Sex-specific immune–brain coupling in hippocampal circuits and Alzheimer’s disease vulnerability

Sex-specific immune–brain coupling in hippocampal circuits and Alzheimer’s disease vulnerability | 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 Sex-specific immune–brain coupling in hippocampal circuits and Alzheimer’s disease vulnerability Dana Parker, Emily Yi, Whitney Tang, Alison Bamford, Lisa Taylor, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9580437/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Women face twice the lifetime risk of Alzheimer's disease (AD) compared with men. Inflammatory burden is widely implicated in AD, but whether sex-differentiated vulnerability is determined by cytokine levels or by the brain’s sensitivity to those signals remains unclear. Here, we examined sex-specific associations between peripheral inflammatory markers, medial temporal lobe (MTL) white matter microstructure using NODDI diffusion MRI, and hippocampal-dependent memory in 121 cognitively unimpaired older adults. Women exhibited widespread alterations in MTL white matter microstructure relative to men. In women, peripheral cytokines (TNFα, IL-10) were associated with microstructural variation in hippocampal-prefrontal tracts, whereas these associations were absent in men. An indirect association between TNFα and memory through hippocampal cingulum neurite density was observed only in women. Despite these microstructural and coupling differences, cytokine levels were comparable between sexes, indicating that risk may be better captured by the coupling between peripheral immune signals and circuit integrity than by cytokine levels alone. These findings identify a sex-specific pattern of immune-brain coupling that reframes inflammatory risk in AD as a property of circuit-level sensitivity rather than overall inflammatory burden. Biological sciences/Neuroscience/Diseases of the nervous system/Alzheimer's disease Biological sciences/Neuroscience/Cognitive ageing Biological sciences/Neuroscience/Neuroimmunology Biological sciences/Neuroscience/Learning and memory/Hippocampus Neuroinflammation sex differences cytokines NODDI diffusion MRI white matter hippocampal circuitry mnemonic discrimination Full Text Additional Declarations Yes there is potential Competing Interest. M.A.Y is co-founder and chief scientific advisor for Augnition Labs. Cite Share Download PDF Status: Posted 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-9580437","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":632964060,"identity":"a94b6540-18fa-4585-b95c-3d28333bf72b","order_by":0,"name":"Dana 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