging marker, was the top protein correlate of earlier menopause. We observed robust replication of menopause timing proteomic shifts in the Women’s Health Initiative Long Life Study (N=1,210). In UKB, proteins associated with earlier menopause, including GDF15, exhibited concordant associations with incident dementia risk and brain atrophy, cerebral small vessel disease burden, and white matter microstructural integrity. 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