Fine particulate air pollution and neuropathology markers of Alzheimer’s disease in donors with and without APOE ε4 alleles – results from an autopsy cohort

Abstract

Introduction: Higher fine particulate matter (PM2.5) exposure has been found to be associated with Alzheimer's disease (AD). PM2.5 has been hypothesized to cause inflammation and oxidative stress in the brain, contributing to neuropathology. A major genetic risk factor of AD, the apolipoprotein E (APOE) gene, has also been hypothesized to modify the association between PM2.5 and AD. However, little prior research exists to support these hypotheses. Therefore, this paper aims to investigate the association between traffic-related PM2.5 and AD hallmark pathology, including effect modification by APOE genotype, in an autopsy cohort. Methods: Brain tissue donors enrolled in the Emory Goizueta Alzheimer's Disease Research Center (ADRC) who died before 2020 (n=224) were assessed for AD pathology including Braak Stage, Consortium to Establish a Registry for AD (CERAD) score, and the combined AD neuropathologic change (ABC score). Traffic-related PM2.5 concentrations were modeled for the metro-Atlanta area during 2002-2019 with a spatial resolution of 200-250m. One-, 3-, and 5-year average PM2.5 concentrations prior to death were matched to participants home address. We assessed the association between traffic-related PM2.5 and AD hallmark pathology, as well as effect modification by APOE genotype, using adjusted ordinal logistic regression models. Results: Traffic-related PM2.5 was significantly associated with CERAD score for the 1-year exposure window (OR: 1.92; 95% CI: 1.12, 3.30), and the 3-year exposure window (OR: 1.87; 95%-CI: 1.01, 3.17). PM2.5 had harmful, but non-significant associations on Braak Stage and ABC score. The strongest associations between PM2.5 and neuropathology markers were among those without APOE ε4 alleles (e.g., for CERAD and 1-year exposure window, OR: 2.31; 95% CI: 1.36, 3.94), though interaction between PM2.5 and APOE genotype was not statistically significant. Conclusions: Our study found traffic-related PM2.5 exposure was associated with CERAD score in an autopsy cohort, contributing to epidemiologic evidence that PM2.5 affects Aβ deposition in the brain. This association was particularly strong among donors without APOE ε4 alleles. Future studies should further investigate the biological mechanisms behind this assocation.

Differential DNA methylation in the brain as potential mediator of the association between traffic‐related PM2.5 and neuropathology markers of Alzheimer's disease

“…The total effect estimated for all mediation analyses was positive but insignificant in this subsample of the cohort (see Christensen et al (2024) for the significant total effect in the full cohort). 25 The summary statistics for all CpG sites detected by DACT are summarized in the Supplement (Table S8).…”

“…(2024) for the significant total effect in the full cohort). 25 The summary statistics for all CpG sites detected by DACT are summarized in the Supplement (Table S8 ).…”

“…Previously, we found higher residential PM 2.5 exposure was associated with increased AD neuropathology in the Emory Goizueta ADRC brain bank. 25 To identify DNAm patterns in brain tissue that potentially mediate the association between PM 2.5 exposure and increased neuropathology markers, we (1) conducted an epigenome-wide association study (EWAS) for the long-term PM 2.5 exposures 1-, 3-, and 5-years prior to death and then investigated whether any differentially methylated CpG sites that were significantly associated with PM 2.5 exposure in the EWAS were also associated with increased neuropathology markers; and (2) conducted a combination of the MITM approach and high-dimensional mediation analysis (HDMA) to identify any mediating CpGs that did not reach genome-wide significance in the EWAS of PM 2.5 (Figure 1). The MITM approach and F I G U R E 1 Graphical overview of the analytical strategy to evaluate the potential mediating CpG sites in the current analysis.…”

“…This model was used to predict annual traffic‐related PM 2.5 for 2012–2019 with a spatial resolution of 200 m. More details can be found elsewhere. 25 Finally, we spatially matched geocoded residential addresses to the centroid of the closest grids and calculated the individual long‐term exposures as the average of specific exposure windows (1‐, 3‐, and 5‐years prior to death). The estimated PM 2.5 concentrations of different exposure windows served as an approximate proxy of individuals’ long‐term exposure, with a subsidiary goal of assessing the robustness of the hypothesis.…”

“…We recently showed a significant association between traffic‐related PM 2.5 exposure and increased AD neuropathology in this dataset. 25 To elucidate the biological mechanisms for this association, we here investigated whether differential DNAm in the prefrontal cortex tissues mediates the association between long‐term exposure to traffic‐related PM 2.5 and the levels of AD‐related neuropathological markers. This hypothesis was tested using a combination of the meet‐in‐the‐middle (MITM) approach and high‐dimensional mediation analysis.…”