Effects of lifecourse traumatic stress on late-life cognitive decline, dementia, and neuroimaging biomarkers

项目摘要/摘要 多达一半的阿尔茨海默病和阿尔茨海默病相关痴呆(AD/ADRD)病例是由于 潜在的可改变的暴露，包括心理社会因素。暴露在创伤性事件中 生命课无处不在，特别是在经历AD/ADRD负担过高的群体中。压力 致敏模型表明，创伤暴露，特别是在生命早期，可以导致大脑变化和 增加精神病态的易感性。然而，应激敏化模型并没有扩展到后期- 生活神经学结果和很少有研究关于生活过程创伤应激暴露对 AD/ADRD风险。这项研究计划的科学目标是了解创伤应激对 在晚年的认知和神经成像，并确定改变这些影响的因素，包括晚年 韧性的贡献者。利用最先进的统计方法，研究将：(1)估计 生活过程中创伤应激对老年认知功能减退、痴呆和神经影像生物标志物的影响 AD/ADRD，(2)确定个人特征和早期生活因素(例如，性别/性别、种族/族裔、教育) 修正生活过程创伤应激对晚年认知功能减退和痴呆的影响，(3)测试压力 确定童年创伤和逆境是否改变成年创伤效果的敏化模型 对晚年认知衰退和痴呆症的压力，以及(4)确定晚年复原力因素(例如社交 支持/融合、财务安全、体力活动)，以减轻生活过程创伤应激对 晚年认知功能衰退和痴呆症。拟议的数据工作使用了来自美国全国代表的数据 健康和退休研究(HRS)和来自两个新获得的、协调的和多样化的队列的汇集数据 具有强大的神经认知评估(Kaiser Healthy Ageing和多样化生活体验[KANDLE]和 非裔美国人健康老龄化研究[STAR]。这项研究是针对NIA的战略研究 与了解个人、人际和社会因素对老龄化的影响和 老龄化方面的差距。了解生活过程创伤应激的影响，包括效果修饰剂和迟发性应激 生活复原力因素，将提高对AD/ADRD决定因素的理解，并提供可行的战略 预防AD/ADRD，减少AD/ADRD差异。这项研究计划与培训计划相辅相成 这是以申请人在流行病学和生物统计学方面的背景为基础的，并包括新的培训，以(1)获得 对脑和认知老化研究的科学和方法有扎实的基础知识；(2)发展 研究创伤和创伤应激及其对大脑健康的影响方面的专业知识，以及(3)掌握以下方面的技能 用于因果推断和识别异质治疗效果的机器学习方法。这个 综合研究和培训计划将使申请者为成功的独立研究生涯做好准备 重点了解创伤和不同人群中AD/ADRD的其他心理社会决定因素。

Project Summary/Abstract Up to half of Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) cases are due to potentially modifiable exposures, including psychosocial factors. Exposure to traumatic events over the lifecourse is pervasive, particularly in groups that experience disproportionately high burden of AD/ADRD. Stress sensitization models suggest that trauma exposure, especially in early life, can result in brain changes and increase vulnerability to psychopathology. However, stress sensitization models have not been extended to late- life neurological outcomes and very little research exists on effects of lifecourse traumatic stress exposure on AD/ADRD risk. The scientific objective of this research plan is to understand effects of traumatic stress on cognition and neuroimaging in late life and to identify factors that modify these effects, including late-life contributors to resilience. Using state-of-the art statistical methods, the research will: (1) estimate the effect of traumatic stress over the lifecourse on late-life cognitive decline, dementia, and neuroimaging biomarkers of AD/ADRD, (2) identify individual characteristics and early-life factors (e.g. sex/gender, race/ethnicity, education) that modify the impact of lifecourse traumatic stress on late-life cognitive decline and dementia, (3) test the stress sensitization model to determine if childhood trauma and adversity modifies the effect of adulthood traumatic stress on late-life cognitive decline and dementia, and (4) identify late-life resilience factors (e.g. social support/integration, financial security, physical activity) that mitigate the impact of lifecourse traumatic stress on late-life cognitive decline and dementia. The proposed data work uses data from the US nationally-representative Health and Retirement Study (HRS) and pooled data from two newly available, harmonized, and diverse cohorts with robust neurocognitive assessments (Kaiser Healthy Aging and Diverse Life Experiences [KHANDLE] and Study of Healthy Aging in African Americans [STAR]). The research addresses the NIA strategic research directions related to understanding effects of personal, interpersonal, and societal factors on aging and disparities in aging. Understanding the impact of lifecourse traumatic stress, including effect modifiers and late- life resilience factors, will improve understanding of determinants of AD/ADRD and inform actionable strategies to prevent AD/ADRD and reduce AD/ADRD disparities. This research plan is complemented by a training plan that builds on the applicant’s background in epidemiology and biostatistics and includes new training to (1) gain strong foundational knowledge in the science and methods of brain and cognitive aging research; (2) develop expertise in the study of trauma and traumatic stress and their impact on brain health, and (3) gain skills in machine learning approaches for causal inference and identifying heterogeneous treatment effects. The combined research and training plans will prepare the applicant for a successful independent research career focused on understanding trauma and other psychosocial determinants of AD/ADRD in diverse populations.