DNA methylation age acceleration mediates the relationship between systemic inflammation and cognitive impairment

<h4>Background</h4>Chronic inflammation and DNA methylation are potential mechanisms in dementia etiology. The linkage between inflammation and DNA methylation age acceleration in shaping dementia risk remains understudied. We explored the association of inflammatory cytokines with cognitive impairment and whether DNA methylation age acceleration mediates this relationship.<h4>Research design and methods</h4>Using data from the 2016 Health and Retirement Study (<i>n</i> = 3,346, age >50), we estimate the associations between each inflammatory cytokine (interleukin-6 (IL-6), C-reactive protein (CRP), and insulin-like growth factor-1 (IGF-1)), and cognitive status, classified using the Langa-Weir method. We tested if DNA methylation age acceleration mediated the relationship between systemic inflammation and cognitive impairment, adjusting for sociodemographic, behavioral factors, chronic conditions, and cell-type proportions.<h4>Results</h4>Cognitive impairment prevalence was 16%. A doubling of IL-6 was associated with a 12% higher odds of cognitive impairment (OR = 1.12, 95% CI: 1.02-1.22), and 0.77 years of GrimAge acceleration (95% CI: 0.64-0.90). Similar associations were found for CRP and IGF-1. Mediation analysis indicated that 17.7% (95% CI: 7.0-50.9%) of the IL-6-cognitive impairment association was mediated by the GrimAge acceleration. Comparable mediated estimates were found for CRP and IGF-1.<h4>Conclusions</h4>Systemic inflammation is associated with cognitive impairment, with suggestive evidence that this relationship is partially mediated through DNA methylation age acceleration.