Protective Genetic Variants for Alzheimer Disease in the Amish - RENEWAL

阿尔茨海默病(AD)是一种毁灭性的神经退行性疾病，影响着世界上数百万人 美国迄今拒绝开发有效疗法的尝试，尽管有许多(失败的)临床试验 在已知目标上，大多数是在20多年前确定的。虽然基因组研究(例如阿尔茨海默病) 测序项目；ADSP)发现了许多额外的风险基因，这些结果主要来自病例- 控制数据集。相比之下，旨在识别可能预防AD的变异的队列，以及那些使用 补充性研究设计很少。我们利用了我们在阿米什社区的丰富经验 印第安纳州和俄亥俄州建立老年人队列，这些老年人患有AD的风险很高，但在认知方面 未受损(CU)。阿米什人提供了一个独特的机会来识别AD的保护性变体，因为他们的 减少背景遗传变异和环境风险因素。他们的创始人口很少， 内婚制为稀有变种提供了丰富。创始人群体还可以进行非加性等位基因测试 影响并可以放大病例对照研究中确定的次要显著关联信号。它的稳定性和 我们阿米什参与者的参与使认知和生物标记物的纵向评估成为可能。我们的 主要目标是识别AD保护性基因，并表征临床前进展为 认知障碍。在我们现有的大量队列的基础上，我们复制的保护基因和几个提示性的 保护性基因座，以及我们现有的DNA和血浆生物库以及GWAS和WGS的数据库，我们建议： 1)在我们以家庭为基础的阿米什队列中进行认知的纵向评估；2)确定保护因素 对于AD和通过分析基因组和纵向认知的进展到认知损害的预测因素， 生物标记物和SDOH数据；以及3)检查现有的和新的基因和变体的功能含义 通过将在计算机注释中使用的基因座优先用于功能后果，其次是体外功能 人物刻画。我们的结果将确定潜在的可用药靶点，并加速开发更好的 治疗阿尔茨海默病。

Alzheimer disease (AD) is a devastating neurodegenerative disorder that affects millions of individuals in the U.S. It has so far resisted attempts to develop effective therapies despite numerous (failed) clinical trials based on known targets, most identified over 20 years ago. While genomic research (e.g. the Alzheimer’s Disease Sequencing Project; ADSP) has identified numerous additional risk loci, these results derive primarily from case- control datasets. In contrast, cohorts designed to identify variants that may protect from AD, and those using complementary study designs, are few. We used our extensive experience with the Amish communities in Indiana and Ohio to establish a cohort of older individuals at high risk of developing AD but who are cognitively unimpaired (CU). The Amish provide a unique opportunity to identify protective variants for AD because of their reduced background genetic variation and environmental risk factors. Their small founding population and endogamy provides enrichment for rare variants. Founder populations also enable testing for non-additive allelic effects and can magnify sub-significant association signals identified in case-control studies. The stability and engagement of our Amish participants enables longitudinal assessments of cognition and biomarkers. Our primary goals are to identify AD protective loci and characterize pre-clinical biomarkers of progression to cognitive impairment. Building on our existing large cohort, our replicated protective locus and several suggestive protective loci, and our existing biobank of DNA and plasma and databank of GWAS and WGS, we propose to: 1) Perform longitudinal assessment of cognition in our family-based Amish cohort; 2) Identify protective factors for AD and predictors of progression to cognitive impairment by analyzing genomic and longitudinal cognitive, biomarker, and SDOH data; and 3) Examine the functional implications of current and novel genes and variants by prioritizing loci using in silico annotation for functional consequences followed by in vitro functional characterization. Our results will identify potential druggable targets and accelerate the development of better treatments for AD.