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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos 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

Address Adult African African American African American population Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos 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

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项目摘要

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。慢性炎症导致许多与年龄有关的疾病的风险升高，包括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。有非洲裔美国人口中ADRD和慢性炎症的燃烧较高，很大程度上可能是由于健康的决定者（SDOH）和社会心理压力。促炎的先天和自适应这些细胞类型中循环免疫细胞和炎症相关的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。我们建议表征单核细胞，T和B细胞的循环比例，以及先天约1440名非裔美国人的免疫细胞中的淋巴细胞（> 50个细胞表型）和基因表达使用收集的样品参加了良好的基于人群的杰克逊心脏研究的参与者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理学，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，在横截面和纵向上在杰克逊心脏研究基线考试和性别的评估差异中，鉴于已知的性别差异免疫系统功能。我们假设促炎性细胞类型和成绩单将与与MCI，痴呆症及其危险因素有关更高的社会心理压力/SDOH伯恩和MCI/痴呆症的风险。我们还将使用来自免疫细胞的数据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人群中更为常见。这项研究对PAR-19-070有反应（NOT-AG-18-047：健康差异和阿尔茨海默氏病），以及2021年1月的NIA批准概念要求在ADRD中增加对适应性免疫学的研究。它将添加独特的免疫学功能和RNA 将数据测序到与非洲裔美国成年人衰老的最大人群研究之一，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症和其他重要疾病结果的风险在横截面和纵向上，在衰老的非洲裔美国人中。识别特定和非侵入性的与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了解并为ADRD选择假定的抗炎疗法选择。