Immune Cell Transcriptomics in Vascular Cognitive Impairment and Dementia

Immune cell transcriptomics in vascular cognitive impairment and dementia Abstract Vascular cognitive impairment and dementia (VCID) is a significant public health issue among the aging population since it is the second most common form of cognitive impairment. However, VCID is understudied compared to AD. The close link of VCID with hypertension, hyperlipidemia, and obesity, all of which have significant inflammatory components, provides compelling support for the involvement of immune cell-mediated inflammation in VCID. Inflammation in neurodegenerative diseases has primarily been characterized by single cytokines (such as TNF) with little focus on the role of the circulating immune cells in the blood. We have recently identified cytokines that could differentiate inflammation in individuals with VCID. This evidence supports the hypothesis that neurodegenerative diseases in general, and specifically VCID, associate with systemic immune cell dysfunction. This will be the first study to evaluate a transcriptomic profile driving immune cell dysfunction in people at risk for VCID because of a history of hypertension, hyperlipidemia, and obesity. We have collected blood samples through the University of Kentucky Alzheimer’s Disease Center, which follows over 500 people longitudinally. We hypothesize that a loss of immune cell homeostasis occurs in VCID, and that systemic immune cell dysfunction will associate with and predict VCID risk factors. We will test our hypothesis in the following specific Aims: Aim 1: We will determine the ability of the blood cell gene expression profile to define and predict overall cognitive status. Aim 2: We will test the ability of blood cell gene expression profiles to identify subjects with any/all of three clinical risk factors for VCID: hypertension, hyperlipidemia, and obesity. Our project will establish the necessary preliminary evidence for future multi-PI R21/R01 applications focused on cell sources and inflammatory pathways of neurodegenerative disease, with future extensions to larger cohorts and longitudinal studies.