Metal Exposures, Omics, and AD/ADRD risk in Diverse US Adults

About This Grant

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 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.