Enhancing the Pathology, Alzheimer’s and Related Dementias Study to Understand Ancestry, Pollution Exposure, and AD/ADRD(PARDoS APEX) - PROJECT SUMMARY/ABSTRACT Growing evidence suggests that exposure to environmental toxicants contributes to Alzheimer’s disease and related dementias (AD/ADRD). Understanding how environmental exposures contribute to disease onset and progression enables policy and/or pharmacological interventions that prevent, mitigate, or potentially even reverse the deleterious consequences of exposure to environmental toxins. Most studies to date are limited by the inability to measure early life or cumulative exposure to toxicants, availability of brain and other tissues at scale (especially from diverse subgroups that are more likely to encounter pollution and develop AD/ADRD), and/or knowledge of the molecular processes through which toxicants act. To overcome these limits, we will leverage the established infrastructure of the Pathology, Alzheimer’s and Related Dementias Study (PARDoS), a major AD/ADRD cohort study that examines neuropathologic and clinical AD/ADRD traits, to study 2,500 deceased Brazilians of European and African ancestry that lived in and around São Paulo, Brazil. Our overall goal is to examine the association of both particulate matter (PM) and metal exposure with AD/ADRD clinical and pathologic traits. This project tests the hypothesis that humans accumulate pollutants in multiple tissues over their lifespan that alter genetic pathways in the brain that can lead to AD/ADRD. Aim 1 will measure toxicant levels in the lung, bone, brain (late life exposure), and teeth (early life exposure) and relate these exposures to brain pathology to determine relationships between environmental pollution exposures across the lifespan and AD/ADRD neuropathological traits. Aim 2 will focus on brain regions known to be important in AD/ADRD (olfactory bulb and dorsolateral prefrontal cortex) to characterize pollutant deposits at the subcellular level and assess the impact of these exposures on transcriptome profiles in relation to AD/ADRD pathogenesis. Importantly, the scale of our data collection effort enables integrative analyses across aims and the opportunity to examine differences by sex and race. These analyses, and the composition of the population from which data will be collected, will provide novel insights relevant for understanding health disparities. The project is led by experts in neurology, olfaction, epidemiology, toxicology, genomics, and environmental health and it will, for the first time, use direct, quantitative measures of PM exposure and metals to identify genes and molecular networks that connect toxicants to AD/ADRD pathology. Policy and therapeutic interventions informed by an improved understanding the relationship between environmental exposures and AD/ADRD, including molecular mechanisms, could benefit brain health worldwide.
