Guo Lei, Zhong Margaret B, Zhang Larry, Zhang Bin, Cai Dongming
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, New York.
Department of Neuroscience, Barnard College of Columbia University, New York, New York.
Biol Psychiatry. 2022 Jan 1;91(1):61-71. doi: 10.1016/j.biopsych.2021.02.968. Epub 2021 Mar 2.
Alzheimer's disease (AD) has complex etiologies, and the impact of sex on AD varies over the course of disease development. The literature provides some evidence of sex-specific contributions to AD. However, molecular mechanisms of sex-biased differences in AD remain elusive. Multiomics data in tandem with systems biology approaches offer a new avenue to dissect sex-stratified molecular mechanisms of AD and to develop sex-specific diagnostic and therapeutic strategies for AD. Single-cell transcriptomic datasets and cell deconvolution of bulk tissue transcriptomic data provide additional insights into brain cell type-specific impact on sex-biased differences in AD. In this review, we summarize the impact of sex chromosomes and sex hormones on AD, the impact of sex-biased differences during AD development, and the interplay between sex and a major AD genetic risk factor, the APOE ε4 genotype, through the multiomics landscape. Several sex-biased molecular pathways such as neuroinflammation and bioenergetic metabolism have been identified. The importance of sex chromosome and sex hormones, as well as the associated pathways in AD pathogenesis, is further strengthened by findings from omics studies. Future research efforts should integrate the multiomics data from different brain regions and different cell types using systems biology approaches, and leverage the knowledge into a holistic examination of sex differences in AD. Advances in systems biology technologies and increasingly available large-scale multiomics datasets will facilitate future studies dissecting such complex signaling mechanisms to better understand AD pathogenesis in both sexes, with the ultimate goals of developing efficacious sex- and APOE-stratified preventive and therapeutic interventions for AD.
阿尔茨海默病（AD）病因复杂，性别对AD的影响在疾病发展过程中有所不同。文献提供了一些关于性别对AD有特定贡献的证据。然而，AD中性别差异的分子机制仍不清楚。多组学数据与系统生物学方法相结合，为剖析AD的性别分层分子机制以及开发针对AD的性别特异性诊断和治疗策略提供了新途径。单细胞转录组数据集和批量组织转录组数据的细胞反卷积为脑细胞类型对AD性别差异的特异性影响提供了更多见解。在这篇综述中，我们通过多组学视角总结了性染色体和性激素对AD的影响、AD发展过程中性别差异的影响，以及性别与主要AD遗传风险因素APOE ε4基因型之间的相互作用。已经确定了一些性别偏向的分子途径，如神经炎症和生物能量代谢。组学研究的结果进一步强化了性染色体和性激素以及相关途径在AD发病机制中的重要性。未来的研究工作应使用系统生物学方法整合来自不同脑区和不同细胞类型的多组学数据，并将这些知识用于对AD性别差异的全面研究。系统生物学技术的进步和越来越多可用的大规模多组学数据集将有助于未来的研究剖析这种复杂的信号机制，以更好地理解两性的AD发病机制，最终目标是开发出针对AD的有效性别和APOE分层的预防和治疗干预措施。
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