Tau spreading precedes the increase in tau load in Alzheimer’s disease

Tau spreading precedes the increase in tau load 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 Tau spreading precedes the increase in tau load in Alzheimer’s disease Pedro Rosa-Neto, Arthur Macedo, Joseph Therriault Therriault, and 29 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5619837/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 Tau pathology spreads and accumulates during Alzheimer’s disease (AD), but the relationship between these processes throughout disease progression remains unclear. We assessed the spatiotemporal dynamics of tau spreading and accumulation using tau-PET data from 1,175 participants in the TRIAD and ADNI cohorts, including 277 with 2-year follow-ups. Tau standardized uptake value ratios (SUVR) indexed tau load, while the spatial extent of tauopathy (SEOT; proportion of abnormal voxels) measured tau spread. Longitudinal analyses showed that tau spreading preceded increases in tau load, particularly in regions with low baseline tau levels. Our findings support a sequential model of tau progression: an initial spreading phase, primarily captured by SEOT, followed by an accumulation phase largely reflected by SUVR. These results provide new insights into the pathological mechanisms underlying tau deposition and highlight tau spread as a promising surrogate outcome for clinical trials targeting early-stage AD. Health sciences/Biomarkers/Diagnostic markers Health sciences/Neurology/Neurological disorders/Dementia/Alzheimer's disease Biological sciences/Neuroscience/Diseases of the nervous system/Alzheimer's disease Health sciences/Health care/Medical imaging/Molecular imaging Alzheimer’s disease positron emission tomography neurofibrillary tangles tau spreading Full Text Additional Declarations Yes there is potential Competing Interest. J.T. has served as a consultant for the Neurotorium educational platform, outside of the scope of the submitted work. N.J.A. has received consulting fees from Quanterix,and has also received payments for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Alamar Bio-sciences, Biogen, Eli-Lilly, and Quanterix. N.J.A. is listed as an inventor on a patent application (Application No.: PCT/US2024/037834, WSGRDocket No. 58484-709.601) related to methods for remote blood collection, extraction, and analysis of neuro biomarkers; serves on the advisory board for Biogen, TargetALS, and TauRx; and receives payments for this role. T.K.K. has consulted for Quanterix Corp., has received honoraria from the NIH for study section membership, and honoraria for speaker/grant review engagements from UPENN, UW-Madison, Advent Health, Brain Health conference, Barcelona-Pittsburgh conference and CQDM Canada, all outside of the submitted work. T.K.K. has received blood biomarker data on defined research cohorts from Janssen and Alamar Biosciences for independent analysis and publication, with no financial incentive and/or research funding included. T.K.K. is an inventor on patent #WO2020193500A1 and patent applications #2450702-2, #63/693,956, #63/679,361, and 63/672,952. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant and at advisory boards for Abbvie, AC Immune, ALZPath, AriBio, Beckman-Coulter, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Quanterix, Roche Diagnostics, Sanofi and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. E.R.Z. has served on scientific advisory boards for Nintx, Novo Nordisk and masima. E.R.Z. is also a co-founder and a minority shareholder at masima. The other authors declare that they have no competing interests. P.R.N. provides consultancy services for Roche, Cerveau Radiopharmaceuticals, Lilly, Eisai, Pfizer, and Novo Nordisk. P.R.N. also serves as a clinical trials investigator for Biogen, Novo Nordisk, and Biogen. 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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N.J.A. has received consulting fees from Quanterix,and has also received payments for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Alamar Bio-sciences, Biogen, Eli-Lilly, and Quanterix. N.J.A. is listed as an inventor on a patent application (Application No.: PCT/US2024/037834, WSGRDocket No. 58484-709.601) related to methods for remote blood collection, extraction, and analysis of neuro biomarkers; serves on the advisory board for Biogen, TargetALS, and TauRx; and receives payments for this role. T.K.K. has consulted for Quanterix Corp., has received honoraria from the NIH for study section membership, and honoraria for speaker/grant review engagements from UPENN, UW-Madison, Advent Health, Brain Health conference, Barcelona-Pittsburgh conference and CQDM Canada, all outside of the submitted work. T.K.K. has received blood biomarker data on defined research cohorts from Janssen and Alamar Biosciences for independent analysis and publication, with no financial incentive and/or research funding included. T.K.K. is an inventor on patent #WO2020193500A1 and patent applications #2450702-2, #63/693,956, #63/679,361, and 63/672,952. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant and at advisory boards for Abbvie, AC Immune, ALZPath, AriBio, Beckman-Coulter, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Quanterix, Roche Diagnostics, Sanofi and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. E.R.Z. has served on scientific advisory boards for Nintx, Novo Nordisk and masima. E.R.Z. is also a co-founder and a minority shareholder at masima. The other authors declare that they have no competing interests. P.R.N. provides consultancy services for Roche, Cerveau Radiopharmaceuticals, Lilly, Eisai, Pfizer, and Novo Nordisk. P.R.N. also serves as a clinical trials investigator for Biogen, Novo Nordisk, and Biogen.","formattedTitle":"Tau spreading precedes the increase in tau load in Alzheimer’s disease","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"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":"Alzheimer’s disease, positron emission tomography, neurofibrillary tangles, tau spreading","lastPublishedDoi":"10.21203/rs.3.rs-5619837/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5619837/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Tau pathology spreads and accumulates during Alzheimer’s disease (AD), but the relationship between these processes throughout disease progression remains unclear. We assessed the spatiotemporal dynamics of tau spreading and accumulation using tau-PET data from 1,175 participants in the TRIAD and ADNI cohorts, including 277 with 2-year follow-ups. Tau standardized uptake value ratios (SUVR) indexed tau load, while the spatial extent of tauopathy (SEOT; proportion of abnormal voxels) measured tau spread. Longitudinal analyses showed that tau spreading preceded increases in tau load, particularly in regions with low baseline tau levels. Our findings support a sequential model of tau progression: an initial spreading phase, primarily captured by SEOT, followed by an accumulation phase largely reflected by SUVR. These results provide new insights into the pathological mechanisms underlying tau deposition and highlight tau spread as a promising surrogate outcome for clinical trials targeting early-stage AD.","manuscriptTitle":"Tau spreading precedes the increase in tau load in Alzheimer’s disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-03 03:57:44","doi":"10.21203/rs.3.rs-5619837/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-aging","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nataging","sideBox":"Learn more about [Nature Aging](https://www.nature.com/nataging/)","snPcode":"","submissionUrl":"","title":"Nature Aging","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c79148a9-bd01-43b3-87c2-c0c878a40421","owner":[],"postedDate":"January 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":41584858,"name":"Health sciences/Biomarkers/Diagnostic markers"},{"id":41584859,"name":"Health sciences/Neurology/Neurological disorders/Dementia/Alzheimer's disease"},{"id":41584860,"name":"Biological sciences/Neuroscience/Diseases of the nervous system/Alzheimer's disease"},{"id":41584861,"name":"Health sciences/Health care/Medical imaging/Molecular imaging"}],"tags":[],"updatedAt":"2025-01-03T03:57:44+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-03 03:57:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5619837","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5619837","identity":"rs-5619837","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}