Early mid-life environmental toxicant exposures and AD/ADRD risk in CARDIA
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Project summary Alzheimer's Disease (AD) and AD-related dementias (ADRD) affect more than 6 million Americans and 55 million people worldwide. Environmental toxicant exposures from younger age have not been systematically investigated for their roles in AD/ADRD risk despite limited suggestive evidence for organochlorine pesticide DDT, organophosphate pesticides, lead, and cadmium. AD/ADRD pathogenesis may take decades to develop before clinical symptoms, thus the role of mid-life exposures on cognitive decline and brain magnetic resonance imaging (MRI) patterns may be critical to examine in identifying preventable environmental risk factors. A crucial mechanism through which these toxicants might act is via epigenetic alterations, alongside processes like neuroinflammation and oxidative stress. There's also a notable racial disparity, with Black older adults having a twice as high prevalence of AD as White older adults. This raises questions about the potential interplay between environmental exposures, epigenetic modifications, and social determinants of health (SDOH). In this proposal, we will leverage the ongoing NHLBI-funded Coronary Artery Risk Development in Young Adults (CARDIA) Study to examine the targeted and untargeted exposome and subsequent cognitive decline and brain MRI patterns in this biracial cohort of more than 5,000 Black and White young adults at baseline (mean age 25 years) with 35 years of follow-up completed. We will repeatedly measure organochlorine pesticides, polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), untargeted exposome in plasma, and metals and metabolites of organophosphate pesticides in urine samples (Aim 1). We will examine exposomic biomarkers for associations with cognitive decline and MRI patterns that increase the AD/ADRD risk (Aim 2). We will conduct an epigenomic- wide association study to identify epigenomic biomarkers associated with exposomic biomarkers and integrate multi-omic (genomic, epigenomic, transcriptomic, exposomic) data with neuroimaging and cognitive function data to decipher the biological links (Aim 3). Finally, we will examine the role of SDOH (including redlining, education, poverty, and discrimination) on the associations between exposomic, epigenomic, and AD/ADRD- related cognitive decline and brain MRI patterns (Aim 4). This project is highly responsive to the request for application that calls for the quantification of the impact of environmental toxicants on AD/ADRD risk in cohort studies, particularly exposure in the mid-age from 30-50 years. The findings will inform the scientific communities and the public about the environmental risk factor of AD/ADRD risk, address health disparities among Black population, and provide novel exposome data and biological insights for future scientific discoveries.
