{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T07:32:11Z","timestamp":1792481531648,"version":"4.5.0"},"reference-count":17,"publisher":"American Medical Association (AMA)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"<jats:sec id=\"ab-zoi260035-4\">\n                    <jats:title>Importance<\/jats:title>\n                    <jats:p>Sex differences are increasingly recognized as modifiers of Alzheimer disease and related dementias, with women exhibiting greater tau burden and faster cognitive decline than men. Even though \u03b1-synuclein copathology frequently occurs in Alzheimer disease, its contribution to sex differences in disease progression is unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-zoi260035-5\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To test whether \u03b1-synuclein positivity, measured using cerebrospinal fluid seed amplification assay (SAA), is differentially associated with tau accumulation in women vs men across the Alzheimer disease continuum.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-zoi260035-6\">\n                    <jats:title>Design, Setting, and Participants<\/jats:title>\n                    <jats:p>This cohort study used longitudinal tau positron emission tomography from the Alzheimer\u2019s Disease Neuroimaging Initiative collected between 2015 and 2023, with a median (IQR) follow-up of 1.23 (0.00-3.84) years. Participants were stratified by cerebrospinal fluid \u03b1-synuclein seed amplification assay status and sex. Participants were cognitively unimpaired or cognitively impaired (mild cognitive impairment or dementia) at baseline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-zoi260035-7\">\n                    <jats:title>Exposure<\/jats:title>\n                    <jats:p>Cerebrospinal fluid \u03b1-synuclein status determined by SAA and dichotomized as SAA negative or SAA positive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-zoi260035-8\">\n                    <jats:title>Main Outcomes and Measures<\/jats:title>\n                    <jats:p>Tau burden was quantified as standardized uptake value ratio (SUVr) in the medial temporal composite region of interest. Linear mixed-effects models tested SAA by sex by time interactions on longitudinal tau accumulation, adjusting for baseline age, baseline cognitive status, apolipoprotein E \u03b54 carrier status, and site. Sample size estimates were calculated to detect 25% and 50% treatment effects with 80% power in those with cognitive impairment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-zoi260035-9\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 415 participants (mean [SD] age, 72.3 [7.6] years; 220 women [53%]; 69 SAA positive [17%] and 346 SAA negative [83%]), there was a significant interaction between SAA status, sex, and time on tau accumulation (\u03b2, 0.061; 95% CI, 0.030-0.093;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009&amp;amp;lt;\u2009.001). Women with positive SAA results exhibited the fastest tau accumulation compared with other groups (0.066 SUVr per year; 95% CI, 0.043 to 0.089 SUVr per year;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009&amp;amp;lt;\u2009.001). Clinical trials targeting tau pathology in cognitively impaired individuals with 18-month follow-up would require 129 SAA-positive women to detect a 25% treatment effect with 80% power, compared with 518 SAA-negative women.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-zoi260035-10\">\n                    <jats:title>Conclusions and Relevance<\/jats:title>\n                    <jats:p>In this cohort study of participants across the Alzheimer disease continuum, \u03b1-synuclein copathology was associated with faster tau accumulation in women than men. These findings may inform sex-specific interpretation of \u03b1-synuclein biomarkers and trial design.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2026.0461","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T16:30:32Z","timestamp":1772641832000},"page":"e260461","source":"Crossref","is-referenced-by-count":5,"title":["Sex-Specific Associations of \u03b1-Synuclein Pathology With Tau Accumulation"],"prefix":"10.1001","volume":"9","author":[{"given":"Elijah","family":"Mak","sequence":"first","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela J.","family":"Fought","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather 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A.","family":"Rocca","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, Minnesota"},{"name":"Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota"},{"name":"Women\u2019s Health Research Center, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley F.","family":"Boeve","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kejal","family":"Kantarci","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Rochester, Minnesota"},{"name":"Women\u2019s Health Research Center, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.\u00a0","family":"Weiner\u00a0","sequence":"additional","affiliation":[{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Aisen","sequence":"additional","affiliation":[{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"Petersen","sequence":"additional","affiliation":[{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurel","family":"Beckett","sequence":"additional","affiliation":[{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard 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