ABSTRACT NUMBER: ESOC2026A271 INTERLEUKIN-6 LEVELS AND RISK OF INCIDENT DEMENTIA: THE ARIC STUDY

Abstract Background and aims Systemic inflammation has been implicated in cognitive decline and dementia pathogenesis. Interleukin-6 (IL-6), a pro-inflammatory cytokine associated with cardiovascular disease, may play a role in cerebrovascular and neurodegenerative processes. We examined the relationship between IL-6 levels and incident dementia risk using the Atherosclerosis Risk In Communities (ARIC) study. Methods ARIC study participants at Visit 4 (1996-1998) had IL-6 measurements and were followed for incident dementia over 25 years. IL-6 levels were dichotomized at the median value of 1.5 pg/mL. Incident dementia cases were identified through standardized surveillance. Cox proportional hazards regression calculated hazard ratios (HR) with 95% confidence intervals (CI), adjusting for age, race, gender, hypertension, diabetes, obesity, physical activity, smoking, alcohol use, education, income, insurance status, and ApoE-ε4 allele status. Results Participants (n=5,662; mean age 62.4±5.6 years, 55% female, 83% White, 17% Black) were followed for a median of 25 years. Those with IL-6 >1.5 pg/mL demonstrated significantly increased dementia risk versus IL-6 ≤1.5 pg/mL. The crude HR was 1.23 (95% CI 1.11-1.37). After adjustment, the association remained significant with HR 1.13 (95% CI 1.01-1.27). Kaplan-Meier survival curves showed progressive divergence between groups, with lower dementia-free survival in the higher IL-6 group, log-rank p<0.001. Conclusions Elevated mid-life IL-6 levels (>1.5 pg/mL) independently predict increased long-term dementia risk over 25 years, even after adjusting for cardiovascular and sociodemographic confounders. These findings support systemic inflammation's role in dementia pathogenesis and highlight IL-6 as a potential biomarker for dementia risk. Conflict of interest Karly Pikel, Natasha Carmichael, Alana E. Barton, Kevin Moss, Christine Downey, Ryan T. Demmer, Pamela L. Lutsey, Souvik Sen: Nothing to disclose Figure 1 - belongs to Conclusions