{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:21:03Z","timestamp":1790889663381,"version":"4.1.0"},"reference-count":69,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":138,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institutes of Health\/National Institute on Aging","doi-asserted-by":"publisher","award":["U01-AG6057195"],"award-info":[{"award-number":["U01-AG6057195"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institutes of Health\/National Institute on Aging","doi-asserted-by":"publisher","award":["R56-AG057195"],"award-info":[{"award-number":["R56-AG057195"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer\u2019s Association","doi-asserted-by":"publisher","award":["AARG-22-926940"],"award-info":[{"award-number":["AARG-22-926940"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer\u2019s Association","doi-asserted-by":"publisher","award":["LDRFP-21-818464"],"award-info":[{"award-number":["LDRFP-21-818464"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer\u2019s Association","doi-asserted-by":"publisher","award":["LEADS GENETICS-19-639372"],"award-info":[{"award-number":["LEADS GENETICS-19-639372"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The growing availability of large-scale biomarker datasets has allowed data-driven methods to characterize Alzheimer\u2019s disease biological heterogeneity. However, most prior studies have focused on cohorts of late-onset amnestic cases, leaving early-onset Alzheimer\u2019s disease underexplored. We aimed to characterize tau-PET-based subtypes through a robust data-driven approach in the Longitudinal Early-Onset Alzheimer\u2019s Disease Study.<\/jats:p>\n                  <jats:p>Baseline [18F]Flortaucipir PET scans from 365 amyloid-PET-positive participants with sporadic early-onset Alzheimer\u2019s disease were quantified in the left and right medial temporal, lateral temporal, occipital, parietal, and frontal cortices. Tau PET values were z-scored against 85 amyloid-PET-negative cognitively normal age-matched participants and fitted into Subtype and Stage Inference (SuStaIn)\u2014an unsupervised clustering algorithm that simultaneously models subtypes and progression from cross-sectional data. The derived subtypes were subsequently characterized by baseline and longitudinal clinical, cognitive, MRI, tau and amyloid PET features. We identified three tau-PET-based subtypes: on average, Subtype 1\/Typical (n = 144, 40%) showed a predominant bilateral temporoparietal pattern typical of Alzheimer\u2019s disease. Subtype 2\/Left temporal (n = 111, 31%) showed predominant left temporal binding. Subtype 3\/Posterior (n = 104, 29%) showed early and permeating occipitoparietal involvement. Subtypes did not differ in demographics or global amyloid burden, but were relatively more enriched for specific clinical presentations: S1\/Typical for amnestic presentations, S2\/Left Temporal for primary progressive aphasia, and S3\/Posterior for posterior cortical atrophy. Baseline tau PET subtypes aligned with cortical atrophy patterns and domain-specific cognitive impairment. When follow-up tau PET scans were fitted to SuStaIn trained on baseline data, 85.6% (n = 172\/201) of participants retained the same subtype classification, indicating subtype temporal stability, and progressed within subtypes by 0.56 \u00b1 0.70 SuStaIn stage\/year. Longitudinal voxel-wise linear mixed-effects modelling revealed tau accumulation patterns for each subtype in regions relatively spared at baseline: occipital lobe accumulation predominated in S1\/Typical, bilateral frontal and right temporal in S2\/Left Temporal, and bilateral frontotemporal lobes in S3\/Posterior. All subtypes showed longitudinal increases in Clinical Dementia Rating-Sum of Boxes, but with slower worsening in S3\/Posterior compared with the other subtypes. Our findings reveal robust subtypes in sporadic early-onset Alzheimer\u2019s disease characterized by distinct spatiotemporal tau patterns that parallel differences in clinical presentations and trajectories of neurodegeneration. These subtypes extend beyond traditional clinical syndromes and support a more nuanced framework for individualized prognosis and care. Incorporating tau PET subtyping into clinical trial design could enable more targeted therapeutic approaches for this younger population.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag176","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T11:48:11Z","timestamp":1778845691000},"source":"Crossref","is-referenced-by-count":2,"title":["Tau topography subtypes account for clinical heterogeneity and longitudinal trajectories in early-onset Alzheimer's disease"],"prefix":"10.1093","volume":"8","author":[{"given":"Marlene","family":"Lin","sequence":"first","affiliation":[{"name":"Memory and Aging Center, Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco Edward and Pearl Fein , San Francisco, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5679-0297","authenticated-orcid":false,"given":"Konstantinos","family":"Chiotis","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco Edward and Pearl Fein , San Francisco, CA ,","place":["USA"]},{"name":"Center for Alzheimer Research, Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet , Stockholm ,","place":["Sweden"]},{"name":"Department of Cognitive Disorders, Karolinska University Hospital , Stockholm ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piyush","family":"Maiti","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco Edward and Pearl Fein , San Francisco, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxiuxiu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco Edward and Pearl Fein , San Francisco, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganna","family":"Blazhenets","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco Edward and Pearl Fein , San Francisco, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma","family":"Rocha","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco Edward and Pearl Fein , San Francisco, CA 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,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ani","family":"Eloyan","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Brown University , Providence, RI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kala","family":"Kirby","sequence":"additional","affiliation":[{"name":"Department of Neurology, Indiana University School of Medicine , Indianapolis, IN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A","family":"Koeppe","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Michigan , Ann Arbor, MI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Aisen","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Therapeutic Research Institute, University of Southern California , San Diego, CA 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of Radiology, Mayo Clinic , Rochester, MN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob W","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Malm\u00f6, Faculty of Medicine, SciLifeLab, Lund University , Lund ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne M","family":"Dufault","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, University of California San Francisco , San Francisco, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, University of California San Francisco , San Francisco, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C","family":"Carrillo","sequence":"additional","affiliation":[{"name":"Medical & Scientific Relations Division, Alzheimer\u2019s Association , Chicago, IL ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5958-3445","authenticated-orcid":false,"given":"Bradford C","family":"Dickerson","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liana G","family":"Apostolova","sequence":"additional","affiliation":[{"name":"Department of Neurology, Indiana University School of Medicine , Indianapolis, IN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gil D","family":"Rabinovici","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco Edward and Pearl Fein , San Francisco, CA ,","place":["USA"]},{"name":"Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2581-8100","authenticated-orcid":false,"given":"Renaud","family":"La Joie","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco Edward and Pearl Fein , San Francisco, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"issue":"1","key":"2026060405482046200_fcag176-B1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00401-011-0910-3","article-title":"National institute on aging\u2013Alzheimer\u2019s association guidelines for the 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