Alzheimer's disease neuropathologic change mediates the relationship between ambient air pollution and dementia severity

Abstract

Background: Exposure to fine particulate matter air pollution (PM2.5) increases risk for dementia. However, it is unknown whether this relationship is mediated by dementia-related neuropathologic change found at autopsy. We aimed to examine relationships between PM2.5 exposure, dementia severity, and dementia-associated neuropathologic change. Methods: This cross-sectional study used harmonized demographic, clinical, genetic, and neuropathological data from autopsy cases collected from 1998 to 2022 at the Center for Neurodegenerative Disease Research brain bank, University of Pennsylvania. Cases who had common neuropathologic forms of dementia and complete data on neuropathologic measures, APOE genotype, and residential address were included in this study cohort. Dementia severity was measured by Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. Ten dementia-associated neuropathologic measures representing Alzheimer's disease, Lewy body disease, limbic-predominant age related TDP-encephalopathy, and cerebrovascular disease were graded or staged according to the consensus criteria. One-year average PM2.5 exposure prior to death was estimated using a spatiotemporal prediction model based on residential addresses as the primary exposure measure. Linear, logistic and structural equation models were used to examine the relationships between PM2.5, CDR-SB and neuropathologic measures. Results: A total of 861 autopsy cases were included (mean age at death 76.6 years [SD 10.3]; 481 [56%] male). Each 1µg/m3 increase in one-year average PM2.5 concentration prior to death was associated with significantly greater cognitive and functional impairment (increase in CDR-SB score of 0.78; 95% confidence interval [CI], 0.52-1.05), faster cognitive and functional decline (change in CDR-SB scores of 0.13; 95% CI, 0.09-0.16), more severe Alzheimer's disease neuropathologic change (ADNC; odds ratio [OR] of 1.07; 95% CI, 1.01-1.13), and a higher prevalence of large infarcts (OR, 1.17; 95% CI, 1.05-1.30). The relationship between PM2.5 exposure and CDR-SB was mediated by ADNC (change in CDR-SB score due to ADNC level of 0.36; 95% CI, 0.13-0.65). Conclusions: PM2.5 exposure may increase dementia risk by increasing ADNC. Measures that improve air quality may represent a population-level intervention for the prevention of dementia.