{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:30:39Z","timestamp":1790814639101,"version":"4.1.0"},"reference-count":53,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":29,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG021155"],"award-info":[{"award-number":["R01AG021155"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AG027161"],"award-info":[{"award-number":["R01 AG027161"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30AG062715"],"award-info":[{"award-number":["P30AG062715"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10OD025245\u201001"],"award-info":[{"award-number":["S10OD025245\u201001"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG080766"],"award-info":[{"award-number":["R01AG080766"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21AG077337"],"award-info":[{"award-number":["R21AG077337"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG089562"],"award-info":[{"award-number":["R01AG089562"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG075788"],"award-info":[{"award-number":["R01AG075788"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG082208"],"award-info":[{"award-number":["R01AG082208"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"publisher","award":["AARF\u201019\u2010614533"],"award-info":[{"award-number":["AARF\u201019\u2010614533"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Amyloid (A) and vascular (V) pathologies often co\u2010occur and progress over decades. We leveraged chronicity, defined as the years above a biomarker\u2010positivity threshold, to examine how the timing of A and V relates to cognitive decline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We modeled Clinical Dementia Rating\u2013Sum of Boxes (CDR\u2010SB) trajectories in\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a0558 participants with [C\u201011] Pittsburgh compound B positron emission tomography (PET), magnetic resonance imaging\u2013derived white matter hyperintensities (WMHs), and longitudinal CDR assessments. In\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a0500 with MK6240 PET, we tested whether tau mediates A\u2013V associations with CDR\u2010SB in a moderated mediation framework.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Whether biomarker \u201cburden\u201d was modeled as chronicity (A+years, V+years), or estimated amyloid and WMH at CDR visits, significant interactions showed a synergistic effect of WMHs and amyloid on accelerated CDR\u2010SB trajectories. Tau significantly mediated these associations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Operationalizing chronicity clarifies how long individuals have exceeded A and V thresholds and improves clinical interpretability. WMH accumulation exacerbates amyloid\u2010related cognitive decline. Longitudinal tau imaging could further inform staging and intervention timing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Longer amyloid (A) and vascular disease (V) chronicity were associated with faster cognitive decline, emphasizing the importance of considering chronic exposure to these pathologies.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Individuals with higher V burden experienced a steeper decline in cognition in the presence of A pathology, highlighting the interaction between V and neurodegenerative processes.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Progression from early to mild dementia was faster with greater white matter hyperintensity chronicity, even when A duration was held constant, supporting the idea that V pathology amplifies the clinical impact of amyloid in Alzheimer's disease.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Tau accumulation played a significant mediating role in linking A and V burden to cognitive decline, suggesting that tau pathology is a critical downstream factor in symptom progression.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Person\u2010level chronicity estimates of A and V provide a more precise understanding of cognitive decline trajectories, offering insights for early intervention strategies.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70831","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T09:00:10Z","timestamp":1761814810000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Tau mediates the impact of amyloid and vascular disease burden on the trajectory of clinical symptoms"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1662-0883","authenticated-orcid":false,"given":"Lianlian","family":"Du","sequence":"first","affiliation":[{"name":"Wisconsin Alzheimer's Institute University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Disease Research Center, Department of Medicine University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Rush Alzheimer's Disease Center Rush University Medical Center  Chicago Illinois USA"},{"name":"Department of Neurological Sciences Rush University Medical Center  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca E.","family":"Langhough","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Institute University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Disease Research Center, Department of Medicine University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce P.","family":"Hermann","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Institute University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Department of Neurology University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin M.","family":"Jonaitis","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Institute University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Disease Research Center, Department of Medicine University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobey J.","family":"Betthauser","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Institute University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Disease Research Center, Department of Medicine University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo A.","family":"Rivera\u2010Rivera","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center, Department of Medicine University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Department of Medical Physics University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karly A.","family":"Cody","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center, Department of Medicine University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Department of Neurology and Neurological Sciences Stanford University  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel A.","family":"Chin","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center, Department of Medicine University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert V.","family":"Cadman","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center, Department of Medicine University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin M.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Medical Physics University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Department of Radiology University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron S.","family":"Field","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center, Department of Medicine University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Department of Radiology University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Asthana","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center, Department of Medicine University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Eisenmenger","sequence":"additional","affiliation":[{"name":"Department of Radiology University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley T.","family":"Christian","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center, Department of Medicine University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Department of Medical Physics University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sterling C.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Institute University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Disease Research Center, Department of Medicine University of Wisconsin\u2013Madison School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000200304"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401\u2010017\u20101717\u20107"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24647"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000207378"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X241237624"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14383"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcac150"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195\u2010020\u201000669\u20104"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac213"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaf158"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201038878\u20108"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/dad2.12007"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26460"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae116"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2015.08.166"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2020.117676"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000012775"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2021.118440"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26891"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(24)00426\u20105"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1017\/s1041610297004870"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/dad2.12360"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dadm.2017.11.007"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dadm.2015.03.003"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.3233\/ADR\u2010170004"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14470"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2010.115"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2013.09.028"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.118.209650"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00265\u2010010\u20101029\u20106"},{"key":"e_1_2_9_32_1","unstructured":"MazerolleMJ MazerolleMMJ Package \u2018AICcmodavg.\u2019 R Package2017;281."},{"key":"e_1_2_9_33_1","unstructured":"LenthRV BolkerB BuerknerP et\u00a0al.emmeans: Estimated Marginal Means aka Least\u2010Squares Means2023."},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v059.i05"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12642"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26447"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2022.12.003"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2019.20780"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.114.006571"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2019.1879"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.02.018"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593\u2010024\u201001763\u20108"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2024.122"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz378"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14406"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcac193"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40035\u2010024\u201000429\u20106"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380\u2010018\u20100342\u20108"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401\u2010024\u201002696\u2010z"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaa132"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(24)01296\u20100"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcad333"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dadm.2018.11.006"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2025.0013"}],"container-title":["Alzheimer's &amp; Dementia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/alz.70831","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T12:32:40Z","timestamp":1764160360000},"score":1,"resource":{"primary":{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/10.1002\/alz.70831"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10]]},"references-count":53,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1002\/alz.70831"],"URL":"https:\/\/doi.org\/10.1002\/alz.70831","archive":["Portico"],"relation":{},"ISSN":["1552-5260","1552-5279"],"issn-type":[{"value":"1552-5260","type":"print"},{"value":"1552-5279","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10]]},"assertion":[{"value":"2025-06-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70831"}}