Minimal levels of amyloid accumulation in the brains of cognitively unimpaired individuals are associated with long-term cognitive impairment up to 20 years later

Minimal levels of amyloid accumulation in the brains of cognitively unimpaired individuals are associated with long-term cognitive impairment up to 20 years later | 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 Minimal levels of amyloid accumulation in the brains of cognitively unimpaired individuals are associated with long-term cognitive impairment up to 20 years later Chengjie Xiong, Jingqin Luo, Sarah Hartz, Suzanne Schindler, Walter Kukull, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8928856/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 The minimal amyloid accumulation (MAA) in cognitively unimpaired individuals that predicts the onset of cognitive impairment remains unknown. In a multi-center amyloid positron emission tomography (PET) study of 1834 cognitively unimpaired participants with longitudinal clinical/cognitive assessments for up to 20.3 years, we found that 48.7% of the amyloid-negative participants with MAA starting from an amyloid PET centiloid of 1.03 had a higher risk of cognitive impairment than those with the lowest centiloid values (20; HR=0.47, p<0.0001). Amyloid positivity was also associated with the fastest longitudinal amyloid accumulation and cognitive decline, followed by the MAA, and finally by the lowest amyloid. These findings suggest that current thresholds of amyloid positivity used for Alzheimer disease diagnosis may be overly restrictive, potentially excluding a large portion of amyloid-negative participants at elevated risk of developing cognitive impairment from prevention trials. Biological sciences/Neuroscience/Neural ageing Health sciences/Neurology/Neurological disorders/Dementia/Alzheimer's disease Biological sciences/Neuroscience/Cognitive ageing Full Text Additional Declarations Yes there is potential Competing Interest. SES has not received any financial compensation from pharmaceutical or diagnostics companies since 2024, when she received honoraria for serving on scientific advisory boards on biomarker testing and education for Eisai and Novo Nordisk and speaking fees from Eisai, Eli Lilly, and Novo Nordisk. She has recently received honoraria for educational presentations from Medscape, PeerView, and the Academy for Continued Healthcare Learning. She has provided unpaid scientific advising to Acumen, Biogen, Cognito Therapeutics, Danaher, Eisai, Eli Lilly, Johnson and Johnson Innovative Medicine, Sanofi, and Siemens. DAW has served as a paid consultant for Beckman Coulter and serves on a DSMB for GSK. ER serves on a data monitoring committee for Eli Lilly. TB participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Janssen, and Roche. TB participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Janssen, and Roche. RAS has served as a consultant for AbbVie, AC Immune, Acumen, Alector, Apellis, Biohaven, Bristol Myers Squibb, Ionis, Janssen, Oligomerix, Prothena, Roche and Vaxxinity over the past 3 years, and has received research funding from Eisai and Eli Lilly for public-private partnership trials. DMH co-founded, has equity, and is on the scientific advisory board of C2N Diagnostics. DMH is on the scientific advisory boards of Denali, Genentech, and Switch and consults for Novartis and Pfizer. SCJ has served on advisory boards for Lantheus, Lilly, Enigma, Alamar, Alzpath and 331 Trillium bio. JH has served as a paid consultant for Prothena, Abbvie, and Quanterix. The other Authors declare no Competing Financial or Non-Financial Interests. This work was supported in part by funding from the National Institutes of Health (grant #AG067505). WU has a financial interest in C2N Diagnostics and may financially benefit if the company is successful in marketing its product(s) that is/are related to this research. 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-8928856","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":598324505,"identity":"99a267c9-0251-4208-828f-aff0f1834760","order_by":0,"name":"Chengjie Xiong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIiWNgGAWjYDACCRDBI8HAD+YVAPEBYrVINoBUGxCtBQgMDhCrhX9287GHX2Qs5Ixv5Bh//mDAIMd3I4GAJXeOpRvL8EgYm93IMZMA2mIsSUiLgUSOmbQEj0Titts5ZiCHJW4grCX/G0hL/ebZOcYfgFrqidCSwyb5gUciwUA6xwDksAQDgn65kWYmDQxkwxn3n5VJnDGQMJx55gF+Lfwzkp9J/uypk+fvObz5Q0WFjTzfcQK2gAAzbw/CVsLKQYDxxw/iFI6CUTAKRsEIBQBsIEGcCeoygwAAAABJRU5ErkJggg==","orcid":"","institution":"Washington University in St. Louis","correspondingAuthor":true,"prefix":"","firstName":"Chengjie","middleName":"","lastName":"Xiong","suffix":""},{"id":598324506,"identity":"74001298-a547-4ceb-bc41-b691c7aed11d","order_by":1,"name":"Jingqin Luo","email":"","orcid":"https://orcid.org/0000-0003-2759-3072","institution":"Washington University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jingqin","middleName":"","lastName":"Luo","suffix":""},{"id":598324507,"identity":"cc7dad66-1130-4592-b26d-dc04d7c73167","order_by":2,"name":"Sarah Hartz","email":"","orcid":"","institution":"Washington University School of Medicine - 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She has recently received honoraria for educational presentations from Medscape, PeerView, and the Academy for Continued Healthcare Learning. She has provided unpaid scientific advising to Acumen, Biogen, Cognito Therapeutics, Danaher, Eisai, Eli Lilly, Johnson and Johnson Innovative Medicine, Sanofi, and Siemens. DAW has served as a paid consultant for Beckman Coulter and serves on a DSMB for GSK. ER serves on a data monitoring committee for Eli Lilly. TB participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Janssen, and Roche. TB participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Janssen, and Roche. RAS has served as a consultant for AbbVie, AC Immune, Acumen, Alector, Apellis, Biohaven, Bristol Myers Squibb, Ionis, Janssen, Oligomerix, Prothena, Roche and Vaxxinity over the past 3 years, and has received research funding from Eisai and Eli Lilly for public-private partnership trials. DMH co-founded, has equity, and is on the scientific advisory board of C2N Diagnostics. DMH is on the scientific advisory boards of Denali, Genentech, and Switch and consults for Novartis and Pfizer. SCJ has served on advisory boards for Lantheus, Lilly, Enigma, Alamar, Alzpath and 331 Trillium bio. JH has served as a paid consultant for Prothena, Abbvie, and Quanterix. The other Authors declare no Competing Financial or Non-Financial Interests. This work was supported in part by funding from the National Institutes of Health (grant #AG067505). WU has a financial interest in C2N Diagnostics and may financially benefit if the company is successful in marketing its product(s) that is/are related to this research.","formattedTitle":"Minimal levels of amyloid accumulation in the brains of cognitively unimpaired individuals are associated with long-term cognitive impairment up to 20 years later","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-8928856/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8928856/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The minimal amyloid accumulation (MAA) in cognitively unimpaired individuals that predicts the onset of cognitive impairment remains unknown. In a multi-center amyloid positron emission tomography (PET) study of 1834 cognitively unimpaired participants with longitudinal clinical/cognitive assessments for up to 20.3 years, we found that 48.7% of the amyloid-negative participants with MAA starting from an amyloid PET centiloid of 1.03 had a higher risk of cognitive impairment than those with the lowest centiloid values (\u003c1.03; hazards ratio (HR)=1.40, p=0.0046), although their risk was clearly lower than amyloid-positive participants (centiloid\u003e20; HR=0.47, p\u003c0.0001). Amyloid positivity was also associated with the fastest longitudinal amyloid accumulation and cognitive decline, followed by the MAA, and finally by the lowest amyloid. These findings suggest that current thresholds of amyloid positivity used for Alzheimer disease diagnosis may be overly restrictive, potentially excluding a large portion of amyloid-negative participants at elevated risk of developing cognitive impairment from prevention trials.","manuscriptTitle":"Minimal levels of amyloid accumulation in the brains of cognitively unimpaired individuals are associated with long-term cognitive impairment up to 20 years later","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-03 07:28:04","doi":"10.21203/rs.3.rs-8928856/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":"75f683d1-8402-4ef7-8720-26e1f6a42fdf","owner":[],"postedDate":"March 3rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":63675389,"name":"Biological sciences/Neuroscience/Neural ageing"},{"id":63675390,"name":"Health sciences/Neurology/Neurological disorders/Dementia/Alzheimer's disease"},{"id":63675391,"name":"Biological sciences/Neuroscience/Cognitive ageing"}],"tags":[],"updatedAt":"2026-03-23T05:56:32+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-03 07:28:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8928856","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8928856","identity":"rs-8928856","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}