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: 10576351
• 负责人: Laura M Raffield
• 金额: $ 78.23万
• 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/10576351
• 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; Chronic; Chronic stress; Cognition; Cohort Studies; Communities; Data; Dementia; Disease; Disease Outcome; Educational Status; Elderly; Enrollment; European; European ancestry; Funding; Gene Expression; Genes; Genetic; Genetic Transcription; Immune; Immune system; Immunologic Markers; Immunophenotyping; Income; Individual; Inflammasome; Inflammation; Inflammatory; Interleukins; Jackson Heart Study; Light; Link; Lymphocyte; Magnetic Resonance Imaging; Measures; Mediating; Mediator; Memory; Mental Depression; 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; Stress; T-Lymphocyte; Therapeutic; Time; Transcript; Underrepresented Populations; United States; Variant; White Matter Hyperintensity; Woman; Work; adaptive immunity; adjudication; age related; brain magnetic resonance imaging; brain volume; cell type; childhood adversity; cohort; comorbidity; 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; participant enrollment; 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.

项目摘要 大多数老年人经历了免疫系统功能的变化，导致长期升高 炎症生物标志物。 阿尔茨海默氏病和相关痴呆症（ADRD）；但是，确切的机制尚不清楚。 非裔美国人人口中ADRD和慢性炎症的负担更高，很可能是 由于健康的决定因素（SDOH）和社会心理压力。 这些细胞类型的循环免疫细胞和炎症相关基因可能与 在社区居住的年长的非洲人中增加了轻度认知障碍（MCI）和痴呆症的风险 美国人。 约1440名非裔美国人的免疫细胞中的淋巴细胞（> 50个细胞表型）和基因表达 使用样品收集器，杰克逊心脏研究中培训良好的杰克逊心脏研究的颗粒 在即将举行的考试4（2021-2023）中，我们将评估免疫细胞的关联 炎症途径基因表达与年龄，社会心理压力和SDOH，血浆生物标志物 阿尔茨海默氏病神经病学，磁共振成像（MRI）的神经变性和 大脑疾病措施以及MCI和痴呆状态。 使用先前资助的RNA测序和免疫表型数据，在横截面和纵向上 在杰克逊头学院考试中，并评估性别的差异，鉴于已知的性别差异 免疫系统功能。 MCI，痴呆症及其危险因素以及炎症可能会统计介导 更高的社会心理压力/SDOH负担和MCI/痴呆症的风险。 确定痴呆危险变异的推定靶基因和生物学机制，尤其是对于变体 在非洲与欧洲血统中更为常见。 （NOT-AG-18-047：健康差异和阿尔茨海默氏病），以及2021年1月的NIA批准 要求增加ADRD自适应免疫研究的概念。 将数据测序到美国成年衰老的最大衰老研究之一， 自2000年以来可用的纵向表型。生成的数据将被广泛使用 科学界通过适当的公共存储库（例如DBGAP），可用于解决如何解决 免疫细胞及其基因表达会影响痴呆和其他重要疾病结果的风险 在截面和纵向上识别非洲裔美国人。 与MCI和痴呆症风险相关的炎症生物标志物将改善对疾病生物学的理解 和ADRD推定的抗炎疗法的信息。