Immunosenescence, socioeconomic disadvantage and dementia in the US aging population

而认知能力下降和阿尔茨海默病及相关痴呆(ADRD)的风险因素 尽管研究广泛，但导致ADRD的生物学途径仍有许多未知之处。这个项目 通过研究认知功能减退和ADRD的病理生理学 外周免疫衰老在这些过程中的作用。现有研究中的一个主要差距是缺乏 可以建立外周免疫衰老和疾病之间病因联系的纵向研究 ADRD事件的发展。此外，很少有基于人群的研究来检验这些过程 在美国有代表性的样本中。基于人群的研究可以评估ADRD的临床表现 患者可以推广到更广泛的人群，并检查社会决定因素在这些方面的作用 流程。尽管在消除种族歧视方面一贯观察到社会不平等，包括基于种族/族裔的不平等， 性别/性别和社会经济地位，社会劣势导致ADRD的途径不是很好 理解，限制全人口的ADRD预防战略。我们的长期目标是阐明这个角色 人群免疫力在预测ADRD中的作用。目前提案的总体目标是评估 外周免疫衰老与特定领域认知功能、认知功能下降和 ADRD在具有全国代表性的美国老年人样本中进行诊断，并检查 免疫衰老解释了认知功能、衰退和ADRD方面的社会不平等。我们的中央 假说是免疫衰老，其特征是衰老的免疫细胞数量增加 (例如CD8+CD45RA-、CD4+CD45RA-)和升高的炎性细胞因子(C-反应蛋白(CRP)， 白介素6，肿瘤坏死因子-α)将与较差的认知结果和免疫衰老有关 将部分解释认知结果中的一些社会不平等。建议的理由是 研究表明，免疫衰老可能是ADRD的一个重要早期风险因素，可能代表着一种 解释ADRD风险中种群异质性和不平等的生物学机制。为了调查这些 关系，我们将追求三个具体目标：1)确定外围设备之间的关联 健康和退休研究(HRS)中的免疫衰老和认知功能下降；2) 确定外周免疫衰老与HRS测量的ADRD事件之间的关联 认知评估和相关的医疗保险索赔数据；以及3)确定 免疫衰老解释了认知功能、衰退和ADRD方面的社会不平等。这项建议是 具有创新性，因为这将是第一次大规模的基于人群的免疫和认知研究。它会屈服的 对我们理解认知衰退和ADRD的病理生理学的重要见解，以及 这些过程。该项目意义重大，因为其结果可能指向能够 识别外周血中预测ADRD的免疫衰老特征。

While risk factors for cognitive decline and Alzheimer's Disease and related dementias (ADRD) have been widely studied, there is still much unknown about the biological pathways that lead to ADRD. This project seeks to improve our understanding of the pathophysiology of cognitive decline and ADRD by examining the role of peripheral immunosenescence in these processes. A major gap in existing research is a lack of longitudinal studies that can establish an etiologic link between peripheral immunosenescence and development of incident ADRD. In addition, there are few population-based studies examining these processes in U.S. representative samples. Population-based studies can evaluate whether clinical findings among ADRD patients are generalizable to the broader population as well as examine the role of social determinants in these processes. Despite consistently observed social inequalities in ADRD, including on the basis of race/ethnicity, sex/gender, and socioeconomic status, the pathways by which social disadvantage lead to ADRD are not well understood, limiting population-wide ADRD prevention strategies. Our long-term goal is to elucidate the role of population immunity in predicting ADRD. The overall objective of the current proposal is to evaluate the relationship between peripheral immunosenescence and domain-specific cognitive function, decline, and ADRD diagnoses in a nationally representative sample of older US adults, and, to examine the extent to which immunosenescence explains social inequalities in cognitive function, decline, and ADRD. Our central hypothesis is that immunosenescence, characterized by an increased number of senescent immune cells (e.g., CD8+CD45RA-, CD4+CD45RA-) and elevated inflammatory cytokines (C-Reactive Protein (CRP), interleukin (IL)-6, TNF-alpha) will be associated with worse cognitive outcomes, and that immunosenescence will partially explain some of the social inequalities in cognitive outcomes. The rationale for the proposed research is that immunosenescence may be an important early risk factor for ADRD, potentially representing a biological mechanism explaining population heterogeneity and inequalities in ADRD risk. To investigate these relationships, we will pursue three specific aims:1) Determine the association between peripheral immunosenescence and cognitive function and decline in the Health and Retirement Study (HRS); 2) Determine the association between peripheral immunosenescence and incident ADRD measured both by HRS cognitive assessment and linked Medicare claim data; and 3) Determine the extent to which immunosenescence explains social inequalities in cognitive function, decline, and ADRD. This proposal is innovative as it will be the first large-scale population-based study of immunity and cognition. It will yield critical insights to our understanding of the pathophysiology of cognitive decline and ADRD, and inequalities in these processes. This project is significant because the results could point to new diagnostic tools able to discern profiles of immunosenescence predictive of ADRD in the peripheral blood.