External Environmental Determinants of Alzheimers Type Dementias and Mechanisms

About This Grant

Emerging evidence highlights a significant role for external environmental exposures (EE) in the development of Alzheimer's Disease and Related Dementias (ADRD). The goal of this multi-institutional collaborative grant between 3 institutions with a long history of collaboration, is to provide new mechanistic links between air pollution, exposures in the natural, social environment and ADRD, in highly relevant human populations and relevant animal models of human AD. This study is predicated by substantial preliminary data linking particulate matter air pollution <2.5 m (PM2.5) and geospatial features of the built/natural environment with ADRD in well phenotyped cohorts, including 2 large health system datasets covering > 10 million lives (Houston Methodist and University Hospitals Cleveland). We also provide direct evidence of AD progression with PM2.5 exposure and relevant molecular pathways including NAD+ depletion using single cell transcriptomic and chromatin remodeling in neuronal cells in an animal model of human AD. Aim 1 focuses on developing and validating an integrated EE fingerprint, using a deep-learning framework that incorporates air pollution, social, natural, and built environment features from street-level and satellite imagery coupled with clinical data, to predict ADRD in the UK Biobank, U.S. Veterans Health Administration (VHA) cohorts, and 2 large regional U.S. health systems, stratified by urban vs. rural location, social vulnerability, and risk factor burden. The relationship between EE, cognitive function and CSF biomarkers in ADRD will be explored in a small cohort of aging subjects (Emory Healthy Brain Study). Aim 2 will investigate mechanisms by which EE mediates ADRD risk. This will be accomplished through creation and validation of an artificial intelligence (AI) pipeline to derive retinal microvascular (oculomic) and brain morphoradiomic measures from color fundus photography and 3T brain MRI images respectively. We will evaluate a mediating relationship of oculomic and brain morphoradiomic measures by EE in ADRD, under the moderating influence of a polygenic risk score for ADRD. Aim 3 will evaluate the impact of inhalational concentrated ambient PM2.5 exposure on cognitive decline and neurodegeneration using mouse models and detailed brain morphometric, metabolomic, single cell (endothelial and glial) transcriptomic, methylation and chromatin structure. We will establish causal relationships of PM2.5 in neurodegeneration, by testing whether PM2.5 cessation and pharmacologic restoration of brain NAD+/NADH levels using P7C3-A20, a pharmacologic nicotinamide phosphoribosyl transferase (NAMPT) activator, that enhances NAD+ salvage, halts neurocognitive decline and reverses epigenetic and metabolomic changes. Together, these findings will yield an integrated molecular footprint linking EE and ADRD risk, potentially guiding future interventions.