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The integration of genomics, transcriptomics, epigenomics, proteomics, and metabolomics enables unprecedented understanding of DS\u2010AD, offering a detailed picture of this complex issue. The vast \u2010omics data also present challenges that reflect the complexity of genetic information flow. These studies nonetheless reveal critical mechanisms behind AD risk, including unique observations in DS that differ from those seen in the general population and familial dominant AD. In addition, the correlations between the AD polygenic risk score and proteins related to female infertility and autoimmune thyroiditis corroborate clinical observations. Metabolomic data reveal disrupted metabolic networks, offering prospects for a dynamic score to create specialized nutritional interventions. By adopting a multidimensional perspective with integrated reductionism, the evolving landscape presents an opportunity to identify promising directions for developing precision strategies to mitigate the impact of AD in the DS population.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Individuals with Down syndrome (DS) are highly susceptible to Alzheimer's disease (AD).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>DS\u2010AD is characterized by its polygenic nature, extending beyond chromosome 21 with significant contributions from various chromosomes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>DS\u2010AD also presents unique features that differ from those observed in the general population and familial dominant AD.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our review consolidates key findings from genomics, transcriptomics, epigenomics, proteomics, and metabolomics, providing a comprehensive view of the molecular mechanisms underlying DS\u2010AD.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We highlight promising research directions to further elucidate the pathogenesis of DS\u2010AD.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.14604","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T04:49:06Z","timestamp":1744260546000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Risk of Alzheimer's disease in Down syndrome: Insights gained by multi\u2010omics"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9317-4488","authenticated-orcid":false,"given":"Hui\u2010Qi","family":"Qu","sequence":"first","affiliation":[{"name":"The Center for Applied Genomics Children's Hospital of Philadelphia  Philadelphia Pennsylvania 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