EFFECTS OF STRESS, ALLOSTATIC LOAD, AND SOCIAL INEQUITIES ON BRAIN STRUCTURE, FUNCTION, AND COGNITION IN THE EARLY-TO-MIDLIFE TRANSITION

项目1的摘要 “压力”会加速生物衰老，增加许多疾病的风险，包括阿尔茨海默病(AD)和 与AD相关的痴呆(ADRD)，并增加死亡率。同素作用是有机体作出反应的过程。 应激以恢复动态平衡，使一系列生理、生化和分子过程运转 在音乐会上。当压力过大时，这些反应会在细胞和器官中产生不健康的长期变化 结构和功能，包括大脑。“动静载荷”是一种包含这种磨损的有用结构。 以及身体和大脑的撕裂，动物和一些人类的研究已经提出了许多方法 慢性应激直接或间接影响神经元、神经胶质细胞和神经化学，并与局部 大脑的连通性和功能会增加晚年患痴呆症的风险。解决何时、如何 压力和不稳定负荷是通过什么机制增加大脑在晚年对AD/ADRD的易感性 需要一个寿命视角和一个大型的、表型丰富的纵向队列。项目1将调查 成年后压力如何影响大脑的结构、功能和神经化学。我们的总体模式 年轻人和中年人的压力水平越高，就会导致更大的非稳态负荷，并与 中年的心血管和代谢健康问题。稳态负荷与高血压、肥胖症和胰岛素 耐药性改变了大脑的炎症、血管和代谢环境，增加了对AD/ADRD的易感性 晚年的痴呆症。项目1将重点关注年轻人到中年的过渡，这是成人生活的一个阶段，当 压力水平最高，大脑脆弱的最早信号出现。从机制上讲，我们关注的是 免疫失调和炎症是慢性应激状态的重要早期特征， 淀粉样蛋白、tau蛋白和神经变性的出现。AABC和Project 1也扩大了其评估范围 描述社会不平等和健康差距在代表性不足的人群中的独特压力来源 民族群体，以增加对这些群体的脆弱性的了解 AD/ADRD。在目标1中，我们确定了应激措施对大脑结构、功能、神经化学的影响 和认知，特别是在AABC的年轻成年人到中年参与者中。在目标2中，我们确定了 应激措施对先天免疫失调、异位负荷和神经退行性变生物标志物的影响及其应用 中介模型，以评估压力、稳态负荷、大脑脆弱性和认知之间的关系。 目的3探讨地位相关社会决定因素、应激源和应激经历对变态反应的影响 民族人群的负荷、脑结构、功能、神经化学和认知。在目标4中，我们将协同 在项目2、3和4中，通过研究压力、先天免疫失调和平衡负荷的影响 与项目2、项目3中的更年期以及 在项目4中，脑血管疾病和AD/ADRD疾病在弹性/抵抗老化与不成功老化中表现出来。

ABSTRACT FOR PROJECT 1 "Stress" accelerates biological aging, increases risk for many diseases, including Alzheimer's disease (AD) and AD-related dementias (ADRD), and increases mortality. Allostasis is the process by which an organism responds to stress to regain homeostasis, engaging a host of physiological, biochemical, and molecular processes working in concert. When over-stressed, these responses produce unhealthy long-lasting changes in cell and organ structure and function, including the brain. "Allostatic load" has been a useful construct encompassing such wear and tear in the body and the brain, and animal and some human research have proposed many ways in which chronic stress directly or indirectly affects neurons, glia and neurochemistry, with associated changes in regional brain connectivity and function that would increase vulnerability to dementia in later life. To address when, how and by what mechanisms stress and allostatic load increase the brain's vulnerability to AD/ADRD in later life requires a lifespan perspective and a large, richly phenotyped longitudinal cohort. Project 1 will investigate how stress affects the brain's structure, function and neurochemistry across adulthood. Our overarching model is that higher levels of stress in younger and middle-aged adults leads to greater allostatic load and associated cardiovascular and metabolic health problems in middle age. Allostatic load and hypertension, obesity and insulin resistance alter the inflammatory, vascular and metabolic milieu of the brain, increasing vulnerability to AD/ADRD dementias of later life. Project 1 will focus on the young adult to mid-life transition, a stage of adult life when stress levels are highest and the earliest signals of brain vulnerability emerge. Mechanistically, we focus on immune dysregulation and inflammation as an important early feature of chronic stress states, allostatic load, and the emergence of amyloid, tau and neurodegeneration. AABC and Project 1 also expands its assessments to characterize the distinctive stressors of social inequities and health disparities in under-represented ethnoracial groups in order to increase understanding of the increased vulnerability these groups have for AD/ADRD. In Aim 1, we determine the effects of stress measures on brain structure, function, neurochemistry and cognition, especially in AABC's younger adult to middle-aged participants. In Aim 2, we determine the effects of stress measures on innate immune dysregulation, allostatic load and neurodegeneration biomarkers and use mediation models to evaluate the relationships among stress, allostatic load, brain vulnerability and cognition. Aim 3 investigate the effects of status-related social determinants, stressors and stress experience on allostatic load, brain structure, function and neurochemistry and cognition in ethnoracial groups. In Aim 4, we will synergize with Projects, 2, 3 and 4 by investigating the effects of stress, innate immune dysregulation and allostatic load in relation to physical activity, sleep and resilient lifestyle factors of Project 2, menopause in Project 3, and the manifest cerebrovascular and AD/ADRD diseases in resilient/resistant vs. unsuccessful aging in Project 4.