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

Abstract

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 1,927 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 A-Beta 42/A-Beta 40 ratio, and higher A-Beta 40, A-Beta 42, total Tau, and NfL levels. IL-6 mediated 5% of the association of T2DM with A-Beta 40 ([1.5%-10%], p-value<2x10-16), 4% with A-Beta 42 ([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<2x10-16), 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.