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.