Science

Boram Kim, MD; Kaitlin Blam, BA; Holly Elser,MD, PhD; Sharon X. Xie, PhD; Vivianna M. Van Deerlin, MD, PhD; Trevor M. Penning, PhD; Daniel Weintraub, MD; David J. Irwin, MD; Lauren M. Massimo, PhD, CRNP; Corey T. McMillan, PhD; Dawn Mechanic-Hamilton, PhD; David A.Wolk, MD; Edward B. Lee, MD, PhD

IMPORTANCE
Exposure to fine particulate matter air pollution (PM2.5)may increase risk for dementia. It is unknown whether this association is mediated by dementia-related neuropathologic change found at autopsy.

OBJECTIVE
To examine associations between PM2.5 exposure, dementia severity, and dementia-associated neuropathologic change.

DESIGN, SETTING, AND PARTICIPANTS
This cohort study used data associated with autopsy cases collected from 1999 to 2022 at the Center for Neurodegenerative Disease Research Brain Bank at the University of Pennsylvania. Data were analyzed from January to June 2025. Participants included 602 cases with common forms of dementia and/or movement disorders and older controls after excluding 429 cases with missing data on neuropathologic measures, demographic factors, APOE genotype, or residential address.

EXPOSURES One-year mean PM2.5 concentration prior to death or prior to last Clinical Dementia Rating Sum of Boxes (CDR-SB) assessment was estimated using a spatiotemporal prediction model at residential addresses.

MAIN OUTCOMES AND MEASURES
Dementia severitywas measured by CDR-SB scores. Ten dementia-associated neuropathologic measures representing Alzheimer disease, Lewy body disease, limbic-predominant age-related transactive response DNA-binding protein (TDP)-43 encephalopathy, and cerebrovascular disease were graded or staged. Linear, logistic, and structural equation models were used to examine the associations between PM2.5, CDR-SB, and neuropathologic measures, adjusting for demographic factors and APOE ε4 allele status.

RESULTS
In a total of 602 autopsy cases (median [IQR] age at death, 78 [71-85] years; 328 male [54.5%] and 274 female [45.5%]), higher PM2.5 exposure prior to death was associated with increased odds of more severe Alzheimer disease neuropathologic change (ADNC) (odds ratio, 1.19; 95% CI, 1.11-1.28). In a subset of 287 cases with CDR-SB records (median [IQR] age at death, 79 [72-86] years; 154 [53.7%] male and 133 female [46.3%]), higher PM2.5 exposure prior to CDR-SB assessment was associated with greater cognitive and functional impairment (β = 0.48; 95%CI, 0.22-0.74). Lastly, 63% of the association between higher PM2.5 exposure and greater cognitive and functional impairment was statistically mediated by ADNC (β = 0.30; 95%CI, 0.04-0.53).

CONCLUSIONS AND RELEVANCE
In this study, PM2.5 exposure was associated with increased dementia severity and increased ADNC. Population-based studies are needed to better understand this relationship.