R01AG070862

Epigenetic Risk Factors for AD Age at Onset and Health Disparities: HABLE Epigenetics Study

The long-term goal of this research is to examine the link between DNA methylation patterns and the presence and progression of Alzheimer's disease (AD) among Mexican Americans (MA) and non-Hispanic whites (NHW). Here, we will address the aims of PAR-19-070 (Research on Current Topics in Alzheimer's Disease and its Related Dementias) - NOT-AG-18-047 - by leveraging the ongoing HABLE cohort (R01AG054073) to identify the epigenetic factors associated with the presence and progression of AD among MAs and NHWs.

In our prior work and recent HABLE data, we examined DNA methylation patterns among N=90 age, gender, and diagnosis-matched participants leveraging the HABLE biorepository (MCI N=45, controls N=45). We identified 10 CPG sites and four regions to be differentially methylated in normally aging controls relative to individuals diagnosed with MCI. Functional gene-set analysis identified four gene sets as significant. Gene ontology and pathway analysis highlighted neuronal cell death, metabolic dysfunction, and inflammatory processes. Using Bayes gene set enrichment, we found MCI diagnosis was associated with processes converging on hypertension, diabetes, loss of hearing and olfaction, synaptic transporter activity, and inflammation. These results link peripheral metabolic dysregulation and inflammation with cognitive decline and suggest that cognitive decline in MAs is a manifestation of factors related to metabolic stress.

By leveraging the HABLE biorepository, we will conduct a longitudinal epigenome-wide association study (EWAS) on biorepository data from N=1800 HABLE (N=900 MA; N=900 NHW) participants to identify differentially methylated DNA in circulating leukocytes to address two specific aims:

Aim 1. Identify DNA methylation patterns in leukocytes that are associated with the presence and progression of Alzheimer's disease among Mexican Americans and non-Hispanic whites.

Aim 2. Identify DNA methylation patterns in leukocytes that covary with the prevalence and progression of AT(N)-defined biomarkers of AD among Mexican Americans and non-Hispanic whites.

Aim 1 results will be validated by comparison with data from a funded project (1R01AG061022-01) that is assessing the role of leukocyte mDNA in AD etiology in the SOL-INCA cohort. Aim 2 results for mDNA patterns associated with amyloid burden will be compared to data from the NEW IDEAS study.

The current proposal is highly significant and innovative:

1) The proposed work is the first large-scale longitudinal examination of mDNA patterns associated with AT(N) framework-defined pathological markers of AD among MAs.

2) This study directly meets NIA-defined milestones for AD/ADRD research among diverse populations.

3) Data from this study will be merged with the HABLE database and made publicly available to the scientific community and the Alzheimer's Disease Sequencing Project (ADSP) and ADSP-Functional Genomics Consortium (ADSP-FGC).

The University Of North Texas Health Science Center At Fort Worth

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]

Fort Worth, Texas 761072644 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the total obligations have increased 381% from $714,920 to $3,440,509.