ABSTRACT Exposure to air pollution may play a role in the development of Alzheimer's disease and related dementias (ADRD), but how it affects neurocognitive aging is largely unknown. Major barriers to understanding include: inadequate assessment of cognitive decline, over-reliance on medical records and claims data to measure dementia status, sparse information on the connection of air pollution exposure to dementia pathology, and poor understanding of underlying mechanisms, including cerebrovascular and olfactory pathways as well as particulate matter (PM) access to the brain. Here, we will remedy these deficiencies by investigating air pollution and ADRD in a setting that: entails regular and systematic longitudinal evaluation of cognitive function and dementia in all participants, postmortem neuropathologic assessments with extensive cerebrovascular detail, and a far-reaching evaluation of the olfactory system, which is uniquely susceptible to airborne insults, as a direct pathway for environmental toxicants to reach the brain and cause ADRD. Covered in this evaluation will be assessments of olfaction, neuropathology of the olfactory bulb, and PM embedded in the olfactory bulb. We take advantage of 5 large, diverse ongoing, harmonized, well-characterized longitudinal cohort studies of neurologic aging that have collected rich clinical information on >4000 older adults: the Memory and Aging Project, the Minority Aging Research Study, the Religious Orders Study, the Latino CORE Study, and the Clinical Core. The data collected include annual assessments of cognition, dementia status, and olfaction, as well as brain specimens at autopsy (N>1600): the Memory and Aging Project, the Minority Aging Research Study, the Religious Orders Study, the Latino CORE Study, and the Clinical Core. We will estimate participants' long-term air pollution exposures using models previously developed by the MESA Air and MESA Coarse projects and use state-of-the-art, advanced microscopy to measure directly PM in the olfactory bulb, a first. We will assess 3 important underlying mechanisms: the olfactory pathway, inflammation (microglial activation), and cerebrovascular disease. Thus, we will be able to determine the effect of air pollution exposure on neurocognitive outcomes, and examine how resultant neuropathology and direct PM deposition explains these relationships. Our goal is to rigorously test the hypothesis that exposure to air pollution impairs cognitive function and accelerates ADRD via PM deposition in the olfactory system resulting in increased AD neuropathology. This project will generate pivotal new information on the contribution of air pollution to ADRD, raising the prospect of reduction of the burden of ADRD on a population scale via public health interventions.

PROJECT NARRATIVE Air pollution may play a role in the development of Alzheimer's disease and related dementias (ADRD) but our knowledge about mechanisms is limited. Here, we test key underlying pathways, and among them, is the pathway through the olfactory system, a direct anatomic connection for environmental toxicants to reach the brain. We will estimate the effect of air pollution exposure on neurocognitive and olfactory outcomes in 5 well- characterized, longitudinal ADRD cohorts using integrated air pollution exposure data from the MESA Air and MESA Coarse studies, and examine how resultant neuropathology and direct deposition of PM (assessed by advanced microscopy) explains these relationships.