{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:18:07Z","timestamp":1792793887939,"version":"4.5.0"},"reference-count":65,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["AARFD-21-849349"],"award-info":[{"award-number":["AARFD-21-849349"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Alzheimer\u2019s Association","id":[{"id":"https:\/\/ror.org\/0375f4d26","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Wu Tsai Neuroscience Institute","id":[{"id":"https:\/\/ror.org\/0240rwx68","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Precision Health and Integrated Diagnostics Center"},{"DOI":"10.13039\/100014373","name":"Wu Tsai Neurosciences Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014373","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005492","name":"Stanford University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005492","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Good Planet Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Approximately 10% of clinically unimpaired individuals with abnormal amyloid (A+; preclinical Alzheimer\u2019s disease) have \u2018divergent\u2019 cortical tau pathology (A+TCortical+), defined as greater than expected tau in cortical regions relative to the medial temporal lobe and\/or cortical asymmetry on tau PET in addition to or instead of traditional medial temporal lobe tau burden. Although these A+TCortical+ individuals have subtle cognitive deficits at baseline, the longitudinal imaging and clinical outcomes are unknown. We aimed to characterize longitudinal trajectories of A+TCortical+ individuals compared with other biomarker-defined clinically unimpaired groups, given that identifying those at highest risk for decline is crucial for informing prevention trials and understanding early disease mechanisms.<\/jats:p>\n                  <jats:p>In this longitudinal study, we examined tau PET, MRI, cognitive and functional data from 395 clinically unimpaired participants, aged 65\u201385 years, enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer\u2019s Disease (A4) Study. Participants had two to five flortaucipir scans over a mean (standard deviation) follow-up period of 4.7 (1.6) years. Changes in regional and voxelwise tau patterns, atrophy, cognition and functioning were examined. Longitudinal trajectories from A+TCortical+ (n = 34) were compared with preclinical Alzheimer\u2019s disease with elevated tau PET signal in the medial temporal lobe only (A+TMTL+, n = 102), preclinical Alzheimer\u2019s disease without significant tau (A+TMTL\u2212, n\u00a0= 210) and those without amyloid or tau (A\u2212TMTL\u2212, n = 49).<\/jats:p>\n                  <jats:p>Cortical tau accumulation was fastest in A+TCortical+ (0.018\u20130.034 standardized uptake value ratios per year), whereas medial temporal lobe tau accumulation was comparable across A+TCortical+, A+TMTL+ and A+TMTL\u2212 groups (0.010\u20130.013 standardized uptake value ratios per year). Tau continued to accumulate in affected regions and contralateral homotopic regions in A+TCortical+ participants with asymmetrical tau at baseline such that asymmetrical patterns were maintained over time. Younger A+TCortical+ participants had an especially fast cortical accumulation rate. The A+TCortical+ group showed significantly greater neurodegeneration and faster clinical decline (Clinical Dementia Rating Scale Sum of Boxes = 0.610 points per year; Mini-Mental State Examination = \u22120.780 points per year) than all other biomarker-defined subgroups (Clinical Dementia Rating Scale Sum of Boxes = 0.048\u20130.182 points per year; Mini-Mental State Examination = \u22120.189\u20130.006 points per year).<\/jats:p>\n                  <jats:p>In summary, individuals with divergent cortical tau patterns continue to accumulate cortical tau at a faster rate, show greater neurodegeneration and have faster cognitive and functional decline than other preclinical Alzheimer\u2019s disease subgroups. Clinical trials and research examining tau progression and clinical decline in preclinical Alzheimer\u2019s disease without subtyping might be disproportionately influenced by this small, high-risk subgroup.<\/jats:p>","DOI":"10.1093\/brain\/awag113","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T12:45:44Z","timestamp":1774442744000},"source":"Crossref","is-referenced-by-count":1,"title":["Longitudinal trajectories of divergent cortical tau patterns in preclinical Alzheimer\u2019s disease"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9535-2137","authenticated-orcid":false,"given":"Christina B","family":"Young","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Palo Alto, CA 94304 ,","place":["USA"]},{"name":"Department of Radiology, University of California Davis , Sacramento, CA 95817 ,","place":["USA"]},{"name":"Department of Neurology, University of California Davis , Sacramento, CA 95817 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8626-5741","authenticated-orcid":false,"given":"Jintao","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Palo Alto, CA 94304 ,","place":["USA"]},{"name":"Department of Psychology, Stanford University , Stanford, CA 94305 ,","place":["USA"]},{"name":"Wu Tsai Neurosciences Institute, Stanford University , Stanford, CA 94305 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4069-3158","authenticated-orcid":false,"given":"Joseph R","family":"Winer","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Palo Alto, CA 94304 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5996-2560","authenticated-orcid":false,"given":"Karly","family":"Cody","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Palo Alto, CA 94304 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isha","family":"Sai","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Palo Alto, CA 94304 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mackenzie L","family":"Carlson","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Palo Alto, CA 94304 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9912-1616","authenticated-orcid":false,"given":"Kyan","family":"Younes","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Palo Alto, CA 94304 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6270-5490","authenticated-orcid":false,"given":"Philip S","family":"Insel","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of California San Francisco , San Francisco, CA 94143 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0418-0999","authenticated-orcid":false,"given":"Aaron P","family":"Schultz","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital , 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