RF1AG074549

The Role of Blood and Brain 5-Hydroxymethylcytosine in Linking Vascular Risk Factors to ADRD in Older White and Black Persons - Project Summary/Abstract

Alzheimer's Disease (AD) is a chronic and disabling condition, the 6th leading cause of death in the US, and a major cause of personal, societal, and global burden. Yet, our understanding of pathobiologic mechanisms underlying dementia and cognitive impairment in aging remains incomplete, and this gap in knowledge hinders scientific advancement and improved clinical care and prevention.

Vascular conditions such as diabetes mellitus (DM) are common, especially among minority racial groups, and recognized as increasing dementia risk. Because these factors are modifiable by treatment and lifestyle approaches, research linking vascular factors to Alzheimer's Disease/Alzheimer's Disease-Related Dementias (AD/ADRD) is more important than ever.

Emerging data suggests that the epigenome likely plays a role in this link, and novel methods to study the epigenome are now available. 5-Hydroxymethylcytosine (5HMC) is an epigenetic modification of cytosine for which we can now measure genome-wide changes in circulating cell-free DNA (cfDNA) in blood and genomic DNA (gDNA) in tissues. Our group has developed a highly sensitive and selective analytic approach to capture and sequence 5HMC-containing DNA fragments in order to map genome-wide distributions, and have successfully used this approach to develop 5HMC scores which distinguish between patients with and without different conditions, including in recent studies of AD and DM.

In response to the pressing need to better understand the pathobiologic underpinnings of AD/ADRD, we propose a collaborative project with the overall goal of elucidating epigenetic mechanisms linking vascular risk factors to AD/ADRD clinical and pathological phenotypes, in older whites and blacks. The proposed study will leverage available resources from two community-based cohort studies, including research participants from which to collect blood specimens, as well as extensive longitudinal clinical data and postmortem neuropathologic data, and biospecimens (e.g., frozen brain tissue samples).

Among white and black persons, we will collect new genome-wide 5HMC data to generate serum-specific (Aims 1 and 4) and brain-specific 5HMC scores (Aims 2 and 4), using discovery and validation experiments in different sets of persons, that distinguishes between persons with and without dementia. We will then link the blood and brain 5HMC data to AD/ADRD clinical and pathologic phenotypes, including incident dementia and cognitive decline (Aims 1 and 4), cerebrovascular and AD pathology (Aim 2). We will further examine if relations are differential by vascular risk factors (DM, blood pressure [BP], and body mass index [BMI]) and by other factors (e.g., sex; Aims 1-4), and if generalizable to black persons (Aim 4).

Because vascular risk factors are common and modifiable, this study, which will elucidate 5HMC mechanisms in AD/ADRD and vascular diseases among white and black older persons, will fill a major gap in scientific knowledge about dementia and provide important data to inform future research and to ultimately improve clinical dementia care and prevention.

Rush University Medical Center

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Chicago, Illinois 606123833 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have decreased 13% from $3,275,232 to $2,840,670.