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，影响着数以百万计的人 尽管进行了大量（失败的）临床试验，但美国迄今为止仍拒绝开发有效疗法的尝试 针对已知目标，大多数是 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）已经确定了许多额外的风险位点，这些结果主要来自案例 - 控制数据集。相比之下，旨在识别可能预防 AD 的变体的队列，以及那些使用 互补的研究设计很少。我们运用了与阿米什社区打交道的丰富经验 印第安纳州和俄亥俄州将建立一组患有 AD 高风险但认知能力较差的老年人群体 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 减少背景遗传变异和环境风险因素。他们的建国人口很少，而且 内婚制丰富了稀有变异。创始人群体还可以测试非加性等位基因 效应，并可以放大病例对照研究中发现的次显着关联信号。稳定性和 阿米什参与者的参与可以对认知和生物标志物进行纵向评估。我们的 主要目标是确定 AD 保护性位点并表征进展为 AD 的临床前生物标志物 认知障碍。建立在我们现有的大型队列、我们复制的保护位点和几个提示性的基础上 保护位点，以及我们现有的 DNA 和血浆生物库以及 GWAS 和 WGS 数据库，我们建议： 1) 对我们以家庭为基础的阿米什队列进行认知纵向评估； 2）识别保护因素 通过分析基因组和纵向认知来确定 AD 和认知障碍进展的预测因素， 生物标志物和 SDOH 数据； 3) 检查当前和新基因及变异的功能含义 通过优先考虑使用计算机注释功能结果的基因座，然后是体外功能 表征。我们的结果将确定潜在的药物靶标并加速开发更好的药物 AD 的治疗。

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.