Trauma Exposure and Cognitive Impairment: Understanding Polygenic Liability and the Causative and Moderating Effects of Exposure, PTSD, and Psychiatric Comorbidity in WTC Responders

标题：创伤暴露和认知损害：理解多基因责任和致因和 WTC应答者暴露、创伤后应激障碍和精神共病的缓解作用 摘要：阿尔茨海默病是一种最终致命的神经退行性疾病。的前驱阶段 这种疾病开始于认知能力的逐渐下降，当这些 损伤影响日常生活的基本活动。本提案回应FOA编号RFA-OH-21-004 (与世界贸易中心健康计划相关的探索性/发展性赠款) 以及支持WTC认知障碍和精神共病的环境交易 响应者。这项建议的研究活动在全球大流行期间是可行的，建立在 团队在数量和分子遗传学、纵向建模、认知老化和 阿尔茨海默病和相关痴呆的发病机制。具体地说，遗传信息丰富， 来自世界贸易中心(WTC)健康计划的纵向数据将被分析，以增加 准确估计WTC应答者的暴露影响，并更好地了解 以及导致认知障碍、抑郁及其纵向共同作用的环境交易。 发生了。WTC应答者的认知障碍发生率高于普通人群， 由创伤后应激障碍和抑郁症状的纵向增加所致。此外，两者之间的联系 世界旅游中心应答者的暴露严重程度和认知损害在APOE-ε4中尤为明显 携带者9，符合基因与环境的相互作用。拟议的数据分析通过以下方式扩展了这项工作 解决(1)暴露严重程度和认知损害之间以及暴露严重程度和认知损害之间的关系 创伤后应激障碍和认知损害符合因果关系；(2)无论暴露的严重程度， 创伤后应激障碍和抑郁症状对WTC应答者认知障碍的多基因易感性是适度的， 同时(3)支持比较性别、种族和民族群体在纵向变化方面的差异 认知健康。了解促成和加剧的致病因素和缓和因素 阿尔茨海默病的前驱症状，包括认知障碍，对理解 发病机制及制定有效的治疗和干预策略。

Title: Trauma Exposure and Cognitive Impairment: Understanding Polygenic Liability and the Causative and Moderating Effects of Exposure, PTSD, and Psychiatric Comorbidity in WTC Responders Abstract: Alzheimer's Disease is a neurodegenerative disorder that is ultimately fatal. The prodromal phase of the disease begins with the gradual decline of cognitive ability, and risk of death increases when these impairments affect basic activities of daily living. This proposal responds to FOA number RFA-OH-21-004 (Exploratory/Developmental Grants Related to the World Trade Center Health Program) by delineating genetic and environmental transactions that undergird cognitive impairment and psychiatric comorbidity in WTC responders. The research activities of this proposal are feasible during a global pandemic, build upon the team's existing expertise in quantitative and molecular genetics, longitudinal modeling, cognitive aging, and the pathogenesis of Alzheimer's Disease and related dementia (ADRD). Specifically, genetically-informative, longitudinal data from the World Trade Center (WTC) Health program will be analyzed to increase the precision with which exposure effects are estimated for WTC responders and better understand the genetic and environmental transactions that contribute to cognitive impairment, depression, and their longitudinal co- occurrence. Incidence of cognitive impairment is higher in WTC responders than in the general population, precipitated by longitudinal increases in PTSD and depressive symptoms. Moreover, the link between exposure severity and cognitive impairment in WTC responders is especially pronounced among APOE-ε4 carriers9, consistent with a gene-by-environment interaction. The proposed data analysis extends this work by addressing (1) whether the association between exposure severity and cognitive impairment, and between PTSD and cognitive impairment are consistent with a cause-effect relation; and (2) whether exposure severity, PTSD, and depressive symptoms moderate polygenic liability for cognitive impairment in WTC responders, while also (3) supporting comparisons of gender, race, and ethnic group differences in longitudinal changes in cognitive health. Understanding the causative and moderating factors that contribute to and exacerbate prodromal symptoms of Alzheimer's Disease, including cognitive impairment, is critical to understanding pathogenesis and the development of effective treatment and intervention strategies.