Inflammation as a mediator of air pollution's role in Alzheimer's disease and related dementias

Background Air pollution has been implicated in cognitive decline and increased risk of Alzheimer's disease (AD) and Alzheimer's disease–related dementias (ADRD). Inflammation, particularly C-reactive protein (CRP), may mediate these associations, but causal evidence remains limited. Objective To examine the associations between particulate matter (PM) exposure and cognitive performance, evaluate the causal effects of air pollutants on genetically predicted AD/ADRD risk using Mendelian randomization (MR), and assess CRP as a potential mediator. Methods We conducted observational analyses among 7087 older adults from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) to evaluate associations between long-term PM exposure and Mini-Mental State Examination (MMSE) scores. Two-sample MR using GWAS summary statistics was performed to estimate the causal effects of PM 2.5 , PM 10 , NO 2 , and NO x on AD risk. Mediation MR assessed CRP's contribution to the PM–AD pathway. Results Higher exposure to finer PM was associated with lower MMSE scores, with the strongest associations observed for PM 1 (β = −0.335; 95% CI: −0.624 to −0.263) and PM 2.5 (β = −0.229; 95% CI: −0.367 to −0.164). MR analyses identified a causal effect of PM 10 on AD risk (OR = 1.926; 95% CI: 1.032–3.598). CRP mediated 42.9% of this effect (p = 0.003). Conclusions Long-term PM exposure, particularly PM 10 , may contribute to increased AD/ADRD susceptibility, potentially through inflammation-related pathways. Finer particles showed stronger observational associations with cognitive decline, highlighting the need for further investigation. These findings support air quality improvement and inflammation-targeted strategies for dementia prevention.