The role of comorbidities in the associations between air pollution and Alzheimer’s disease: A national cohort study in the American Medicare population

BACKGROUND: Air pollution and several common comorbidities-such as hypertension, stroke, and depression-are established risk factors for Alzheimer's disease (AD). However, whether these comorbidities mediate or amplify the effects of fine particulate matter (PM2.5) on AD remains unclear. We aimed to investigate whether these conditions modify or mediate the association between PM2.5 exposure and incident AD. METHODS AND FINDINGS: We conducted a nationwide cohort study including 27.8 million US Medicare beneficiaries aged 65 years and older from 2000 to 2018. Exposure to PM2.5 was assessed using high-resolution air pollution datasets. Cox proportional hazards models were applied to estimate the associations between exposure to PM2.5, incident AD, and comorbidities. The potential for comorbidities to modify and mediate the association between PM2.5 and AD was evaluated by stratified analyses and mediation analysis. We identified approximately 3.0 million incident AD cases. PM2.5 exposure (5-year moving average prior to AD onset) was associated with increased risk of AD in the overall population (hazard ratio [HR]) per interquartile range [IQR, 3.8 µg/m3] increase: 1.085 (95% CI: 1.078, 1.091]. This association was slightly stronger in individuals with stroke (HR per IQR increase: 1.105; 95% CI: 1.096, 1.114), but there was little effect modification for hypertension and depression. PM2.5 exposure was also significantly associated with higher risks of hypertension, depression, and stroke, all of which were also linked to increased AD risk. However, mediation effects were minimal, with 1.6% of the association between PM2.5 and incident AD mediated by hypertension, 4.2% by stroke, and 2.1% by depression. Study limitations include use of administrative claims data and potential exposure misclassification from area-level PM2.5 estimates. CONCLUSIONS: Our findings suggest that PM2.5 exposure was associated with increased AD risk, primarily through direct rather than comorbidity-mediated pathways. Stroke may modestly increase susceptibility. These findings highlight the need for air quality interventions as part of dementia prevention strategies in aging populations, especially those facing overlapping environmental and clinical vulnerabilities.