Systems Genetics Analysis of Sex Differences in Alzheimer's Disease

项目摘要 我们提出的研究旨在确定神经病理学，认知和神经功能障碍的性别特异性遗传驱动因素。 阿尔茨海默病的代谢表型通过整合纵向行为和分子数据， AD小鼠与来自人类队列的遗传、基因组和临床数据。我们将利用新产生的 在遗传多样性背景下合并高风险家族性AD（FAD）突变的小鼠群体 (BXD图）以鉴定在该“人源化”小鼠群体中有助于AD恢复的修饰剂。在 与此同时，我们将采用最先进的单细胞组学方法来生成人类的分子图谱。 来自FAD突变携带者（在APP、PSEN1和PSEN2中）和散发性AD非携带者的脑。通过 结合并验证小鼠和人类数据集的分析，我们希望找到分子候选者， 这有力地促进了AD症状的性别特异性变化。我们将进一步验证这些候选人 使用无与伦比的体内小鼠技术，不仅可以在实验上评估它们在性别特异性 疾病的机制，而且还评估性别X基因型X治疗的候选人的子集的相互作用 (i.e., Apoe），以告知更多的个性化治疗方法。我们提出的方法得益于 增强现有人类遗传资源和新型精密AD小鼠的发现能力和价值 跨多个机构的模型，以调查AD性别差异的机制。

PROJECT SUMMARY Our proposed research aims to identify sex-specific genetic drivers of neuropathologic, cognitive, and metabolic phenotypes of Alzheimer’s disease by integrating longitudinal behavioral and molecular data from AD mice with genetic, genomic and clinical data from human cohorts. We will leverage a newly generated mouse population that incorporates high-risk familial AD (FAD) mutations on a genetically diverse background (BXD panel) to identify modifiers that contribute to AD resilience in this ‘humanized’ mouse population. In parallel, we will incorporate cutting-edge single-cell omic approachs to generate a molecular atlas of human brains from carriers of FAD mutations (in APP, PSEN1 and PSEN2) and non-carriers with sporadic AD. By combining and validating analyses in both mouse and human datasets, we expect to find molecular candidates that robustly contribute to sex-specific variation in symptoms of AD. We will further validate these candidates using unparalleled in vivo mouse technology to not only empircally assess their role in sex-specific mechanisms of disease, but also to evaluate sex X genotype X treatment interactions in a subset of candidates (i.e., Apoe) to inform more personalized therapeutic approaches. The approach we propose benefits from the enhanced discovery power and value of existing human genetics resources and novel, precision AD mouse models across multiple institutions to investigate the mechanisms of sex differences in AD.