R01AG093805

Metal exposures, omics, and AD/ADRD risk in diverse US adults - Summary

Metals are neurotoxic at high doses yet can contribute to motor and cognitive deficits even at environmentally relevant doses.

Metals contribute to amyloid β misfolding and tau hyperphosphorylation, which are pathological hallmarks of Alzheimer’s disease (AD) and AD-related dementia (ADRD) risk as well as cognitive decline.

Metals also interact with the APOE4 allele to influence AD risk, advance neurodegeneration, and have vascular effects that may further contribute to dementia risk.

Metals may thus represent multiple hits for risk of cognitive impairment and dementia.

Yet, few cohort studies have comprehensively evaluated the association of metal exposures with mild cognitive impairment (MCI) and AD/ADRD.

To fill this knowledge gap, we propose to leverage the NIH-funded Atherosclerosis Risk in Communities (ARIC) and Multi-Ethnic Study of Atherosclerosis (MESA) cohorts of diverse US adults to test the hypothesis that widespread exposure to metals—determined by established and novel biomarkers—is associated with MCI and AD/ADRD risk and with key pathophysiological processes that explain this risk.

ARIC and MESA have rich biorepositories, as well as examination, laboratory, omics, and clinical data.

In these unique and diverse cohorts, we propose to add a metallome profile to quantify metal exposure and internal dose for each participant by measuring metals in urine, blood, and serum at repeated visits in all participants, as well as in brain-derived extracellular vesicles in a subset of participants.

Priority metals include lead, cadmium, copper, mercury, manganese, and zinc, although other metals will also be measured.

We will connect these metallome profiles with rich brain health and multi-omics data (whole genome sequencing, epigenomic/methylomic, transcriptomic, proteomics, targeted and untargeted metabolomics).

We will use powerful, state-of-the-art analyses to determine the prospective associations of long-term metal exposures with risk of cognitive decline, MCI, and AD/ADRD risk (Aim 1), and with the trajectory of plasma AD and brain imaging biomarkers (Aim 2) in diverse US adults overall and by sex, race/ethnicity, and APOE4 genotype.

We will then develop a predictive multi-omics fingerprint that quantifies risk of MCI, AD/ADRD, and cognitive decline due to metal exposures (Aim 3).

Because metal exposures are preventable and treatable, adding high-quality measures of the metallome profile to diverse cohorts with longitudinal brain health and extensive omics data will enable this project to contribute key knowledge of the molecular/biological pathways involved in the development of cognitive decline as well as identify new targets for the prevention and treatment of AD/ADRD.

This work will generate critical knowledge and serve as a robust model for generating highly valuable data that can be leveraged to prevent/mitigate harmful metal exposures and protect cognitive health.

The Trustees Of Columbia University In The City Of New York

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]

New York United States

State-Wide

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-22-093)

Amendment Since initial award the total obligations have increased 26% from $8,092,495 to $10,223,348.