Mechanistic understanding of the role of the lung–brain axis in the pathogenesis of PM2.5-induced Alzheimer’s disease

Abstract

Air pollution, particularly fine particulate matter (PM2.5), has emerged as an important yet under-recognised environmental contributor to cognitive decline and Alzheimer’s disease (AD) across the life course. Although epidemiological studies consistently associate long-term PM2.5 exposure with impaired cognition, from reduced neurodevelopmental performance in children to accelerated neurodegeneration in older adults, the biological mechanisms linking inhaled particles to AD-related brain pathology remain incompletely defined. In the present review, we synthesise current epidemiological and experimental evidence to position the lung-brain axis as a central mechanistic framework through which PM2.5 may influence brain aging and AD pathogenesis. Rather than acting solely through direct particle entry into the brain, PM2.5-induced pulmonary injury initiates systemic signalling cascades, including inflammatory mediators, oxidative stress, blood-brain barrier disruption, and extracellular vesicle-mediated intercellular communication, which together propagate disease signals from the lung to the brain. We further examine how these pathways intersect with core AD-related processes, including amyloid-β accumulation, tau pathology, impaired protein clearance, maladaptive microglial responses, and autophagy-lysosomal dysfunction. We also discuss important modifiers of susceptibility and heterogeneity in reported associations, including pollutant composition, co-exposure to other air pollutants, sex, APOE genotype, and epigenetic reprogramming. Overall, the present review proposes an integrated multi-organ model of PM2.5 neurotoxicity that aligns environmental exposure with key mechanisms of AD pathogenesis and highlights priorities for strengthening causal inference and future translational research.