Brain, behavior, & immunity - health · 2025
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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Hallab Asma, Health and Aging Brain Study (HABS-HD) Study Team, HABS-HD MPIs, HABS-HD Investigators
Аннотация
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.
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.