Alzheimer's Disease Neuropathologic Change Mediates the Relationship Between Ambient Air Pollution and Dementia Severity

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. ### Competing Interest Statement EBL serves as a paid consultant to Wavebreak Therapeutics. DAW has served as a paid consultant to Eli Lilly, GE Healthcare, and Qynapse. DAW serves on a DSMB for Functional Neuromodulation and GSK. DAW receives research support paid to his institution from Biogen. TMP is founder of Penzymes, LLC; he is a consultant for Propella therapeutics and member of the Expert Panel for the Research Institute of Fragrance Materials. All other authors declare no competing interests. ### Funding Statement This work was funded by the US National Institutes of Health (P30AG072979, P01AG066597, U19AG062418, P30ES013508). We thank the patients and their families for contributing to our research and for participating in the brain donation program. We are indebted to John Q. Trojanowski for his contributions which persist posthumously. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data used in preparation of this article were obtained from the Integrated Neurodegenerative Disease (INDD) database at the Center for Neurodegeneration Disease Research (CNDR) at the University of Pennsylvania. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.