Early Cognitive Impairment as a function of Alzheimer's Disease and Trauma

痴呆症的风险，包括迟发性阿尔茨海默病（AD）和血管性痴呆， 由环境、健康和遗传因素的复杂组合决定。老兵 血管问题、创伤后应激障碍、战斗创伤和创伤性脑损伤的发生率更高， 都与年龄相关的认知障碍和痴呆症的发病率增加有关。 此外，研究表明，这些退伍军人相关的暴露可能与AD相互作用 遗传学，以进一步增加认知能力下降的风险。此应用程序代表了 一个研究痴呆症和环境相关基因（GxE）的项目的结果 百万退伍军人计划（MVP），世界上最大的电子医疗之一， 记录（EMR）链接的生物库。最初的2年MVP伽马项目（MVP 015）生成 轻度认知功能障碍（MCI）、AD和全因痴呆的工作定义 电子病历。研究人员对这些人进行了与战斗暴露、头部受伤和创伤后应激障碍的相关性检查， 老退伍军人我们发现有证据表明，头部受伤，战斗，创伤后应激障碍， 遗传风险变异都与自我报告的认知困难和MCI相关， 45-55岁的退伍军人，以及65岁以上的AD和相关痴呆症患者。我们 另外鉴定了几个基因中候选变体之间的GxE相互作用， 战斗/头部损伤对MCI和AD风险的影响。在本申请中，我们建议在最初的 研究，通过1）进行痴呆病例的全基因组关联研究（GWAS）， 控制在多个祖先群体，以及检查的性能， 非裔美国人和西班牙裔MVP参与者的遗传风险评分，2）执行 检查一系列退伍军人相关健康暴露的多变量GxE分析，3）进一步 在MVP中开发和验证痴呆症诊断，用于遗传分析，包括机器 以学习为基础的痴呆症病例识别方法。该项目将扩大我们的 继续工作，增加我们对退伍军人特定环境影响的了解 暴露及其与AD基因的相互作用对AD和痴呆风险的影响。

Risk for dementia, including late-onset Alzheimer’s disease (AD) and vascular dementia, is determined by a complex mix of environmental, health, and genetic factors. Veterans have higher rates of vascular problems, PTSD, combat trauma, and traumatic brain injuries, which have all been linked to increased rates of age-related cognitive impairment and dementia. Further, studies have indicated that these Veteran-relevant exposures may interact with AD genetics to further increase the risk of cognitive decline. This application represents an outgrowth of a project examining dementia and combat related gene by environment (GxE) interactions in the Million Veteran Program (MVP), one of the world’s largest electronic-medical record (EMR) linked biobanks. The original 2-year MVP Gamma project (MVP015) generated working definitions of mild cognitive impairment (MCI), AD, and all-cause dementia from the VA EMR. These were examined for association with combat exposure, head injury, and PTSD in aging Veterans. We found evidence that head injury, combat, PTSD symptomatology, and AD genetic risk variants were all associated with self-reported cognitive difficulties and MCI in Veterans as young as 45-55, and with AD and related dementias in those age 65+. We additionally identified GxE interactions between candidate variants in several genes and combat/head injury on MCI and AD risk. In this application, we propose expanding on the initial study, by 1) performing a genome wide association study (GWAS) of Dementia cases and controls in multiple ancestry groups as well as examining the performance of GWAS-based genetic risk scores in African American and Hispanic MVP participants, 2) performing multivariate GxE analyses examining a range of Veteran relevant health exposures, 3) Further developing and validating dementia diagnoses in MVP for genetic analyses including a machine learning based method of identification of Dementia cases. This project will expand on our continuing work and increase our knowledge of the impact of Veteran specific environmental exposures and their interactions with AD genes on risk for AD and dementia.