Genetic Drivers of Resilience to Alzheimer's Disease

阿尔茨海默病抵抗力的遗传驱动因素

• 批准号: 9577410
• 负责人: Timothy J Hohman
• 金额: $ 84.69万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9577410
• 关键词: Age; Age of Onset; Alzheimer' s Disease; Autopsy; Biological Markers; Biology; Brain; Case-Control Studies; Cell Cycle; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Cohort Studies; Data; Databases; Dementia; Disease Progression; Education; Endocrine-Gland-Derived Vascular Endothelial Growth Factor; Evaluation; Frequencies; Future; Gene Expression; Gene Proteins; Genes; Genetic; Genetic Diseases; Genetic Markers; Genetic Variation; Genome Stability; Genomics; Goals; Heritability; Impaired cognition; Individual; International; Intervention; Late Onset Alzheimer Disease; Life; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Neuropsychology; Neurosciences; Onset of illness; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Population; Positioning Attribute; Psychometrics; Public Health; Research; Research Infrastructure; Research Proposals; Resources; Risk; Role; Sample Size; Selection Bias; Senile Plaques; Sex Characteristics; Symptoms; Testing; Therapeutic Intervention; Tissue-Specific Gene Expression; Variant; Vascular Endothelial Growth Factors; Work; angiogenesis; base; cerebral atrophy; data resource; genetic analysis; genetic architecture; genetic variant; genome sequencing; genome wide association study; genome-wide; human old age (65+); in vivo; innovation; insight; mild cognitive impairment; neuroinflammation; neuropathology; new therapeutic target; novel; pre-clinical; rare variant; resilience; secondary analysis; sex; statistics; tau aggregation; telomere; ward; whole genome

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.

抽象的 随着人口老龄化，晚发性阿尔茨海默病（AD）正成为一个日益重要的公众问题 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，但仍下降。因此，迫切需要针对新的治疗方法 治疗目标。将焦点从风险转向韧性具有获得主要公众关注的巨大潜力 通过强调自然抵消 AD 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% 认知正常的个体具有 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之间观察到的一些脱节。然而，小 样本量在表征复原力的遗传性和遗传结构方面取得的进展有限 综合方式。因此，该项目将对遗传进行大规模、全面的分析。 通过将体内生物标志物和尸检数据整合到统一的恢复力模型中来恢复恢复力。我们建议 利用范德比尔特大学称为“阿尔茨海默病复原力”(RAD) 数据库的资源来发现 新的保护性遗传效应。在 RAD，我们开发并验证了连续的弹性指标 量化个体对认知缺陷和神经退行性疾病的恢复能力的程度 与 AD 神经病理学相关。我们强大的跨学科团队具有独特的优势来描述 利用 AD 遗传基础设施和丰富数据资源的复原力遗传架构 联盟和 AD 测序项目。我们将识别并复制常见和罕见的基因变异 预测对认知障碍的保护和对神经变性的保护。此外，我们将 将已知的性别差异整合到 AD 神经病理学的下游后果中，以识别性别 促进恢复力的特定基因和途径。确定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，赋予机体恢复能力 AD 神经病理学的破坏性影响。