PROJECT SUMMARY/ABSTRACT Wildfires are widespread and expected to increase. Already, nearly 70% of the US population experiences some wildfire smoke exposure each year, with 30% experiencing more severe levels. Wildfires lead to two types of exposure: elevated levels of ambient fine particulate matter (PM2.5) and destructive disasters. Wildfire PM2.5 may cause neurodegeneration. Moreover, experiencing disasters has physiological and psychological effects that can hasten cognitive decline. The relationship between these two wildfire-related exposures and increased risk of Alzheimer’s disease (AD) and AD-related dementias (ADRD) has not been assessed. The wildfire exposures have differing geographic extents: (1) wildfire PM2.5 can spread over hundreds of square- kilometers; and (2) wildfire disaster severely affects populations in direct proximity of a wildfire event. The pro- posed project seeks to answer the questions: does wildfire exposure affect mild cognitive impairment (MCI, AD/ADRD precursor) or AD/ADRD incidence, progression, or death, and if so, who is most affected? Answers to these questions will determine the acute and chronic health consequences and geographic extent of multi- faceted wildfire exposures for cognitive decline, with the ultimate goal to inform healthcare delivery and target interventions. The overarching hypothesis is that short-term and long-term cumulative wildfire exposure affects MCI- and AD/ADRD outcomes, modified by individual- and area-level factors. The project leverages two cohorts with complementary information during 2008–2020: the entire Medicare population (>97% of US adults ³65 years) and Kaiser Permanente Southern California members (1.6 million adults aged ³45 years with more detailed health records from a region plagued by major wildfires). We propose the following specific aims: (1) estimate the association between wildfire PM2.5 and MCI and AD/ADRD in both the short- and long-term; (2) identify individual and neighborhood-level susceptibility factors that exacerbate the association between wildfire PM2.5 and MCI and AD/ADRD; (3) evaluate the association between wildfire disaster exposure and MCI and AD/ADRD. Daily wildfire and non-wildfire PM2.5 will be estimated at the ZIP code (nationwide) and census tract (California) levels. Effect modification by individual- (age, race/ethnicity, socioeconomic and marital status, nursing home residence) and area-level factors (rural residence, socioeconomic status, power outage and evacuation exposure) will be evaluated. The proposed research is innovative because it captures both wildfire PM2.5 and wildfire disaster exposure as potential risk factors for MCI and AD/ADRD outcomes in the nationwide Medicare cohort and the Kaiser cohort supported by rich electronic health record data. The proposed work is expected to uncover novel relationships between transient but extreme wildfire air pollution and/or disaster and acute or chronic MCI and AD/ADRD outcomes. It wil...