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 (TDM) 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

TDM and IL-6 were associated with worse executive function, Hippocampus atrophy, lower Aß/Aß ratio, and higher Aß, Aß, total Tau, and NfL levels. IL-6 mediated 5% of the association of TDM with Aß ([1.5%-10%], value<2×10), 4% with Aß ([0.7%-11%], -value=0.014), 8% with TMT-B ([0.2%-35%], value=0.046), 11% with total Tau ([2.5%-40%], -value=0.010), 5% with NfL ([1.6%-8%], value<2×10), and 12% hippocampus atrophy ([3%-49%], value=0.004). The results, except TMT-B, were replicated in the longitudinal analysis of long-lasting TDM on non-previously diagnosed cognitive impairment.

CONCLUSIONS

The study captured a pre-clinical stage of the TDM-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.