Project Summary There is growing consensus that environmental factors influence risk for Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD). Consistent with this hypothesis, cognitive trajectories of participants in the UC Davis Alzheimer’s Disease Research Center (UCD ADRC) Longitudinal Diversity Cohort (LDC) differ geographically. These geographical differences may arise from differential exposures to environmental contaminants. In this translational study, we will test our central hypothesis that ultrafine particulate matter (UFPM) enters the brain of exposed individuals and increases risk of cognitive decline and incident AD/ADRD. Human and animal studies have largely focused on PM2.5 (fine particulate matter with an aerodynamic diameter < 2.5 µm) in AD/ADRD risk. UFPM is a subset of PM2.5. Because of its smaller size (< 0.1 µm), inhaled UFPM can cross biological barriers to gain access to multiple organs, including the brain. Our prior work found UFPM in the brain of rats exposed to traffic-related air pollution (TRAP), but not filtered air controls, indicating UFPM may be a mechanism of brain injury. To date, no human studies and few animal studies have focused specifically on UFPM in AD/ADRD. Unlike most air pollutants that are relatively spatially homogeneous, UFPM are more concentrated near pollutant sources, so they are geographically discrete. To test our hypothesis, we will leverage resources unique to UCD: (1) the LDC, which has already geocoded 500 individuals in Northern California at the census tract level with associated longitudinal cognitive measures; (2) neuropathological samples on some of these individuals, (3) an UFPM exposure model that quantifies levels and sources of specific air pollutants over the LDC capture area from 2000 to 2019; (4) brains containing UFPM from rats exposed to unchanged ambient TRAP in real time; and (5) hyperspectral and Raman spectroscopy for characterizing the chemical composition of UFPM in rat and human brains to assess brain distribution and further inform source. Using these resources, we will address the following Aims: 1. Identify the source of UFPM in brains of TgF344-AD rats exposed to TRAP and assess the spatial relationship of UFPM to AD-relevant neuropathology in rat brains. 2. Determine whether human exposure to UFPM is associated with (a) incident cognitive impairment and AD/ADRD and (b) accelerated rate of cognitive decline. 3. Initiate exploratory studies in human AD/ADRD brain samples to determine whether UFPM in select brain regions of LDC individuals are related to AD pathology. Data from this project will identify AD/ADRD-relevant neuropathology associated with UFPM, a first step in developing mechanistic hypotheses that can be tested in future studies. Additionally, this project addresses (1) biological plausibility and clinical relevance of UFPM in air pollution as an environmental factor that modifies AD/ADRD initiation and progression and contributes to AD/ADRD racial/ethnic disparities; (2) relevance of the AD/ADRD rat model to humans exposed to UFPM in polluted air; and (3) generation of data needed to support public health and regulatory strategies for controlling key sources of UFPM associated with AD/ADRD.

Project Narrative Alzheimer’s disease and related dementias (ADRD) affect one in nine older Americans, and are the 6th leading cause of death. We propose to test the hypothesis that ultra-fine particulate matter in polluted air promotes the onset and progression of AD/ADRD by determining whether (a) ultrafine particles are found in the brain of exposed individuals and whether this is associated with AD neuropathology (animal studies) or rate of cognitive decline (human studies) and (b) spatial-temporal distributions of ultrafine particles in northern California over the last 20+ years are associated with AD/ADRD. Addressing these data gaps is critically important for developing public health and regulatory strategies for reducing emissions of ultrafine particulate matter and for addressing the relevance of the rat model to the human condition, which is essential for future mechanistic studies.