Ambient Air Pollution and the Severity of Alzheimer Disease Neuropathology

Abstract

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 severity was 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.

Figure 1.. PM_2.5 exposure and dementia-related neuropathologies in the full autopsy cohort

Abbreviations: OR, odds ratio; CI, confidence interval; CERAD, Consortium to Establish a Registry for Alzheimer’s Disease; ADNC, Alzheimer’s disease neuropathologic change; LBD, Lewy body disease; LATE, limbic-predominant age-related transactive response DNA-binding protein (TDP)-43 encephalopathy; VCING, vascular cognitive impairment neuropathology guidelines. Odds ratios (ORs) and 95% confidence intervals (CIs) are reported for each neuropathologic outcome corresponding to every 1 μg/m³ increase in 1-year average PM_2.5 exposure before death from a series of ordinal logistic regression models with ordinal Thal amyloid phase, ordinal Braak stage, ordinal CERAD score, ordinal ADNC level, ordinal LATE-NC stage, and ordinal VCING score as outcome variables, and binary logistic regression models with dichotomously treated LBD stage, presence of large infarcts, presence of occipital cerebral amyloid angiopathy, and presence of arteriolosclerosis as outcome variables in the full autopsy cohort (n=602). All models were controlled for sex, age at death, race, APOE ε4 status, and years of education. ORs and 95% CIs greater than 1 indicate worse neuropathologic outcomes. P values less than 0.05 were considered statistically significant.

Figure 2.. Alzheimer’s disease neuropathologic change mediates the relationship between PM_2.5 exposure and Clinical Dementia Rating–Sum of Boxes

Abbreviations: CI, confidence interval; ADNC, Alzheimer’s disease neuropathologic change; CDR-SB, Clinical Dementia Rating Scale-Sum of Boxes. A path diagram of the structural equation modelling shows relationships among PM_2.5 exposure, ADNC, and CDR-SB with 1-year average PM_2.5 exposure before last CDR assessment prior to death as the exposure variable, ordinal ADNC level as the potential mediator, and CDR-SB at last assessment prior to death as the outcome variable in the CDR cohort (n=287), after adjusting for sex, age at CDR, race, years of education, and APOE ε4 status as confounding variables. In this model, the indirect effect is the effect of PM_2.5 exposure on CDR-SB through ADNC and the direct effect is the effect of PM_2.5 exposure on CDR-SB that is independent from ADNC. β estimates of indirect, direct, and total effects with 95% confidence intervals (CIs) were calculated with SEM using a bias-corrected and accelerated bootstrap confidence interval method with 2000 simulations. Positive values indicate greater cognitive and functional impairment. This model exhibited good fit indices as follows: comparative fit index [CFI], 0.98; root mean square error of approximation [RMSEA], 0.02; Tucker-Lewis index [TLI], >0.99).