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Association analysis between\n SORL1<\/jats:italic>\n haplotypes and AD\u2010associated traits or plasma biomarkers was conducted. The effects of non\u2010synonymous mutations were assessed in cell\u2010based systems.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n Protective\n SORL1<\/jats:italic>\n variants\/haplotypes were identified in the East Asian and European populations. Haplotype Hap_A showed a strong protective effect against AD in East Asians, linked to less severe AD phenotypes, higher\n SORL1<\/jats:italic>\n transcript levels, and plasma proteomic changes. A missense variant within Hap_A, rs2282647\u2010C allele, was linked to a lower risk of AD and decreased expression of a truncated SORL1 protein isoform.\n <\/jats:p>\n <\/jats:sec>\n \n DISCUSSION<\/jats:title>\n \n Our transethnic analysis revealed key\n SORL1<\/jats:italic>\n haplotypes that exert protective effects against AD, suggesting mechanisms of the protective role of SORL1 in AD.\n <\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n \n We examined the AD\u2010protective mechanisms of\n SORL1<\/jats:italic>\n in the general population across diverse ancestral backgrounds by jointly analyzing data from three East Asian cohorts (ie, mainland China, Hong Kong, and Japan) and a European cohort.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Comparative analysis unveiled key ethnic\u2010specific\n SORL1<\/jats:italic>\n genetic variants and haplotypes. Among these, the\n SORL1<\/jats:italic>\n minor haplotype, Hap_A, emerged as the primary AD\u2010protective factor in East Asians. Hap_A exerts significant AD\u2010protective effects in both\n APOE<\/jats:italic>\n \u03b54 carriers and non\u2010carriers.\n <\/jats:p>\n <\/jats:list-item>\n \n \n SORL1<\/jats:italic>\n haplotype Hap_A is associated with cognitive function, brain volume, and the activity of specific neuronal and immune\u2010related pathways closely connected to AD risk.\n <\/jats:p>\n <\/jats:list-item>\n \n Protective variants within Hap_A are linked to increased SORL1 expression in human tissues.<\/jats:p>\n <\/jats:list-item>\n \n We identified an isoform\u2010specific missense variant in Hap_A that modifies the function and levels of a truncated SORL1 protein isoform that is poorly investigated.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/alz.14214","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T06:25:19Z","timestamp":1733811919000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Transethnic analysis identifies\n SORL1<\/i>\n variants and haplotypes protective against Alzheimer's disease"],"prefix":"10.1002","volume":"21","author":[{"given":"Xiaopu","family":"Zhou","sequence":"first","affiliation":[{"name":"Division of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center The Hong Kong University of Science and Technology Hong Kong China"},{"name":"Hong Kong Center for Neurodegenerative Diseases Hong Kong China"},{"name":"Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development HKUST Shenzhen Research Institute Shenzhen Guangdong 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