Behavioral and brain-wide neural signatures of sundowning in Alzheimer’s disease

Behavioral and brain-wide neural signatures of sundowning in Alzheimer’s disease | 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 Behavioral and brain-wide neural signatures of sundowning in Alzheimer’s disease Michelle Jin, Yujing Fu, Xinyue Chen, Holly Hunsberger, Sophia Sorid, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9272255/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 Sundowning, a common yet poorly understood neuropsychiatric syndrome in Alzheimer’s disease (AD), manifests as evening-specific increases in agitation, confusion, and anxiety. Despite its prevalence and contribution to patient distress, its neural mechanisms remain elusive. Here, we establish a preclinical model of sundowning by characterizing sleep-wake, behavioral, and network-level alterations in an AD mouse model. Aged AD mice exhibit disrupted sleep-wake patterns and reduced slow-wave sleep. Behavioral and pose-tracking analyses revealed motor agitation and a distinct sundowning-like behavioral fingerprint selectively at Sundown. The suprachiasmatic nucleus (SCN) showed disruptions in time-of-day-dependent activation of vasopressin-expressing cells and brain-wide activity-dependent tagging identified hyperconnectivity amongst sensorimotor regions in AD mice at Sundown. Resting-state fMRI data from the Alzheimer’s Disease Neuroimaging Initiative revealed analogous Salience Network alterations in AD subjects. Overall, these cross-species findings define a systems-level framework for sundowning and highlight regions that may be targeted to alleviate a debilitating symptom of AD. Biological sciences/Neuroscience/Diseases of the nervous system/Alzheimer's disease Biological sciences/Neuroscience/Circadian rhythms and sleep Biological sciences/Neuroscience/Diseases of the nervous system/Dementia immediate early gene Arc/Arg3.1 APP/PS1 sleep-wake anxiety nighttime wandering Full Text Additional Declarations There is NO Competing Interest. Supplementary Files 7TableS1.pdf Supplementary Table 1 7TableS2.pdf Supplementary Table 2 7TableS3.pdf Supplementary Table 3 7TableS4.pdf Supplementary Table 4 8VideoS1.mp4 Supplementary Video 1 8VideoS2.mp4 Supplementary Video 2 8VideoS3.mp4 Supplementary Video 3 8VideoS4.mp4 Supplementary Video 4 8VideoS5.mp4 Supplementary Video 5 8VideoS6.mp4 Supplementary Video 6 5ExtendedTable1.pdf Extended Data Table 1. 5ExtendedTable2.pdf Extended Data Table 2 5ExtendedTable3.pdf Extended Data Table 3 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-9272255","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":616081104,"identity":"41db1d74-a6ff-42e3-a866-727ff35522b7","order_by":0,"name":"Michelle Jin","email":"","orcid":"https://orcid.org/0000-0002-8696-1958","institution":"Columbia University","correspondingAuthor":false,"prefix":"","firstName":"Michelle","middleName":"","lastName":"Jin","suffix":""},{"id":616081105,"identity":"6ea147a2-edf7-48ce-a952-df3b9b00d7a8","order_by":1,"name":"Yujing Fu","email":"","orcid":"","institution":"Mailman School of Public Health, Columbia 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disease","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"immediate early gene, Arc/Arg3.1, APP/PS1, sleep-wake, anxiety, nighttime wandering","lastPublishedDoi":"10.21203/rs.3.rs-9272255/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9272255/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Sundowning, a common yet poorly understood neuropsychiatric syndrome in\r\nAlzheimer’s disease (AD), manifests as evening-specific increases in agitation,\r\nconfusion, and anxiety. Despite its prevalence and contribution to patient distress, its\r\nneural mechanisms remain elusive. Here, we establish a preclinical model of\r\nsundowning by characterizing sleep-wake, behavioral, and network-level alterations in\r\nan AD mouse model. Aged AD mice exhibit disrupted sleep-wake patterns and\r\nreduced slow-wave sleep. Behavioral and pose-tracking analyses revealed motor\r\nagitation and a distinct sundowning-like behavioral fingerprint selectively at Sundown.\r\nThe suprachiasmatic nucleus (SCN) showed disruptions in time-of-day-dependent\r\nactivation of vasopressin-expressing cells and brain-wide activity-dependent tagging\r\nidentified hyperconnectivity amongst sensorimotor regions in AD mice at Sundown.\r\nResting-state fMRI data from the Alzheimer’s Disease Neuroimaging Initiative revealed\r\nanalogous Salience Network alterations in AD subjects. Overall, these cross-species\r\nfindings define a systems-level framework for sundowning and highlight regions that\r\nmay be targeted to alleviate a debilitating symptom of AD.","manuscriptTitle":"Behavioral and brain-wide neural signatures of sundowning in Alzheimer’s disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-20 07:49:07","doi":"10.21203/rs.3.rs-9272255/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0fbe94bf-8e4e-48e9-825f-63a80c762ced","owner":[],"postedDate":"April 20th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":65560015,"name":"Biological sciences/Neuroscience/Diseases of the nervous system/Alzheimer's disease"},{"id":65560016,"name":"Biological sciences/Neuroscience/Circadian rhythms and sleep"},{"id":65560017,"name":"Biological sciences/Neuroscience/Diseases of the nervous system/Dementia"}],"tags":[],"updatedAt":"2026-04-30T21:40:06+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-20 07:49:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9272255","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9272255","identity":"rs-9272255","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}