Background

Epidemiological evidence suggests air pollution adversely affects cognition and increases the risk of Alzheimer's disease (AD), but little is known about the biological effects of fine particulate matter (PM2.5, particulate matter with aerodynamic diameter ≤2.5μm) on early predictors of future disease risk.

Objectives

We investigated the association between 1-, 3-, and 5-y exposure to ambient and traffic-related PM2.5 and cerebrospinal fluid (CSF) biomarkers of AD.

Methods

We conducted a cross-sectional analysis using data from 1,113 cognitively healthy adults (45-75 y of age) from the Emory Healthy Brain Study in Georgia in the United States. CSF biomarker concentrations of Aβ42, tTau, and pTau, were collected at enrollment (2016-2020) and analyzed with the Roche Elecsys system. Annual ambient and traffic-related residential PM2.5 concentrations were estimated at a 1-km and 250-m resolution, respectively, and computed for each participant's geocoded address, using three exposure time periods based on specimen collection date. Associations between PM2.5 and CSF biomarker concentrations, considering continuous and dichotomous (dichotomized at clinical cutoffs) outcomes, were estimated with multiple linear/logistic regression, respectively, controlling for potential confounders (age, gender, race, ethnicity, body mass index, and neighborhood socioeconomic status).

Results

Interquartile range (IQR; IQR=0.845) increases in 1-y [β:-0.101; 95% confidence interval (CI): -0.18, -0.02] and 3-y (β:-0.078; 95% CI: -0.15, -0.00) ambient PM2.5 exposures were negatively associated with Aβ42 CSF concentrations. Associations between ambient PM2.5 and Aβ42 were similar for 5-y estimates (β:-0.076; 95% CI: -0.160, 0.005). Dichotomized CSF variables revealed similar associations between ambient PM2.5 and Aβ42. Associations with traffic-related PM2.5 were similar but not significant. Associations between PM2.5 exposures and tTau, pTau tTau/Aβ42, or pTau/Aβ42 levels were mainly null.

Conclusion

In our study, consistent trends were found between 1-y PM2.5 exposure and decreased CSF Aβ42, which suggests an accumulation of amyloid plaques in the brain and an increased risk of developing AD. https://doi.org/10.1289/EHP13503.

Introduction

Growing evidence indicates that fine particulate matter (PM_2.5) is a risk factor for Alzheimer's disease (AD), but the underlying mechanisms have been insufficiently investigated. We hypothesized differential DNA methylation (DNAm) in brain tissue as a potential mediator of this association.

Methods

We assessed genome-wide DNAm (Illumina EPIC BeadChips) in prefrontal cortex tissue and three AD-related neuropathological markers (Braak stage, CERAD, ABC score) for 159 donors, and estimated donors' residential traffic-related PM_2.5 exposure 1, 3, and 5 years prior to death. We used a combination of the Meet-in-the-Middle approach, high-dimensional mediation analysis, and causal mediation analysis to identify potential mediating CpGs.

Results

PM_2.5 was significantly associated with differential DNAm at cg25433380 and cg10495669. Twenty-four CpG sites were identified as mediators of the association between PM_2.5 exposure and neuropathology markers, several located in genes related to neuroinflammation.

Discussion

Our findings suggest differential DNAm related to neuroinflammation mediates the association between traffic-related PM_2.5 and AD.

Highlights

First study to evaluate the potential mediation effect of DNA methylation for the association between PM2.5 exposure and neuropathological changes of Alzheimer's disease. Study was based on brain tissues rarely investigated in previous air pollution research. Cg10495669, assigned to RBCK1 gene playing a role in inflammation, was associated consistently with 1-year, 3-year, and 5-year traffic-related PM2.5 exposures prior to death. Meet-in-the-middle approach and high-dimensional mediation analysis were used simultaneously to increase the potential of identifying the differentially methylated CpGs. Differential DNAm related to neuroinflammation was found to mediate the association between traffic-related PM2.5 and Alzheimer's disease.

Previous research has found that living in a disadvantaged neighborhood is associated with poor health outcomes. Living in disadvantaged neighborhoods may alter inflammation and immune response in the body, which could be reflected in epigenetic mechanisms such as DNA methylation (DNAm). We used robust linear regression models to conduct an epigenome-wide association study examining the association between neighborhood deprivation (Area Deprivation Index; ADI), and DNAm in brain tissue from 159 donors enrolled in the Emory Goizueta Alzheimers Disease Research Center (Georgia, USA). We found one CpG site (cg26514961, gene PLXNC1) significantly associated with ADI after controlling for covariates and multiple testing (p-value=5.0e-8). Effect modification by APOE ε4 was statistically significant for the top ten CpG sites from the EWAS of ADI, indicating that the observed associations between ADI and DNAm were mainly driven by donors who carried at least one APOE ε4 allele. Four of the top ten CpG sites showed a significant concordance between brain tissue and tissues that are easily accessible in living individuals (blood, buccal cells, saliva), including DNAm in cg26514961 (PLXNC1). Our study identified one CpG site (cg26514961, PLXNC1 gene) that was significantly associated with neighborhood deprivation in brain tissue. PLXNC1 is related to immune response, which may be one biological pathway how neighborhood conditions affect health. The concordance between brain and other tissues for our top CpG sites could make them potential candidates for biomarkers in living individuals.