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。 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较高， 所有这些都与年龄相关的认知障碍和痴呆症发病率增加有关。 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。 一个项目的成果，通过环境检查痴呆症和对抗相关基因（GxE） 百万退伍军人计划 (MVP) 中的互动，这是世界上最大的电子医疗项目之一 记录（EMR）链接的生物库生成了原始的 2 年 MVP Gamma 项目（MVP015）。 VA 对轻度认知障碍 (MCI)、AD 和全因痴呆的工作定义 EMR 检查了这些与战斗暴露、头部受伤和创伤后应激障碍 (PTSD) 的关系。 我们发现了头部受伤、战斗、创伤后应激障碍 (PTSD) 症状和 AD 的证据。 遗传风险变异均与自我报告的认知困难和 MCI 有关 年龄在 45-55 岁之间的退伍军人，以及患有 AD 和相关痴呆症的年龄在 65 岁以上的人。 另外还确定了多个基因中候选变体之间的 GxE 相互作用， 战斗/头部受伤对 MCI 和 AD 风险的影响 在此应用中，我们建议扩展最初的内容。 研究，通过 1) 对痴呆症病例进行全基因组关联研究 (GWAS) 和 多个祖先群体的控制以及检查基于 GWAS 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) 多变量 GxE 分析检查一系列退伍军人相关的健康暴露，3) 在 MVP 中开发和验证痴呆症诊断，以进行基因分析，包括机器 该项目将扩展我们基于学习的痴呆症病例识别方法。 继续工作并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。