Genetic Drivers of Resilience to Alzheimer's Disease

摘要 随着人口老龄化，晚发性阿尔茨海默病（AD）正成为越来越重要的公众 健康问题。旨在减少AD进展的临床试验表明，患者继续 尽管有治疗干预，因此，迫切需要针对新疾病的新治疗方法。 治疗目标从风险到复原力的重点转移具有巨大的潜力， 通过强调自然抵消AD破坏性影响的机制， 神经病理学有趣的是，在尸检中，大约30%的认知正常的人有 AD的病理特征。我们小组和其他人的研究已经开始揭示遗传因素 这解释了神经病理学和临床痴呆症之间的一些观察到的脱节。但小 样本量限制了在表征弹性的遗传力和遗传结构方面的进展， 全面的方式。因此，本项目将对遗传学进行大规模、全面的分析， 通过将体内生物标志物和尸检数据整合到弹性的统一模型中，我们建议 利用范德比尔特的一个名为阿尔茨海默病恢复力（RAD）数据库的资源， 新的保护性基因效应。在RAD中，我们开发并验证了持续的弹性指标， 量化一个人对认知缺陷和神经退行性变的适应程度， 与AD神经病理学有关。我们强大的跨学科团队具有独特的优势， 利用AD基因的基础设施和丰富的数据资源， 财团和AD测序项目。我们将识别和复制常见和罕见的遗传变异 可以预防认知障碍和神经退化。此外，我们将 将已知的性别差异整合到AD神经病理学的下游结果中，以确定性别- 特定的基因和途径，促进恢复力。所确定的基因和途径将提供新的 治疗目标的干预，旨在激活补偿机制，赋予弹性， AD神经病理学的损害作用。

Abstract As the population ages, late-onset Alzheimer's disease (AD) is becoming an increasingly important public health issue. Clinical trials targeted at reducing AD progression have demonstrated that patients continue to decline despite therapeutic intervention. Thus, there is a pressing need for new treatments aimed at novel therapeutic targets. A shift in focus from risk to resilience has tremendous potential to have a major public health impact by highlighting mechanisms that naturally counteract the damaging effects of AD neuropathology. Interestingly, at autopsy, approximately 30% of cognitively normal individuals have the pathological features of AD. Research from both our group and others has begun to uncover genetic factors that explain some of the observed disconnect between neuropathology and clinical dementia. However, small sample sizes have limited advances in characterizing the heritability and genetic architecture of resilience in a comprehensive manner. Therefore, this project will perform a large, comprehensive analysis of genetic resilience by integrating in vivo biomarker and autopsy data into a unified model of resilience. We propose to leverage a Vanderbilt resource called the Resilience from Alzheimer's Disease (RAD) database to uncover novel protective genetic effects. In RAD, we have developed and validated continuous metrics of resilience that quantify the degree to which an individual is resilient to both the cognitive deficits and the neurodegeneration associated with AD neuropathology. Our strong interdisciplinary team is uniquely positioned to characterize the genetic architecture of resilience leveraging the infrastructure and rich data resources of the AD genetic consortium and the AD sequencing project. We will identify and replicate common and rare genetic variants that predict protection from cognitive impairment and protection from neurodegeneration. Additionally, we will integrate known sex differences in the downstream consequences of AD neuropathology to identify sex- specific genes and pathways that promote resilience. The genes and pathways identified will offer novel therapeutic targets for intervention aimed at activating compensatory mechanisms that confer resilience to the damaging effects of AD neuropathology.