Prevention of cognitive decline and delay of onset of Alzheimer's disease (AD) are public health priorities, and improving brain health is a firm commitment of the National Institutes of Health. Since ambient air pollution exposures are pervasive and modifiable, they are an appropriate target for research on brain health. Evidence for air pollution links to neurodegeneration is accumulating with recent studies implicating fine particulate matter (PM2.5), ozone (O3), oxides of nitrogen (NOx and NO2) and traffic-related pollution in lower cognitive function, cognitive decline, incidence of AD and all-cause dementia, and brain atrophy. The effects of air pollutants on neuropathology in the aging brain are unknown. Deeper understanding of air pollutants as potential risk factors will lead to better characterization of disease mechanisms. Improvements in public health will follow since air pollution exposures can be modified by changes in regulations and individual behaviors. Few epidemiological studies have been well-positioned to overcome many of the inherent weaknesses in exposure assessment, study design, and outcome data availability, including a unique set of neuropathology measures, needed to advance our understanding of the role of time-varying air pollution exposures on cognitive health, AD, and aging. This study is a unique collaboration between leading experts in the fields of aging and AD research, statistical, and environmental health sciences. It will use a long-term prospective cohort study design to examine the effects of air pollution on cognitive decline, all-cause dementia and AD incidence, and brain neuropathologies. It leverages the community-based sample of 5,088 adults free of dementia at the time of enrollment from the NIA-funded Adult Changes in Thought (ACT) study. ACT is an outstanding resource representative of the community with prospective, long-term (up to 20 years), and high- quality cognitive follow-up, careful diagnosis of incident dementia by subtype, and outstanding data availability including 633 brain autopsies, genetic data, and decades of extensive medical, and residential history data extending decades prior to study enrollment. We will collect new air pollution measurements to develop for ACT participants state-of-the-art long-term average air pollution predictions for ambient PM2.5, O3, NOx, and NO2 of the highest quality to address our study hypotheses. Our overarching goal is to identify air pollution risk factors and quantify their effects in order to promote healthy aging. This study provides an extraordinary opportunity to advance our comprehensive understanding of the effects of air pollution exposures on cognition in the aging brain and on risk of AD. It aligns well with the 2012-2017 NIEHS Strategic Plan by advancing fundamental research using state-of-the-art exposure science.

This study provides an extraordinary opportunity to develop comprehensive insights into the effects of air pollution on the aging brain, including the effects of air pollution on cognition, the risk of Alzheimer's disease, and various potential mechanisms of neurodegenerative disease and cerebrovascular disease. The proposed study aligns well with the 2012-2017 NIEHS Strategic Plan in that it seeks to advance fundamental research using state-of-the-art exposure science. A deeper understanding of these environmental exposures will contribute significantly to the identification of disease mechanisms and improvements in public health, particularly because these exposures can be modified by changes in regulations and individual behaviors.