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

杰克逊心脏研究中阿尔茨海默病和相关痴呆症中的免疫细胞

• 批准号: 10370451
• 负责人: Laura M Raffield
• 金额: $ 80.48万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370451
• 关键词: Address; Adult; African; African American; African American population; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; Amyloid; Anti-Inflammatory Agents; B-Lymphocytes; Biological; Biological Markers; Biology; Brain; C-reactive protein; CD8-Positive T-Lymphocytes; Cause of Death; Cells; Cellular Immunity; Cerebrovascular Disorders; Childhood; Chronic; Chronic stress; Cognition; Cohort Studies; Communities; Data; Dementia; Disease; Disease Outcome; Educational Background; Elderly; Enrollment; European; Funding; Gene Expression; Genes; Genetic; Genetic Transcription; Immune; Immune system; Immunologic Markers; Immunophenotyping; Individual; Inflammasome; Inflammation; Inflammatory; Interleukins; Jackson Heart Study; Lead; Light; Link; Lymphocyte; Magnetic Resonance Imaging; Measures; Mediating; Mediator of activation protein; Memory; Microglia; Morbidity - disease rate; Nerve Degeneration; Neuropsychological Tests; Not Hispanic or Latino; Outcome; Participant; Pathogenesis; Pathway interactions; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Population; Population Study; Psychosocial Stress; Public Health; Quantitative Trait Loci; RNA Splicing; Reporting; Research; Resource Sharing; Resources; Risk; Risk Factors; Role; Sampling; Sex Differences; Signal Transduction; T-Lymphocyte; Therapeutic; Time; Transcript; Underrepresented Populations; United States; Variant; White Matter Hyperintensity; Work; adaptive immunity; adjudicate; age related; base; brain magnetic resonance imaging; brain volume; cell type; cohort; cost; database of Genotypes and Phenotypes; dementia risk; experience; genetic variant; genome wide association study; health disparity; high risk; immune RNA; immune activation; immune function; immune system function; improved; men; mild cognitive impairment; monocyte; mortality; neurofilament; neuroinflammation; neuropathology; normal aging; novel; phenotypic data; population based; public repository; racism; risk variant; senescence; sex; social health determinants; tau-1; therapeutic target; transcriptome; transcriptome sequencing

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.

项目概要 大多数老年人都会经历免疫系统功能的变化，从而导致慢性升高 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升高，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 非裔美国人群体中 ADRD 和慢性炎症的负担可能在很大程度上更高 由于健康的社会决定因素（SDOH）和社会心理压力。促炎先天性和适应性 循环免疫细胞以及这些细胞类型中的炎症相关基因可能与 居住在社区的非洲老年人患轻度认知障碍（MCI）和痴呆的风险增加 美国人。我们建议描述单核细胞、T 细胞和 B 细胞以及先天性细胞的循环比例。 约 1440 名非裔美国人免疫细胞中的淋巴细胞（> 50 种细胞表型）和基因表达 参与者使用收集的样本参加了基于人群的杰克逊心脏研究 并存储在即将举行的考试 4（2021-2023）中。然后我们将评估免疫细胞和 炎症通路基因表达与年龄、心理社会压力和 SDOH、血浆生物标志物的关系 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、MCI 和痴呆状态。我们将检查这些关系 使用先前资助的 RNA 测序和免疫表型数据进行横断面和纵向研究 在杰克逊心脏研究基线检查中，考虑到已知的性别差异，评估性别差异 免疫系统功能。我们假设促炎细胞类型和转录本相关 与 MCI、痴呆及其危险因素相关，并且炎症可能在统计学上介导 较高的心理社会压力/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 识别痴呆风险变异的假定目标基因和生物机制，特别是变异 与欧洲血统人群相比，在非洲血统人群中更为常见。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 NIA 批准的 呼吁加强 ADRD 适应性免疫研究的概念。它将增加独特的免疫功能和RNA 对老年非裔美国成年人进行的最大的正在进行的队列研究之一的测序数据， 纵向表型分析自 2000 年起可用。生成的数据将广泛提供给 科学界通过适当的公共存储库（例如 dbGaP），可用于解决如何 免疫细胞及其基因表达影响痴呆症和其他重要疾病结果的风险 非洲裔美国人老龄化的横向和纵向。特异性和非侵入性的识别 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。