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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：
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
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/10576351
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 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

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.

项目总结