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.