Non-compacted, PET-insensitive amyloid states increase after systemic inflammation and predict neuritic damage across Aβ pathology models and Alzheimer patients

Non-compacted, PET-insensitive amyloid states increase after systemic inflammation and predict neuritic damage across Aβ pathology models and Alzheimer patients | 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 Non-compacted, PET-insensitive amyloid states increase after systemic inflammation and predict neuritic damage across Aβ pathology models and Alzheimer patients Jonas Neher, Ping Liu, Ann-Christin Wendeln, Jessica Wagner, Fabian Brückner, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8269406/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 Neuroinflammation is a key modulator of Alzheimer’s disease (AD) risk, yet the impact of non-genetic inflammatory risk factors – such as systemic inflammation – remains poorly defined. Building on our previous work, here we show that 9 months after systemic lipopolysaccharide (LPS) challenge in APP23 mice, microglia-plaque interaction is disturbed and shifts Aβ aggregates toward a less compacted state, as revealed by conformation-sensitive amyloid dyes. Importantly, these structural changes are associated with increased plaque-associated neuritic dystrophy, phenocopying the effects of microglial risk genes. Generalising these findings, we show that across aging in APP23 and APPPS1 mice, and in AD patient tissue, non-compacted amyloid and microgliosis – but not compacted amyloid – are consistent predictors of neuritic damage. Notably, both in mouse and human tissue, ex vivo amyloid-PET signal largely reflects compacted but not non-compacted amyloid load. Our findings suggest that genetic and environmental risk factors converge on shared mechanisms of impaired microglial-plaque interaction and amyloid restructuring, and that commonly used amyloid-PET measures insufficiently capture amyloid states that define the severity of neuritic damage, with important implications for clinical trials in AD. Biological sciences/Neuroscience/Diseases of the nervous system/Alzheimer's disease Health sciences/Medical research/Experimental models of disease Biological sciences/Immunology/Neuroimmunology Full Text Additional Declarations Yes there is potential Competing Interest. M.B. is a member of the Neuroimaging Committee of the EANM. M.B. has received speaker honoraria from Roche, GE Healthcare, Iba, and Life Molecular Imaging; has advised Life Molecular Imaging and GE healthcare; and is currently on the advisory board of MIAC, all outside the submitted work. All other authors declare no conflict of interest. Supplementary Files Supplementarytable1patientsamplesinfo.xlsx Patient sample information 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-8269406","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":572203419,"identity":"4c8c9cee-90a6-4c8e-9067-31c4d54b3b17","order_by":0,"name":"Jonas 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