Genetic predisposition to AD and inflammation determine vulnerable brain regions to air pollution

Abstract Background The detrimental effects of air pollution on health are well‐documented, yet its impact on brain structure in the early asymptomatic stages of Alzheimer’s disease (AD) remains under‐explored. This study investigated the relationship between air pollution and brain imaging features, focusing on the moderating role of genetic factors associated with AD and inflammation. Methods A total of 1,153 individuals from the ALFA cohort, many within the Alzheimer’s continuum, with available genotyping, air pollution estimation and magnetic resonance imaging were included (62.6% women, average age 55,6 years). Land use regression models were used to estimate individual levels of air pollution, including nitrogen oxide (NO2) and particulate matter (PM2.5, PM10), at the participants’ residential addresses. Functional genetic scores, including plasma pQTLs for inflammatory markers (PRS‐CCL2, PRS‐IL6, PRS‐CCL19), CSF pQTLs for AD pathology (PRS‐Aß42, PRS‐ptau), genetic predisposition to clinical AD (PRS‐AD), and APOE‐e4 carriership, were assessed. General linear models, corrected for age at MRI visit, sex and years of education, were computed to assess the main effects of air pollution on brain volumes. Modifiable genetic effects in gene‐environment interaction models were investigated. Results Individuals at higher genetic predisposition to AD and APOE‐e4 carriers exhibited increased vulnerability to air pollution, particularly in temporal and frontal regions [Figure 1A]. Individuals with high genetic predisposition for inflammatory markers showed distinct patterns of vulnerability, particularly affecting regions within the parietal and limbic lobes, with notable impact on hippocampal volumes and the subfields within the hippocampal formation [Figure 1B]. Finally, as pollution levels increased, reduction in transverse temporal volumes was observed in individuals at high risk of AD and altered CCL2 protein plasma levels [Figure 2]. Multiple comparison corrections were performed within brain lobes by regions. Conclusions Our results suggested a differential impact of air pollution on brain structure, modulated by genetic predisposition to AD and inflammation. This underscores the importance of considering genetic information when assessing the neurological impact of environmental exposures. These findings pave the way for more personalized approaches in public health interventions, and highlight the need for targeted strategies to mitigate the impact of environmental factors on neurological health.