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This study aimed to identify genetic loci associated with plasma tau biomarkers (phosphorylated tau [p\u2010tau]181, p\u2010tau217, total tau [t\u2010tau]) and tau positron emission tomography (PET) in DS.<\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n We examined 375 people with DS from the Alzheimer's Biomarker Consortium\u2013Down Syndrome (ABC\u2010DS) with data on all four tau biomarkers, and 133 subjects from another study of DS with plasma t\u2010tau. Single\u2010trait and multi\u2010trait genetic association analyses were conducted. AD polygenic risk scores (PRSs) were tested with tau biomarkers.<\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n Three genome\u2010wide significant associations were identified for p\u2010tau181:\n TUBAP\/<\/jats:italic>\n rs76523946,\n P\u00a0<\/jats:italic>\n =\u00a02.21E\u201008;\n CTNND2<\/jats:italic>\n \/rs142510573,\n P\u00a0<\/jats:italic>\n =\u00a03.04E\u201008;\n CLSTN2\/<\/jats:italic>\n rs112448655,\n P\u00a0<\/jats:italic>\n =\u00a03.04E\u201008, and one for t\u2010tau (\n JHY\/<\/jats:italic>\n rs77264104,\n P\u00a0<\/jats:italic>\n =\u00a02.84E\u201008). AD PRS was associated with higher concentrations of tau PET (\n \u03b2<\/jats:italic>\n \u00a0=\u00a00.30,\n P\u00a0<\/jats:italic>\n =\u00a06.57E\u201004), p\u2010tau217\n (\u03b2<\/jats:italic>\n \u00a0=\u00a00.11,\n P\u00a0<\/jats:italic>\n =\u00a04.10E\u201002), and t\u2010tau (\n \u03b2<\/jats:italic>\n \u00a0=\u00a00.12,\n P\u00a0<\/jats:italic>\n =\u00a03.60E\u201002).\n <\/jats:p>\n <\/jats:sec>\n \n DISCUSSION<\/jats:title>\n These data indicate the presence of novel genetic loci in DS affecting plasma tau biomarkers and that AD risk PRS may modify tau neuroimaging and plasma biomarkers in DS.<\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n Four loci were linked to plasma total tau (t\u2010tau) or phosphorylated tau (p\u2010tau)181 with genome\u2010wide significance.<\/jats:p>\n <\/jats:list-item>\n \n \n JHY<\/jats:italic>\n \/rs77264104 stays genome\u2010wide significant for plasma t\u2010tau in a meta genome\u2010wide association study (GWAS).\n <\/jats:p>\n <\/jats:list-item>\n \n Alzheimer's disease (AD) polygenic risk score is associated with tau positron emission tomography (PET), regardless of apolipoprotein E genotype and region.<\/jats:p>\n <\/jats:list-item>\n \n Tau\u2010PET genes in Down syndrome (DS) are enriched in the cerebrospinal fluid phosphorylated tau Alzheimer's disease dementia GWAS catalog.<\/jats:p>\n <\/jats:list-item>\n \n T\u2010tau genes in DS are enriched in a verbal memory GWAS catalog within a mild cognitive impairment cohort.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/alz.70398","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T03:00:47Z","timestamp":1752721247000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genome\u2010wide association of tau neuroimaging and plasma biomarkers in adults with Down syndrome"],"prefix":"10.1002","volume":"21","author":[{"given":"Kang\u2010Hsien","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Human Genetics School of Public Health University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3230-2625","authenticated-orcid":false,"given":"Ruyu","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Human Genetics School of Public Health University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asma Naseer","family":"Cheema","sequence":"additional","affiliation":[{"name":"Department of Human Genetics School of Public Health University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lam\u2010Ha T.","family":"Dang","sequence":"additional","affiliation":[{"name":"Sergievsky Center Department of Neurology Vagelos College of Physicians and Surgeons Columbia University New York New York USA"},{"name":"Department of Epidemiology Mailman School of Public Health Columbia University New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Xicota","sequence":"additional","affiliation":[{"name":"Sergievsky Center Department of Neurology Vagelos College of Physicians and Surgeons Columbia University New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Krinsky\u2010McHale","sequence":"additional","affiliation":[{"name":"Department of Psychology New York Institute for Basic Research Staten Island New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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