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

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 exisits 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 ε 4 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 ε 4 alleles. Future studies should further investigate the biological mechanisms behind this assocation. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the HERCULES Pilot Project via NIEHS P30ES019776 (Huels), the Goizueta Alzheimer's Disease Research Center: Pilot Grant via NIA P50AG025688 (Huels/Liang), the Rollins School of Public Health Dean's Pilot and Innovation Grant (Huels) and NIA R01AG079170 (Huels/Wingo). GMC was supported by the NIEHS T32 Training Program in Environmental Health and Toxicology (5T32ES12870). The air pollution exposure assessment was supported by the NIH grant R21ES032117 (Liang). ### 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: Samples were obtained using research protocols approved by the Emory University Institutional Review Board. 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