Hierarchical Reconfiguration of Interhemispheric Dialogue in Alzheimer’s Disease: A Multicenter Analysis

Hierarchical Reconfiguration of Interhemispheric Dialogue in Alzheimer’s Disease: A Multicenter Analysis | 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 Research Article Hierarchical Reconfiguration of Interhemispheric Dialogue in Alzheimer’s Disease: A Multicenter Analysis Chonggang Tong, Yuwei Su, Wenjiang Zhang, Pinyuan Hu, Cui Zhao, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8313664/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Homotopic functional connectivity (HFC) reflects direct communication between corresponding brain hemispheres, enabling seamless information integration. Previous studies have highlighted the potential role of hemispheric asymmetry in AD, yet the specific alterations in HFC and its potential as a neuroimage biomarker remain relatively unexplored. Methods The study consists of 799 subjects from 7 sites with 289 AD, 253 mild cognitive impairment (MCI) and 257 normal controls (NC). Structural measures, including gray matter volume (GMV), fraction dimension (FD), cortical thickness (CT), sulci Depth (SD) and gyral index (GI), and HFC were measured for all participants, along with the clinical symptoms, Mini-Mental State Examination (MMSE). Results AD exhibited an anterior-posterior hierarchical reconfiguration of HFC with the systematic reduced HFC in the posterior and subcortical regions, but a focal increased HFC exclusively within the prefrontal cortex. Genetic association analyses linked pathways of neurodegeneration multiple diseases to the hierarchical reconfiguration of HFC of AD. Moreover, the hierarchical reconfiguration of HFC was a robust AD neuroimaging biomarker with an averaged ACC of 74.5% and with performance significantly enhanced the most 12.9% with structural measures. Conclusions HFC exhibits widespread reduction in AD, and this alteration demonstrates significant associations with underlying genetic correlates and clinical measures. The potential of HFC as a biomarker for AD is furtherly showcased across multi-modal classification and prediction models, opening new avenues for further research and clinical applications. Alzheimer’s disease Asymmetry Homotopic functional connectivity Multimodal Multicenter Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterials.pdf Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 23 Mar, 2026 Reviews received at journal 23 Feb, 2026 Reviews received at journal 29 Jan, 2026 Reviewers agreed at journal 14 Jan, 2026 Reviewers agreed at journal 08 Jan, 2026 Reviewers agreed at journal 29 Dec, 2025 Reviewers invited by journal 10 Dec, 2025 Editor assigned by journal 09 Dec, 2025 Submission checks completed at journal 09 Dec, 2025 First submitted to journal 09 Dec, 2025 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-8313664","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":559511944,"identity":"c1aa281d-c832-4eab-8648-bbabc441490e","order_by":0,"name":"Chonggang Tong","email":"","orcid":"","institution":"Beijing University of Posts and Telecommunications","correspondingAuthor":false,"prefix":"","firstName":"Chonggang","middleName":"","lastName":"Tong","suffix":""},{"id":559511945,"identity":"4db73fdb-2480-4ad6-a0bc-978be8948ac8","order_by":1,"name":"Yuwei Su","email":"","orcid":"","institution":"Beijing University of Posts and 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Analysis","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Alzheimer’s disease, Asymmetry, Homotopic functional connectivity, Multimodal, Multicenter","lastPublishedDoi":"10.21203/rs.3.rs-8313664/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8313664/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eAlzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Homotopic functional connectivity (HFC) reflects direct communication between corresponding brain hemispheres, enabling seamless information integration. Previous studies have highlighted the potential role of hemispheric asymmetry in AD, yet the specific alterations in HFC and its potential as a neuroimage biomarker remain relatively unexplored.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThe study consists of 799 subjects from 7 sites with 289 AD, 253 mild cognitive impairment (MCI) and 257 normal controls (NC). Structural measures, including gray matter volume (GMV), fraction dimension (FD), cortical thickness (CT), sulci Depth (SD) and gyral index (GI), and HFC were measured for all participants, along with the clinical symptoms, Mini-Mental State Examination (MMSE).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAD exhibited an anterior-posterior hierarchical reconfiguration of HFC with the systematic reduced HFC in the posterior and subcortical regions, but a focal increased HFC exclusively within the prefrontal cortex. Genetic association analyses linked pathways of neurodegeneration multiple diseases to the hierarchical reconfiguration of HFC of AD. Moreover, the hierarchical reconfiguration of HFC was a robust AD neuroimaging biomarker with an averaged ACC of 74.5% and with performance significantly enhanced the most 12.9% with structural measures.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eHFC exhibits widespread reduction in AD, and this alteration demonstrates significant associations with underlying genetic correlates and clinical measures. The potential of HFC as a biomarker for AD is furtherly showcased across multi-modal classification and prediction models, opening new avenues for further research and clinical applications.\u003c/p\u003e","manuscriptTitle":"Hierarchical Reconfiguration of Interhemispheric Dialogue in Alzheimer’s Disease: A Multicenter Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-15 22:46:12","doi":"10.21203/rs.3.rs-8313664/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-23T10:25:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-24T04:47:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-29T18:06:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"159834069572870541495557190560192608022","date":"2026-01-15T03:32:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"323876776797581090649622949694070089716","date":"2026-01-08T16:25:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"66215596821813751334585141420592975791","date":"2025-12-29T14:36:15+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-10T12:04:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-09T07:12:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-09T07:08:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Medicine","date":"2025-12-09T05:59:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2398a385-fae5-49b8-98ae-d85669aace82","owner":[],"postedDate":"December 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-14T09:41:08+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-15 22:46:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8313664","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8313664","identity":"rs-8313664","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}