Traffic-Related Air Pollution, APOE ε4 Status, and Neurodevelopmental Outcomes among School Children Enrolled in the BREATHE Project (Catalonia, Spain)

Abstract

Background: Traffic-related air pollution is emerging as a risk factor for Alzheimer's disease (AD) and impaired brain development. Individual differences in vulnerability to air pollution may involve the ε4 allele of Apolipoprotein E (APOE) gene, the primary genetic risk factor for AD.

Objective: We analyzed whether the association between traffic air pollution and neurodevelopmental outcomes is modified by APOEε4 status in children.

Methods: Data on parent-reported behavior problems (total difficulties scores, Strengths and Difficulties Questionnaire), teacher-reported attention-deficit hyperactivity disorder (ADHD) symptom scores, cognitive performance trajectories (computerized tests of inattentiveness and working memory repeated 2-4 times during January 2012-March 2013), and APOE genotypes were obtained for 1,667 children age 7-11 y attending 39 schools in or near Barcelona. Basal ganglia volume (putamen, caudate, and globus pallidum) was measured in 163 of the children by MRI (October 2012-April 2014.) Average annual outdoor polycyclic aromatic hydrocarbons (PAHs), elemental carbon (EC), and nitrogen dioxide (NO₂) concentrations were estimated based on measurements at each school (two 1-wk campaigns conducted 6 months apart in 2012).

Results: APOEε4 allele carriers had significantly higher behavior problem scores than noncarriers, and adverse associations with PAHs and NO₂ were stronger or limited to ε4 carriers for behavior problem scores (P-interaction 0.03 and 0.04), caudate volume (P-interaction 0.04 and 0.03), and inattentiveness trajectories (P-interaction 0.15 and 0.08, respectively). Patterns of associations with the same outcomes were similar for EC.

Conclusion: PAHs, EC, and NO₂ were associated with higher behavior problem scores, smaller reductions in inattentiveness over time, and smaller caudate volume in APOEε4 allele carriers in our study population, and corresponding associations were weak or absent among ε4 noncarriers. These findings support a potential role of APOE in biological mechanisms that may contribute to associations between air pollution and neurobehavioral outcomes in children. https://doi.org/10.1289/EHP2246.

Figure 1.

Differences according to APOE $\mathrm{\epsilon }4$ status in associations between annual average PAHs, EC, and ${\text{NO}}_2$ concentrations at schools and selected outcomes. (A) Mean ratios [with 95% confidence interval (CI) bands] for associations with baseline parent-reported SDQ total difficulties scores (a measure of behavior problems) from negative binomial mixed effects models with schools as random effects, adjusted for gender, age at baseline, maternal education, and residential neighborhood SES. A positive slope indicates that increasing TRAP concentrations are associated with higher scores for behavior problems. Interaction P-values are for two-way interaction terms between APOE $\mathrm{\epsilon }4$ status and air pollutants. $\mathrm{\epsilon }4$ carriers $n=366$, noncarriers $n=\mathrm{1,223}$. (B) Coefficients from linear mixed-effects models for average changes in HRT-SE (a measure of inattentiveness) over 12 months (2–4 follow-up visits), with children nested within schools as random effects, adjusted for gender, age at baseline, maternal education, and residential neighborhood SES. A positive slope indicates that higher TRAP concentrations are associated with smaller average decreases in HRT-SE (ms) over time (suggesting less improvement in attention with age). Interaction P-values are for three-way interaction terms between APOE $\mathrm{\epsilon }4$ status, air pollutants, and age (centered at baseline). $\mathrm{\epsilon }4$ carriers $n=379$, noncarriers $n=\mathrm{1,264}$. (C) Coefficients from linear mixed-effects models with schools as random effects, adjusted for gender, age at MRI examination, maternal education, residential neighborhood SES, and intracranial volume. A negative slope indicates that increasing TRAP concentrations are associated with smaller average caudate volumes (mm³). P-values are for two-way interaction terms between APOE $\mathrm{\epsilon }4$ status and air pollutants. $\mathrm{\epsilon }4$ carriers $n=37$, noncarriers $n=126$.