Qu Hui-Qi, Liu Yichuan, Connolly John J, Mentch Frank D, Kao Charlly, Hakonarson Hakon
The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Alzheimers Dement. 2025 Apr;21(4):e14604. doi: 10.1002/alz.14604.
Individuals with Down syndrome (DS) are highly susceptible to Alzheimer's disease (AD). The integration of genomics, transcriptomics, epigenomics, proteomics, and metabolomics enables unprecedented understanding of DS-AD, offering a detailed picture of this complex issue. The vast -omics 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. HIGHLIGHTS: Individuals with Down syndrome (DS) are highly susceptible to Alzheimer's disease (AD). DS-AD is characterized by its polygenic nature, extending beyond chromosome 21 with significant contributions from various chromosomes. DS-AD also presents unique features that differ from those observed in the general population and familial dominant AD. Our review consolidates key findings from genomics, transcriptomics, epigenomics, proteomics, and metabolomics, providing a comprehensive view of the molecular mechanisms underlying DS-AD. We highlight promising research directions to further elucidate the pathogenesis of DS-AD.
唐氏综合征（DS）患者极易患阿尔茨海默病（AD）。基因组学、转录组学、表观基因组学、蛋白质组学和代谢组学的整合使人们对DS-AD有了前所未有的理解，为这个复杂问题提供了详细的图景。海量的组学数据也带来了挑战，反映了遗传信息流的复杂性。尽管如此，这些研究揭示了AD风险背后的关键机制，包括DS中与普通人群和家族性显性AD不同的独特观察结果。此外，AD多基因风险评分与女性不孕和自身免疫性甲状腺炎相关蛋白之间的相关性证实了临床观察结果。代谢组学数据揭示了代谢网络的紊乱，为创建专门的营养干预措施的动态评分提供了前景。通过采用综合还原论的多维视角，不断演变的格局为确定有前景的方向提供了机会，以制定精准策略来减轻AD对DS人群的影响。
唐氏综合征（DS）患者极易患阿尔茨海默病（AD）。DS-AD的特点是其多基因性质，不仅涉及21号染色体，其他各种染色体也有重大贡献。DS-AD还呈现出与普通人群和家族性显性AD不同的独特特征。我们的综述整合了基因组学、转录组学、表观基因组学、蛋白质组学和代谢组学的关键发现，全面概述了DS-AD潜在的分子机制。我们强调了有前景的研究方向，以进一步阐明DS-AD的发病机制。
