U01AG088425

Impact-ADRD: Investigating the multi-omics perturbations associated with complex environmental toxicants and their contribution to Alzheimer's disease and related dementias - Abstract

Increased risks of chronic illnesses, including Alzheimer’s disease and related dementias (AD/ADRD), have been linked to exposures to ambient air pollution, particularly fine particulate matter (PM2.5).

Despite the observed epidemiological evidence, central and unsolved questions remain on what components of PM2.5 (e.g., sulfate, nitrate, ammonium, elemental carbon, organic carbon, metals, etc.) are most neurotoxic and how they contribute to the observed risk of developing AD/ADRD.

A better understanding of the specific exposure components and underlying causal biological mechanisms and pathways revealing the link between PM2.5 toxicants and AD/ADRD will provide valuable insight into disease etiology and pathophysiology and inform environmental regulation and health policy to reduce disease burden of AD/ADRD.

Although omics applications in environmental health research are still nascent, several studies conducted by our team and others demonstrate that various single omics approaches, including epigenomics, proteomics, and metabolomics can be used to sensitively map internal biological perturbations following exposures to PM2.5.

We propose deeper molecular profiling to investigate the molecular connections underlying the neurotoxicity of individual PM2.5 pollutants and mixtures using high resolution spatio-temporal modeling of PM2.5 components as well as targeted and untargeted profiling of PM2.5 toxicants in blood, cerebrospinal fluid (CSF), and brain tissue.

The body’s biological response to these toxicants will be determined by measuring perturbations in DNA methylation, proteins, and metabolites in the same tissues.

Our study will be based on three well-characterized, diverse cohorts with comprehensive assessment of AD/ADRD and related indicators and biomarkers.

Participants come from two longitudinal cohort studies prospectively followed at biennial clinical visits and a brain bank from the same study area.

They span a wide range of age and cognitive status and reflect the racial diversity of Georgia (i.e., 32% African American).

Replication of significant findings will be done in the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

We will 1) characterize individual exposures to chemical and metal components of PM2.5 and determine their impact on AD/ADRD risk;

2) elucidate patterns of biological perturbations in single- and multi-omics signatures of the brain associated with PM2.5 toxicants (modeled individually and as mixtures) and how they manifest in CSF and blood of individuals with versus without AD/ADRD;

and 3) determine the relative contribution of environmental and genetic factors to AD/ADRD risk.

This study provides a critical opportunity to address research gaps in molecular mechanisms underlying PM2.5 toxicants neurotoxicity and their role in the development of AD/ADRD, supporting future efforts that aim to inform environmental regulation and health policy to mitigate air pollution-related risk for AD/ADRD.

Moreover, it provides a critical opportunity to enrich deeply phenotyped AD/ADRD cohorts with state-of-the-art exposure assessment and omics profiling to understand the environmental impact on AD/ADRD.

Emory University

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]

Atlanta, Georgia 30322 United States

Single Zip Code

Quantifying the Impact of Environmental Toxicants on Alzheimer's Disease (AD) and AD-Related Dementias (ADRD) Risk in Cohort Studies (U01 Clinical Trial Not Allowed) (RFA-AG-24-022)

Amendment Since initial award the total obligations have increased 98% from $2,278,304 to $4,511,944.