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)正成为日益重要的公共疾病 健康问题。旨在减缓AD进展的临床试验表明，患者继续 尽管进行了治疗干预，但死亡率仍在下降。因此，迫切需要针对新奇生物的新疗法。 治疗靶点。将重点从风险转移到韧性具有巨大的潜力，可以让主要公众 通过强调自然地抵消AD的破坏性影响的机制来影响健康 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的病理特点。我们小组和其他人的研究已经开始揭示遗传因素 这解释了一些观察到的神经病理学和临床痴呆症之间的脱节。然而，很小 样本大小在表征恢复力的遗传性和遗传结构方面进展有限 全面的态度。因此，这个项目将对基因进行大规模、全面的分析 通过将体内生物标记物和尸检数据整合到一个统一的复原力模型中，提高复原力。我们建议 利用Vanderbilt资源名为Resilience From阿尔茨海默病(RAD)数据库来发现 新的保护性遗传效应。在RAD中，我们开发并验证了弹性的连续度量 量化一个人对认知缺陷和神经退化的适应程度 与阿尔茨海默病神经病理有关。我们强大的跨学科团队具有得天独厚的优势 利用AD Genetic的基础架构和丰富的数据资源实现恢复力的遗传架构 财团和AD测序项目。我们将识别和复制常见和罕见的基因变异 预测保护免受认知损伤和神经退化的保护。此外，我们还将 将已知的性别差异与AD神经病理的下游后果相结合，以确定性别- 促进韧性的特定基因和途径。已识别的基因和途径将提供新的 干预的治疗目标，旨在激活补偿机制，赋予患者弹性 阿尔茨海默病的神经病理损害作用。

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.