Immunosenescence, socioeconomic disadvantage and dementia in the US aging population

虽然认知能力下降和阿尔茨海默病及相关痴呆症（ADRD）的风险因素已经被发现， 尽管已经被广泛研究，但对于导致ADRD的生物学途径仍有很多未知之处。这个项目 旨在通过检查认知功能下降和ADRD的病理生理学， 外周免疫衰老在这些过程中的作用。现有研究的一个主要差距是缺乏 纵向研究，可以建立外周免疫衰老和 ADRD事件的发展。此外，很少有基于人口的研究来检查这些过程 在美国的代表性样品中。基于人群的研究可以评估ADRD的临床结果是否 患者可推广到更广泛的人群，并检查社会决定因素在其中的作用。 流程.尽管在民主与复兴运动中始终观察到社会不平等，包括基于种族/族裔的不平等， 性别、社会经济地位、社会弱势导致ADRD的途径并不好 这限制了全人群ADRD预防策略。我们的长期目标是阐明 在预测ADRD中的作用。当前提案的总体目标是评估 外周免疫衰老与领域特异性认知功能、衰退和 ADRD诊断在美国老年人的全国代表性样本，并检查在何种程度上， 免疫衰老解释了认知功能、衰退和ADRD中的社会不平等。我们的中央 一种假说认为，免疫衰老，其特征在于衰老免疫细胞数量的增加， (e.g., CD 8 + CD 45 RA-，CD 4 + CD 45 RA-）和升高的炎性细胞因子（C-反应蛋白（CRP）， 白细胞介素（IL）-6，TNF-α）将与更差认知结果相关， 将部分解释认知结果中的一些社会不平等。建议的理由 研究表明，免疫衰老可能是ADRD的一个重要的早期风险因素，可能代表了ADRD的一个潜在危险因素。 解释ADRD风险的人群异质性和不平等的生物学机制。调查这些 我们将追求三个具体目标：1）确定周边之间的关联 健康和退休研究（HRS）中的免疫衰老和认知功能以及下降; 2） 确定外周免疫衰老与通过HRS测量的ADRD事件之间的相关性 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中的社会不平等。这项建议是 这将是第一个大规模的基于人群的免疫和认知研究。它将产生 关键的见解，我们的认知能力下降和ADRD的病理生理学的理解，以及不平等， 这些过程。该项目意义重大，因为其结果可能指向新的诊断工具， 辨别外周血中ADRD的免疫衰老预测谱。

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.