RF1AG054047

Genomic and metabolomic data integration in a longitudinal cohort at risk for Alzheimer's disease - project summary.

A longitudinal multi-omics examination of beta amyloid deposition (A), pathologic tau (T), neurodegeneration (N), and cognitive decline in the years prior to Alzheimer's disease (AD) diagnosis is critical to better understand, predict, prevent, diagnose, and treat the disease.

Gaps in knowledge include the timing, trajectory, and etiology of metabolite changes in the disease process.

This renewal application augments two existing longitudinal cohort studies of preclinical and clinical AD, the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center, with rich phenotypic data from blood, cerebrospinal fluid (CSF), imaging, lifestyle questionnaires, and neuropsychological testing.

The overall objective is to measure plasma and CSF metabolomics in additional longitudinal samples and use sophisticated data analysis approaches to establish the timing, trajectory, and etiology of metabolite changes in the disease process.

The central hypothesis is that changes in metabolites are influenced by genetics and lifestyle and occur at distinct stages of AD pathology.

The rationale for the proposed research is that a better understanding of the timing, trajectory, and etiology of AD-related metabolomic changes is critical to prevent (e.g., lifestyle interventions), diagnose (metabolomic biomarkers), and treat (new therapeutic targets) the disease.

The central hypothesis will be tested by executing the following specific aims:

1) Determine the timing and trajectory of plasma and CSF metabolites throughout the AD process using sophisticated longitudinal modeling approaches.

2) Integrate genomics and metabolomics to determine which AD-associated metabolites are in the causal pathway to AD using Mendelian randomization analyses.

3) Determine which AD-associated plasma and CSF metabolites mediate the relationships between AD-associated lifestyle factors and AD-related outcomes.

At the conclusion of this project, expected outcomes include:

1) Identification of metabolites/pathways that are precursors to AD pathologic changes and may be therapeutic targets versus those that change in the early stages and can be used as early biomarkers versus diagnostic/prognostic metabolites that are markers of more advanced disease.

2) Identification of metabolites that are in the causal pathway and may inform therapeutic targets.

3) A better understanding of mechanisms linking metabolic and vascular disease processes with AD.

4) Identification of metabolites linking lifestyle factors to AD risk that can inform future intervention trials and clinical practice by identifying more specific behavior changes and providing biomarkers of biologic change to monitor the effectiveness of interventions with a shorter period of follow up.

University Of Wisconsin System

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]

Madison, Wisconsin 53715 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 End Date has been extended from 08/31/25 to 08/31/27 and the total obligations have increased 66% from $2,285,690 to $3,789,122.