Air pollution exposure interacts with Alzheimer’s genetic susceptibility to reshape microglial epigenomic and transcriptional programs

Chronic exposure to fine particulate matter air pollution (PM 2.5 ) is associated with cognitive decline and neurodegenerative disease, but the biology connecting inhaled particles to the brain remains incompletely defined. Among 475,325 eligible UK Biobank participants, long-term PM 2.5 exposure and Alzheimer disease (AD) polygenic risk were both independently associated with higher risk of AD and related dementias (ADRD). The PM 2.5 -by-polygenic risk score (PRS) interaction in Cox models was statistically significant but sub-multiplicative or below unity (interaction HR 0.981, 95% CI 0.965–0.998; p = 0.026), indicating that the combined association was smaller than the simple product of the two individual associations. To define the underlying biology, we exposed 5xFAD mice, an amyloid-based model of AD, and wild-type (WT) littermates to concentrated ambient PM 2.5 or filtered air for 20 weeks. PM 2.5 exposure activated microglia, disrupted the blood-brain barrier, depleted the brain NAD + /NADH pool required for resilience and repair, impaired postnatal hippocampal neurogenesis, and caused cognitive deficits. In 5xFAD mice it additionally increased amyloid burden. Paired RNA-seq and ATAC-seq of microglia isolated from the same animals showed that exposure remodeled both gene expression and chromatin accessibility, and that that magnitude and direction of this response depended on genotype, converging on inflammatory, lysosomal, oxidative-stress, synaptic, and amyloid-related pathways.​ ​These population-scale data in humans and experimental data in mice​ support PM 2.5 as an environmental neurotoxicant and define microglial regulatory programs through which genetic background shapes the biological response to a common and modifiable exposure.