Unique cognitive trajectories associated with inflammatory markers of blood‐brain barrier permeability in atrial fibrillation: An analysis of the Cardiovascular Health Study Cohort

Abstract

AbstractBackgroundAtrial fibrillation (AF) increases risk of cognitive decline independent of stroke, but mechanisms remain unclear. Elevated levels of peripheral inflammatory markers common in AF are associated with increased blood‐brain barrier (BBB) permeability and may contribute to neuroinflammation and degeneration. To examine the role of these markers in dementia risk, we estimated associations of plasma C‐reactive protein (CRP), interleukin‐6 (IL‐6), and fibrinogen with dementia and cognitive decline in aging adults with and without AF.MethodDementia free adults aged ≥ 65 years were identified from the Cardiovascular Health Cognition Study. Exposures were plasma CRP, IL‐6, and fibrinogen at baseline and follow‐up and primary outcomes were dementia and cognitive function, measured and adjudicated annually with the Modified Mini‐Mental State Examination (3MS). Competing risks Cox proportional hazards regression was used to estimate associations between time‐varying exposures and dementia. Latent class growth models were used to identify cognitive trajectories adjusted binomial logistic regression to test associations between these trajectories and baseline markers. All models were stratified by AF status, with interaction terms for sex and apolipoprotein E (APOE) ε4 status.ResultAmong 3,375 adults (505 with AF and 2,870 without), 480 developed dementia over a median follow‐up of 9.3 years. No associations between inflammatory markers and dementia hazard were observed, but latent class analyses identified two unique cognitive trajectories, with 82% showing a stable trajectory and 18% showing rapidly progressing decline. Among those with AF, elevated CRP and IL‐6 increased the odds of cognitive decline by 10% (95% CI 1.05 – 1.15) and 32% (95% CI 1.22 – 1.44), respectively. Sex‐specific models indicated that a 1g/L increase in fibrinogen increased the odds of cognitive decline by 57% among females with AF only (95% CI 1.36‐1.81). Among those with AF, inflammatory markers were more positively associated with cognitive decline in the presence of the APOE ε4 allele.ConclusionElevated IL‐6 was associated with cognitive decline in aging adults both with and without AF and elevated CRP and fibrinogen were associated with cognitive decline in those with AF only. Critically, sex and APOE genotype significantly modified these associations. Future work using more sensitive markers of central inflammation is needed.