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We identified methylation differences between the non\u2010protective and rs10423769_A haplotypes. An expanded variable number tandem repeat (VNTR) containing multiple MEF2\u2010family transcription factor binding motifs in LD with the protective haplotype. Further, rs10423769 is an eQTL for\n ZNF222<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n DISCUSSION<\/jats:title>\n \n The protective haplotype is unique, with haplotype changes in DNA methylation and SV that could contribute to the protective mechanism of rs10423769_A. The study generates hypothesis for future studies on this important protective mechanism for\n APOE\u03b54<\/jats:italic>\n carriers.\n <\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n \n We investigated an African\u2010specific haplotype harboring a protective locus for\n APOE\u03b54<\/jats:italic>\n carriers that significantly reduces the risk for Alzheimer Disease.\n <\/jats:p>\n <\/jats:list-item>\n \n \n The protective locus lies in an area of segmental duplications 2MB from\n APOE<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:list-item>\n \n We found that the protective haplotype is unique within the segmental duplications.<\/jats:p>\n <\/jats:list-item>\n \n The haplotype is found in all African ancestry tested but not in other ancestries.<\/jats:p>\n <\/jats:list-item>\n \n Long read whole genome sequencing identified an expanded VNTR associated with the protective haplotype containing multiple MEF2 transcription factor binding motifs.<\/jats:p>\n <\/jats:list-item>\n \n Differences in DNA methylation were found between the protective and the reference haplotype.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/alz.70500","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T09:41:54Z","timestamp":1753350114000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Exploring potential mechanisms of an African protective locus for Alzheimer's disease in\n APOE\u03b54<\/i>\n carriers"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1518-1409","authenticated-orcid":false,"given":"Luciana","family":"Bertholim\u2010Nasciben","sequence":"first","affiliation":[{"name":"Hussman Institute for Human Genomics University of Miami Miller School of Medicine Miami Florida 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