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

阿尔茨海默病和创伤导致的早期认知障碍

• 批准号: 10479319
• 负责人: MARK W LOGUE
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10479319
• 关键词: Address; African; African American; African ancestry; Age; Age-associated memory impairment; Aging; Algorithms; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Area; Benchmarking; Blood Vessels; Clinical; Cognitive; Cohort Studies; Complex; Computerized Medical Record; Craniocerebral Trauma; Data; Dementia; Development; Diabetes Mellitus; Diagnosis; Disparity; Early Diagnosis; Environment; Environmental Exposure; Environmental Risk Factor; Genes; Genetic; Genetic Diseases; Genetic Risk; Genome; Genomics; Genotype; Health; Hispanic; Hispanic Populations; Hispanic ancestry; Impaired cognition; Individual; International Classification of Disease Codes; Knowledge; Late Onset Alzheimer Disease; Link; Machine Learning; Medical Records; Methods; Military Personnel; Not Hispanic or Latino; Participant; Pathology; Patient Self-Report; Patients; Performance; Phenotype; Population; Post-Traumatic Stress Disorders; Prevalence; Proxy; Psychopathology; Reporting; Research Priority; Risk; Risk Factors; Sensitivity and Specificity; Source; Techniques; Toxin; Trauma; Traumatic Brain Injury; Variant; Vascular Dementia; Veterans; Work; agent orange; biobank; cognitive testing; cohort; combat; combat trauma; dementia risk; disorder risk; effective therapy; follow-up; gene environment interaction; genetic analysis; genetic architecture; genetic association; genetic risk factor; genetic variant; genome wide association study; genome-wide; health disparity; improved; machine learning method; mild cognitive impairment; phenotyping algorithm; polygenic risk score; programs; risk prediction; risk variant; symptomatology

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.

痴呆症的风险，包括晚期阿尔茨海默氏病（AD）和血管痴呆的风险 由环境，健康和遗传因素的复杂混合物决定。退伍军人有 血管问题，PTSD，战斗创伤和脑损伤的率更高，这 全部与年龄相关的认知障碍和痴呆症的率提高有关。 此外，研究表明，这些与退伍军人相关的暴露可能与AD相互作用 遗传学进一步增加认知能力下降的风险。此应用程序代表 通过环境研究痴呆和战斗相关基因的项目的产物（GXE） 百万退伍军人计划（MVP）的互动，这是世界上最大的电子医学之一 记录（EMR）链接的生物库。最初生成的最初的2年MVP Gamma项目（MVP015） VA的轻度认知障碍（MCI），AD和全因痴呆的工作定义 emr。检查了这些与战斗暴露，头部受伤和PTSD相关的检查 老化的退伍军人。我们发现了头部受伤，战斗，PTSD症状和AD的证据 遗传风险变异都与自我报告的认知难度和MCI有关 年轻时的退伍军人，以及65岁以上的AD和相关痴呆症。我们 此外，还鉴定了几个基因中候选变体之间的GXE相互作用 MCI和AD风险的战斗/头部受伤。在此应用程序中，我们建议扩展初始 研究，通过1）进行痴呆病例的基因组广泛关联研究（GWAS）和 多个祖先的控制以及检查基于GWA的表现 非裔美国人和西班牙裔MVP参与者的遗传风险评分，2）表演 多元GXE分析检查了一系列老兵相关健康暴露，3）进一步 在MVP中开发和验证痴呆症诊断，以进行包括机器在内的遗传分析 基于学习鉴定痴呆症病例的方法。这个项目将扩大我们的 继续工作并增加我们对资深特定环境影响的知识 暴露及其与AD基因的AD和痴呆症的相互作用。