Air Pollution and Alzheimer's Disease and Related Dementias: A National Study

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Dementia is a major public health challenge with substantial economic and social burden, affecting more than 47 million people worldwide. Alzheimer's disease (AD) constitutes about two-thirds of dementia cases and is the sixth leading cause of death in the United States, and the only diagnosis among the top 10 that cannot be cured. There is a pressing need to support Alzheimer's disease and related dementias (AD/ADRD) patients by identifying novel and modifiable risk factors that may reduce morbidity. Emerging evidence suggests that air pollution – in particular fine particulate matter (PM2.5) – plays an important role in AD/ADRD pathogenesis. However, little is known about the relative contributions of different air pollutants (PM2.5, NO2, ozone), nor about PM2.5 components. To facilitate the targeting of pollution control efforts, the National Academy of Sciences (NAS) and the World Health Organization (WHO) have placed a high priority on determining which air pollutants and/or which components of PM2.5 are most toxic. In addition, one major gap in the emerging epidemiologic evidence on air pollution and AD/ADRD morbidity is that many previous studies have relied on hospitalizations as the measure of morbidity. Yet, hospitalization is not the typical course for AD/ADRD diagnosis and initial treatment. Instead, if it does occur for patients, hospitalization happens during the more advanced stages of the disease and usually for treating complications of the disease. Thus, hospitalization records do not accurately reflect disease incidence, and thus underestimate case numbers. Therefore, we propose a study that will leverage the massive datasets of high-resolution environmental exposure data and Medicare claims (including doctor visits where most AD/ADRD diagnoses would occur) across the contiguous US to better understand the influence of air pollution on AD/ADRD morbidity among US elderly, and identify potential vulnerable subpopulations, with the ultimate goal of informing environmental policy. We will (1) generate and validate a comprehensive, high- resolution, multiple-species, air pollution dataset across the contiguous US for 2000-2021, including criteria air pollutants (PM2.5 mass, NO2, and ozone), PM2.5 components (including trace metals), as well as aerosol water and fine particle pH that may influence metal dissolution; (2) estimate the chronic effects of criteria pollutants (PM2.5, NO2, and ozone) on AD/ADRD risks using the nationwide Medicare Chronic Conditions Warehouse (CCW) database, which includes Medicare inpatient and outpatient claims, doctor visits, skilled nursing facility, and home health-care claims for AD/ADRD among ~100 million Medicare beneficiaries; (3) assess the relative contributions of PM2.5 components and potential effect modification by aerosol water/pH on AD/ADRD risks using the nationwide Medicare cohort; and (4) conduct sensitivity analyses by correcting for exposure measurement error and outcome misclassification. Our proposed research will fill major knowledge gaps in the epidemiology of environmental exposures and AD/ADRD morbidity, and inform policy for targeted source-specific regulations and facilitate actionable measures that can prevent or mitigate the AD health burden due to air pollution.