Immune Cells in Alzheimer’s Disease and Related Dementias in the Jackson Heart Study

项目摘要 大多数老年人的免疫系统功能发生变化，导致慢性升高， 炎症生物标志物。慢性炎症会导致许多与年龄相关的疾病的风险增加，包括 阿尔茨海默病和相关痴呆症（ADRD）;然而，确切的机制仍不清楚。有 非裔美国人人群中ADRD和慢性炎症的负担更高，可能在很大程度上 由于健康的社会决定因素（SDOH）和心理社会压力。先天性和适应性促炎 循环免疫细胞和这些细胞类型中的炎症相关基因可能与 社区居住的非洲老年人患轻度认知障碍（MCI）和痴呆症的风险增加 美国人我们建议表征单核细胞、T和B细胞以及先天性巨噬细胞的循环比例。 淋巴细胞（>50种细胞表型）和免疫细胞中的基因表达 参与者参加了基于人群的杰克逊心脏研究，使用收集的样本 并在即将到来的考试4（2021-2023）中存储。然后，我们将评估免疫细胞的关联， 炎症通路基因表达与年龄、心理社会应激和SDOH， 阿尔茨海默病神经病理学、基于磁共振成像（MRI）的神经变性和 脑血管疾病测量，以及MCI和痴呆状态。我们将研究这些关系， 使用先前资助的RNA测序和免疫表型数据， 在杰克逊心脏研究基线检查时，并根据已知的性别差异评估性别差异， 免疫系统功能。我们推测，促炎细胞类型和转录本将与 与MCI、痴呆及其危险因素有关，炎症可能在统计学上介导MCI、痴呆及其危险因素之间的关联， 更高的心理社会压力/SDOH负担和MCI/痴呆的风险。我们还将使用来自免疫细胞的数据 确定痴呆症风险变体的假定靶基因和生物学机制，特别是对于 在非洲和欧洲血统的人群中更常见。本研究响应PAR-19-070 （NOT-AG-18-047：健康差异和阿尔茨海默病），以及2021年1月批准的NIA 这一概念要求增加ADRD中获得性免疫的研究。它将增加独特的免疫功能和RNA 测序数据，以一个最大的正在进行的队列研究，老龄化的非洲裔美国人， 自2000年以来可获得纵向表型分析。生成的数据将广泛提供给 科学界通过适当的公共存储库（如dbGaP），并可用于解决如何 免疫细胞及其基因表达影响痴呆和其他重要疾病结局的风险 在老龄化的非裔美国人中，横向和纵向。识别特异性和非侵入性 与MCI和痴呆风险相关的炎症生物标志物将提高对疾病生物学的理解 并为ADRD的假定抗炎疗法的选择提供信息。

PROJECT SUMMARY Most older adults experience changes in immune system function which lead to chronic elevations in inflammation biomarkers. Chronic inflammation leads to elevated risk of many age-related disorders, including Alzheimer’s disease and related dementias (ADRD); however, the exact mechanisms remain unclear. There is a higher burden of both ADRD and chronic inflammation in African American populations, likely in large part due to social determinants of health (SDOH) and psychosocial stress. Pro-inflammatory innate and adaptive circulating immune cells, and inflammation related genes in these cell types, may be associated with an increased risk of mild cognitive impairment (MCI) and dementia among community-dwelling older African Americans. We propose to characterize the circulating proportions of monocytes, T and B cell, and innate lymphocytes (>50 cellular phenotypes) and gene expression in immune cells in ~1440 African American participants enrolled in the well-characterized population-based Jackson Heart Study, using samples collected and stored at the upcoming Exam 4 (2021-2023). We will then evaluate associations of immune cells and inflammation pathway gene expression with age, psychosocial stress and SDOH, plasma biomarkers of Alzheimer’s disease neuropathology, magnetic resonance imaging (MRI) based neurodegeneration and cerebrovascular disease measures, and MCI and dementia status. We will examine these relationships both cross-sectionally and longitudinally, using previously funded RNA-sequencing and immune phenotyping data at the Jackson Heart Study baseline exam, and assess differences by sex, given known sex differences in immune system function. We hypothesize that pro-inflammatory cell types and transcripts will be associated with MCI, dementia, and its risk factors and that inflammation may statistically mediate associations between higher psychosocial stress/SDOH burden and risk of MCI/dementia. We will also use data from immune cells to identify putative target genes and biological mechanisms for dementia risk variants, especially for variants more common in African versus European ancestry populations. This study is responsive to PAR-19-070 (NOT-AG-18-047: Health Disparities and Alzheimer’s Disease), as well as the January 2021 NIA approved concept calling for increased study of adaptive immunity in ADRD. It will add unique immune function and RNA sequencing data to one of the largest ongoing cohort studies of aging African American adults, with longitudinal phenotyping available since 2000. The generated data will be made widely available to the scientific community through appropriate public repositories (such as dbGaP) and can be used to address how immune cells and their gene expression influence risk of both dementia and other important disease outcomes in aging African Americans, cross-sectionally and longitudinally. Identification of specific and non-invasive inflammation biomarkers associated with MCI and dementia risk will improve understanding of disease biology and inform selection of putative anti-inflammatory therapeutics for ADRD.