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We measured misfolded syn aggregates (syn\u2010seeds) via qualitative seed amplification assays (synSAA) and examined relationships with markers of Alzheimer's disease (AD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>Cerebrospinal fluid (CSF) was obtained from 420 participants in two AD risk cohorts (35% male; 91% cognitively unimpaired; mean [standard deviation] age, 65.42 [7.78] years; education, 16.17 [2.23]) years). synSAA results were compared to phosphorylated tau (T), amyloid beta (A), and clinical outcomes. Longitudinal cognition was modeled with mixed effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Syn positivity (synSAA+) co\u2010occurred with T (in synSAA+ vs. synSAA\u2212, 36%\u00a0vs. 20% T+; P\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.011) and with cognitive impairment (10%\u00a0vs. 7% mild cognitive impairment; 10%\u00a0vs. 0% dementia;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.00050). synSAA+ participants\u2019 cognitive performance declined \u2248 40% faster than synSAA\u2013 for Digit Symbol Substitution, but not other tests.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Findings support prevalent syn copathology in a mostly unimpaired AD risk cohort. Relationships with progression should be evaluated once more have declined.<\/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>In a middle\u2010aged sample, misfolded \u2010synuclein (syn) co\u2010occurred with phosphorylated tau181 (T).<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>syn+\/T+ status was linked with higher levels of other cerebrospinal fluid biomarkers.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>syn+ individuals were more likely than syn\u2013 to be cognitively impaired.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>syn+ status was linked to faster decline on an executive function task.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70205","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T00:00:15Z","timestamp":1747094415000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Misfolded \u03b1\u2010synuclein co\u2010occurrence with Alzheimer's disease proteinopathy"],"prefix":"10.1002","volume":"21","author":[{"given":"Erin M.","family":"Jonaitis","sequence":"first","affiliation":[{"name":"Wisconsin Alzheimer's Institute, School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Disease Research Center School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"},{"name":"Department of Medicine Division of Geriatrics and Gerontology School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"MacLeod","sequence":"additional","affiliation":[{"name":"Amprion Inc.  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Lamoureux","sequence":"additional","affiliation":[{"name":"Amprion Inc.  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beckie","family":"Jeffers","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Institute, School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Disease Research Center School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"},{"name":"Department of Medicine Division of Geriatrics and Gerontology School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel L.","family":"Studer","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Institute, School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Middleton","sequence":"additional","affiliation":[{"name":"Amprion Inc.  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael E.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel A.","family":"Chin","sequence":"additional","affiliation":[{"name":"Department of Medicine Division of Geriatrics and Gerontology School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozioma C.","family":"Okonkwo","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"},{"name":"Department of Medicine Division of Geriatrics and Gerontology School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara B.","family":"Bendlin","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"},{"name":"Department of Medicine Division of Geriatrics and Gerontology School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Asthana","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Disease Research Center School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"},{"name":"Department of Medicine Division of Geriatrics and Gerontology School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia M.","family":"Carlsson","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer's Institute, School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Disease Research Center School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"},{"name":"Department of Medicine Division of Geriatrics and Gerontology School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine L.","family":"Gallagher","sequence":"additional","affiliation":[{"name":"Department of Neurology School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Hermann","sequence":"additional","affiliation":[{"name":"Department of Neurology School of Medicine and Public Health, University of Wisconsin\u2013Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"McEvoy","sequence":"additional","affiliation":[{"name":"Amprion Inc.  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