Polygenic risk for Alzheimer’s disease shapes microglial inflammatory and antigen-presentation programs in vivo

Polygenic risk for Alzheimer’s disease shapes microglial inflammatory and antigen-presentation programs in vivo | 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 Biological Sciences - Article Polygenic risk for Alzheimer’s disease shapes microglial inflammatory and antigen-presentation programs in vivo Bart De Strooper, Annerieke Sierksma, Daan Moechars, Sarah Borrie, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7794221/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 How polygenic risk translates into cellular dysfunction remains largely unknown in Alzheimer’s disease and related disorders. Here, we selected 31 donors broadly spanning the Caucasian-based polygenic risk distribution for AD and show that human polygenic architecture modulates microglial immune responses to amyloid pathology in vivo. We developed a “microglia village” model by xenotransplanting pooled iPSC-derived microglia from these genetically diverse donors into amyloid-bearing (AppNLGF) and control (AppHu) mouse brains, allowing the effect of genetic background to be separated from shared environmental influences. Marked inter-donor transcriptomic differences were observed in hMG derived from homeostatic, non-amyloid brain environments, demonstrating divergent baseline states across individuals. Amyloid exposure induced highly varied expression of MHC class II genes across donor, which correlated with individual’s AD polygenic risk scores. These findings demonstrate that polygenic risk can be decoded into functional immune phenotypes in human microglia and establish a scalable in vivo platform to dissect the genetic regulation of cellular responses in complex brain disorders. Biological sciences/Neuroscience/Molecular neuroscience Biological sciences/Neuroscience/Glial biology/Microglia Biological sciences/Genetics/Functional genomics/Gene expression profiling Health sciences/Medical research/Experimental models of disease Health sciences/Neurology/Neurological disorders/Dementia/Alzheimer's disease Full Text Additional Declarations Yes there is potential Competing Interest. B.D.S. has been a consultant for Eli Lilly, Biogen, Janssen Pharmaceutica, Eisai, AbbVie and other companies and is now consultant to Muna Therapeutics. B.D.S is a scientific founder of Augustine Therapeutics and a scientific founder and stockholder of Muna Therapeutics. M.F. is a consultant to Muna Therapeutics. R.V.’s institution has clinical trial agreements (R.V. as PI) with Alector, AviadoBio, BMS, Eli Lilly, Johnson & Johnson, and UCB. R.V.’s institution has consultancy agreements (R.V. as DSMB/DMC member) with AC Immune and Novartis. D.R.T. received consultant fees from Muna Therapeutics and collaborated with Novartis Pharma AG and GE-Healthcare. All other authors have no competing interests. Supplementary Files SupplTablesNatureSierksmaMoecharsBorrie.xlsx Supplementary Tables S1-S9 20251002PRSFigsNaturefinal.pdf 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-7794221","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":541640223,"identity":"a067db23-84e9-46a3-92f6-fc332cd0a55f","order_by":0,"name":"Bart De Strooper","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYBACAwST+QADQwGERUgLYwOEyZYAM4FoLTwGxGkxZ2B//riiwiaPX/rMN4kfBgzy/A08xgb4tFg28Bg2njmTVizZl7tNsseAwXDGAR7jBLwOO8DD2NjYdjhxwxnebdJAhzFuYOAxPoBfC/tDsJb9Z3iegbTYE6GFwRBiCw8PG0hLIkgLXodZNvMYzmwA+kXiDJuxZY+BRPKMw2zFeL1vzt7+4GMDKMR6mB/e+FFhY9vf3rxZAp8WWBzAnCJBKFYQAK/rR8EoGAWjYIQDANeLQCCZ14VjAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-5455-5819","institution":"VIB/KU Leuven Center for Brain \u0026 Disease Research and UKDRI/University College London, UK","correspondingAuthor":true,"prefix":"","firstName":"Bart","middleName":"","lastName":"De Strooper","suffix":""},{"id":541640224,"identity":"4137896e-610c-4044-afad-fe5bc05f9f7d","order_by":1,"name":"Annerieke Sierksma","email":"","orcid":"https://orcid.org/0000-0001-9233-972X","institution":"VIB Center for the Biology of Disease, Leuven, Belgium Center for Human Genetics, Universitaire ziekenhuizen and LIND, KU, Leuven, Belgium.","correspondingAuthor":false,"prefix":"","firstName":"Annerieke","middleName":"","lastName":"Sierksma","suffix":""},{"id":541640225,"identity":"64ca1b47-38c3-4689-8b84-3367f3fe4856","order_by":2,"name":"Daan Moechars","email":"","orcid":"","institution":"VIB KU Leuven","correspondingAuthor":false,"prefix":"","firstName":"Daan","middleName":"","lastName":"Moechars","suffix":""},{"id":541640226,"identity":"e838483f-96f3-41cc-931b-6444365453f8","order_by":3,"name":"Sarah Borrie","email":"","orcid":"https://orcid.org/0000-0002-6880-772X","institution":"VIB/KU Leuven Center for Brain \u0026 Disease Research","correspondingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"","lastName":"Borrie","suffix":""},{"id":541640227,"identity":"3a0ffbc2-499f-47b7-94fa-9d9b8fc53387","order_by":4,"name":"An Snellinx","email":"","orcid":"","institution":"KU Leuven","correspondingAuthor":false,"prefix":"","firstName":"An","middleName":"","lastName":"Snellinx","suffix":""},{"id":541640228,"identity":"66386ab8-fcfd-458b-bee6-8a12f35be2e7","order_by":5,"name":"Pierre Bourdely","email":"","orcid":"","institution":"VIB/KU Leuven Center for Cancer Biology","correspondingAuthor":false,"prefix":"","firstName":"Pierre","middleName":"","lastName":"Bourdely","suffix":""},{"id":541640229,"identity":"6a35674d-c32c-40ba-b90d-489d121a25f9","order_by":6,"name":"Nicola Thrupp","email":"","orcid":"","institution":"VIB/KU Leuven Center for Brain \u0026 Disease Research","correspondingAuthor":false,"prefix":"","firstName":"Nicola","middleName":"","lastName":"Thrupp","suffix":""},{"id":541640230,"identity":"2af4deeb-14bb-4484-a088-dab5bd928fed","order_by":7,"name":"Sebastiaan Moonen","email":"","orcid":"","institution":"VIB/KU Leuven Center for Brain \u0026 Disease Research","correspondingAuthor":false,"prefix":"","firstName":"Sebastiaan","middleName":"","lastName":"Moonen","suffix":""},{"id":541640231,"identity":"442a1614-b1ae-49fe-84a8-24079feedb00","order_by":8,"name":"Emanuela Pasciuto","email":"","orcid":"","institution":"VIB/UAntwerpen Center for Molecular Neurology","correspondingAuthor":false,"prefix":"","firstName":"Emanuela","middleName":"","lastName":"Pasciuto","suffix":""},{"id":541640232,"identity":"eaee4a78-0057-4c0e-8e7a-cc9953e7627a","order_by":9,"name":"Stephanie Humblet-Baron","email":"","orcid":"","institution":"KU Leuven","correspondingAuthor":false,"prefix":"","firstName":"Stephanie","middleName":"","lastName":"Humblet-Baron","suffix":""},{"id":541640233,"identity":"d808c98e-b5c8-40f1-b78d-03cfea2dd5d4","order_by":10,"name":"Joshua Stevenson-Hoare","email":"","orcid":"","institution":"Cardiff University","correspondingAuthor":false,"prefix":"","firstName":"Joshua","middleName":"","lastName":"Stevenson-Hoare","suffix":""},{"id":541640234,"identity":"642c3d96-95c1-4102-a80e-4fa1226f5381","order_by":11,"name":"Emily Simmonds","email":"","orcid":"","institution":"UK DRI - Cardiff University","correspondingAuthor":false,"prefix":"","firstName":"Emily","middleName":"","lastName":"Simmonds","suffix":""},{"id":541640235,"identity":"e2ace608-7813-4017-85b7-e34d3cf2a52d","order_by":12,"name":"Dietmar Thal","email":"","orcid":"https://orcid.org/0000-0002-1036-1075","institution":"University Hospitals Leuven","correspondingAuthor":false,"prefix":"","firstName":"Dietmar","middleName":"","lastName":"Thal","suffix":""},{"id":541640236,"identity":"8387893a-896c-44d4-b863-7d057008c976","order_by":13,"name":"Massimiliano Mazzone","email":"","orcid":"https://orcid.org/0000-0001-8824-4015","institution":"VIB-KU Leuven","correspondingAuthor":false,"prefix":"","firstName":"Massimiliano","middleName":"","lastName":"Mazzone","suffix":""},{"id":541640237,"identity":"f009eebc-d4ee-4ffd-9acc-5bb3eccf2d2d","order_by":14,"name":"Tracy Young-Pearse","email":"","orcid":"https://orcid.org/0000-0001-7846-1542","institution":"Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Tracy","middleName":"","lastName":"Young-Pearse","suffix":""},{"id":541640238,"identity":"8be64ae8-6259-4f1f-a44e-b26d310539a3","order_by":15,"name":"Rik Vandenberghe","email":"","orcid":"https://orcid.org/0000-0001-6237-2502","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Rik","middleName":"","lastName":"Vandenberghe","suffix":""},{"id":541640239,"identity":"92432cab-db11-49fc-a2d1-162876773454","order_by":16,"name":"Valentina Escott-Price","email":"","orcid":"https://orcid.org/0000-0003-1784-5483","institution":"Cardiff University","correspondingAuthor":false,"prefix":"","firstName":"Valentina","middleName":"","lastName":"Escott-Price","suffix":""},{"id":541640240,"identity":"d008e3c8-8308-47c2-9d05-269958d9d6e3","order_by":17,"name":"Mark Fiers","email":"","orcid":"","institution":"VIB/KU Leuven Center for Brain \u0026 Disease Research","correspondingAuthor":false,"prefix":"","firstName":"Mark","middleName":"","lastName":"Fiers","suffix":""}],"badges":[],"createdAt":"2025-10-06 20:50:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7794221/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7794221/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104402808,"identity":"09a8c8a4-8654-403b-be5d-85efd97cb65d","added_by":"auto","created_at":"2026-03-11 12:16:32","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1753102,"visible":true,"origin":"","legend":"Article File","description":"","filename":"20251006SierksmaNatureFinal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7794221/v1_covered_f074b1b0-cc54-442c-be18-c6fde7ce77ca.pdf"},{"id":95516460,"identity":"4e36ac6e-321c-448c-bc22-a0f4e39f4abe","added_by":"auto","created_at":"2025-11-10 08:35:10","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1200444,"visible":true,"origin":"","legend":"Supplementary Tables S1-S9","description":"","filename":"SupplTablesNatureSierksmaMoecharsBorrie.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7794221/v1/1a3791d3f8299d0eca3aa07d.xlsx"},{"id":95516461,"identity":"e6cb09d0-f2a4-4d32-a51e-4c63ddbb9c13","added_by":"auto","created_at":"2025-11-10 08:35:10","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":5087463,"visible":true,"origin":"","legend":"","description":"","filename":"20251002PRSFigsNaturefinal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7794221/v1/e98af9d23946ca29d85601b0.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nB.D.S. has been a consultant for Eli Lilly, Biogen, Janssen Pharmaceutica, Eisai, AbbVie and other companies and is now consultant to Muna Therapeutics. B.D.S is a scientific founder of Augustine Therapeutics and a scientific founder and stockholder of Muna Therapeutics. M.F. is a consultant to Muna Therapeutics. R.V.’s institution has clinical trial agreements (R.V. as PI) with Alector, AviadoBio, BMS, Eli Lilly, Johnson \u0026 Johnson, and UCB. R.V.’s institution has consultancy agreements (R.V. as DSMB/DMC member) with AC Immune and Novartis. D.R.T. received consultant fees from Muna Therapeutics and collaborated with Novartis Pharma AG and GE-Healthcare. All other authors have no competing interests.","formattedTitle":"Polygenic risk for Alzheimer’s disease shapes microglial inflammatory and antigen-presentation programs in vivo","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7794221/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7794221/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"How polygenic risk translates into cellular dysfunction remains largely unknown in Alzheimer’s disease and related disorders. Here, we selected 31 donors broadly spanning the Caucasian-based polygenic risk distribution for AD and show that human polygenic architecture modulates microglial immune responses to amyloid pathology in vivo. We developed a “microglia village” model by xenotransplanting pooled iPSC-derived microglia from these genetically diverse donors into amyloid-bearing (AppNLGF) and control (AppHu) mouse brains, allowing the effect of genetic background to be separated from shared environmental influences. Marked inter-donor transcriptomic differences were observed in hMG derived from homeostatic, non-amyloid brain environments, demonstrating divergent baseline states across individuals. Amyloid exposure induced highly varied expression of MHC class II genes across donor, which correlated with individual’s AD polygenic risk scores. These findings demonstrate that polygenic risk can be decoded into functional immune phenotypes in human microglia and establish a scalable in vivo platform to dissect the genetic regulation of cellular responses in complex brain disorders.","manuscriptTitle":"Polygenic risk for Alzheimer’s disease shapes microglial inflammatory and antigen-presentation programs in vivo","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-10 08:35:06","doi":"10.21203/rs.3.rs-7794221/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f81e4e47-c4ae-427e-95a8-476e4424703e","owner":[],"postedDate":"November 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":57627501,"name":"Biological sciences/Neuroscience/Molecular neuroscience"},{"id":57627502,"name":"Biological sciences/Neuroscience/Glial biology/Microglia"},{"id":57627503,"name":"Biological sciences/Genetics/Functional genomics/Gene expression profiling"},{"id":57627504,"name":"Health sciences/Medical research/Experimental models of disease"},{"id":57627505,"name":"Health sciences/Neurology/Neurological disorders/Dementia/Alzheimer's disease"}],"tags":[],"updatedAt":"2026-03-05T14:27:52+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-10 08:35:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7794221","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7794221","identity":"rs-7794221","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}