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
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Introduction
Type-2 diabetes (T 2 DM) 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
T 2 DM and IL-6 were associated with worse executive function, Hippocampus atrophy, lower Aß 42 /Aß 40 ratio, and higher Aß 40 , Aß 42 , total Tau, and NfL levels. IL-6 mediated 5% of the association of T 2 DM with Aß 40 ([1.5%-10%], p- value<2×10 −16 ), 4% with Aß 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<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 T 2 DM on non-previously diagnosed cognitive impairment.
Conclusions
The study captured a pre-clinical stage of the T 2 DM-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.
