Sex differences in the genetic etiology of cognitive resilience to Alzheimer's disease

项目摘要 阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，其特征在于标志性病理学， 淀粉样斑块和神经纤维缠结，导致下游后果，包括 神经变性和认知障碍。然而，30%的老年人对AD具有认知弹性， 表现出AD病理，但从未表现出下游后果。应用认知 遗传研究的弹性框架导致了新的遗传位点的鉴定， 已知的AD遗传位点。然而，迄今为止，认知弹性框架尚未在性别- 具体方式。AD发病机制的性别差异已得到充分证实，越来越多的证据表明， 遗传因素可能导致这些差异。因此，本F31提案将调查以下方面的性别差异： AD认知恢复力的遗传病因学。我们将利用认知，生物标志物和遗传数据， 11个特征明确的认知老化队列。为了建立强大的认知弹性表型，我们将 实施潜在变量建模，然后对结果进行一系列性别感知基因组分析。 表型首先，我们将进行性别分层和性别相互作用的全基因组关联研究（GWAS）， 随后进行基因水平测试，包括应用性别特异性预测基因表达模型。二是 将进行X范围关联研究（XWAS）。到目前为止，还没有关于AD认知的XWAS 表型，由于性别之间的剂量差异引起的X染色体的额外挑战。 为此，我们将应用为X染色体量身定制的遗传管道，以允许其包含在内。三是 将使用上述GWAS和XWAS以及 来自英国生物银行的数千份性别分层的GWAS健康相关特征汇总统计数据。这些测试 将确定认知弹性和其他复杂特征之间的共同遗传结构，指出 可能的性别特异性生物途径驱动认知弹性。总体而言，拟议的研究目标将 识别与AD认知恢复力相关的新遗传位点、候选基因和分子通路 发病机制以性别特异性的方式。为了实现所有目标，F31提案将利用尖端的 资源和协作环境的范德比尔特记忆和阿尔茨海默氏症中心。候选人， Jaclyn Bethesman将在专家指导下独立完成所有统计分析 团队该团队在计算基因组学、临床和生物标志物对AD的贡献以及性别方面具有专业知识- 了解复杂性状的遗传模型。概述的研究目标沿着的是详细和平行的 培训计划将使候选人具备成功完成拟议研究目标的技能 并提高她的专业发展技能，为从事科学事业做好准备。F31的发现 该提案将有助于揭示AD进展的新见解，并确定新的治疗方法， 根据个体的遗传背景和生物性别，选择最适合个体的目标。

PROJECT SUMMARY Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder marked by hallmark pathologies, amyloid plaques, and neurofibrillary tangles, leading to downstream consequences including neurodegeneration and cognitive impairment. However, 30% of elderly adults are cognitively resilient to AD, presenting with AD pathology yet never presenting with downstream consequences. Applying the cognitive resilience framework to genetic studies has resulted in the identification of novel genetic loci that differ from known AD genetic loci. However, to date, the cognitive resilience framework has yet to be explored in a sex- specific manner. Sex differences in AD pathogenesis are well-established, with growing evidence suggesting genetic factors may contribute to these differences. Thus, this F31 proposal will investigate sex differences in the genetic etiology of cognitive resilience to AD. We will leverage cognitive, biomarker, and genetic data from eleven well-characterized cohorts of cognitive aging. To build robust cognitive resilience phenotypes, we will implement latent variable modeling, and then perform a series of sex-aware genomic analyses on the resulting phenotypes. First, we will perform sex-stratified and sex-interaction genome-wide association studies (GWAS), followed by gene-level tests, including applying sex-specific predicted gene expression models. Second, we will perform X-wide association studies (XWAS). To date, there have been no XWAS on AD cognitive phenotypes, due to the X-chromosome’s additional challenges arising from dosage differences between sexes. To this end, we will apply genetic pipelines tailored for the X-chromosome to allow for its inclusion. Third, we will perform genetic correlation tests with the aforementioned GWAS and XWAS and a unique resource of thousands of sex-stratified GWAS summary statistics on health-related traits from the UK Biobank. These tests will identify shared genetic architecture between cognitive resilience and other complex traits, pointing to possible sex-specific biological pathways driving cognitive resilience. Overall, the proposed research aims will identify novel genetic loci, candidate genes, and molecular pathways associated with cognitive resilience to AD pathogenesis in a sex-specific manner. To complete all aims, this F31 proposal will leverage cutting-edge resources and the collaborative environment of the Vanderbilt Memory & Alzheimer’s Center. The candidate, Jaclyn Eissman, will independently complete all statistical analyses with guidance from an expert mentorship team. This team has expertise in computational genomics, clinical and biomarker contributions to AD, and sex- aware genetic models of complex traits. The outlined research aims along with the detailed and parallel training plan will allow the candidate to have the skills to successfully complete the proposed research aims and enhance her professional development skills in preparation for a career in science. Findings from this F31 proposal will contribute to revealing novel insight into AD progression and to identifying novel therapeutic targets that best suit an individual based on their genetic context and biological sex.