Mediating role of Interleukin-6 in the predictive association of diabetes with Hippocampus atrophy, Amyloid, Tau, and Neurofilament pathology at pre-clinical stages of diabetes-related cognitive impairment

Introduction: Type-2 diabetes (T₂DM) has been associated with higher dementia risks, but the mechanisms are still unclear, and there is increasing evidence of the role of cytokines. Interleukin-6 (IL-6) mediating effect has never been explored. Methods: The study included a subset of 1927 community-dwelling participants from the Health and Aging Brain Study: Healthy Disparities (HABS-HD) cohort with complete data. Cross-sectional and longitudinal analyses were performed. Associations were studied using multivariable linear, logistic, and mediation analysis with non-parametric bootstrapping. Results: T₂DM and IL-6 were associated with worse executive function, Hippocampus atrophy, lower Aß₄₂/Aß₄₀ ratio, and higher Aß₄₀, Aß₄₂, total Tau, and NfL levels. IL-6 mediated 5 % of the association of T₂DM with Aß₄₀ ([1.5 %–10 %], p-value<2 × 10⁻¹⁶), 4 % with Aß₄₂ ([0.7 %–11 %], p-value = 0.014), 8 % with TMT-B ([0.2 %–35 %], p-value = 0.046), 11 % with total Tau ([2.5 %–40 %], p-value = 0.010), 5 % with NfL ([1.6 %–8 %], p-value<2 × 10⁻¹⁶), and 12 % Hippocampus atrophy ([3 %–49 %], p-value = 0.004). The results, except TMT-B, were replicated in the longitudinal analysis of long-lasting T₂DM on non-previously diagnosed cognitive impairment. Conclusions: The study captured a pre-clinical stage of the T₂DM-dementia association. The mediating effect of IL-6 is a novelty that has to be further explored and accounted for in risk stratification and preventive measures, particularly in ethnic minorities.