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

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-...

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Main Authors: Asma Hallab, Sid E. O'Bryant, Kristine Yaffe, Arthur Toga, Robert Rissman, Leigh Johnson, Meredith Braskie, Kevin King, James R. Hall, Melissa Petersen, Raymond Palmer, Robert Barber, Yonggang Shi, Fan Zhang, Rajesh Nandy, Roderick McColl, David Mason, Bradley Christian, Nicole Phillips, Stephanie Large, Joe Lee, Badri Vardarajan, Monica Rivera Mindt, Amrita Cheema, Lisa Barnes, Mark Mapstone, Annie Cohen, Amy Kind, Ozioma Okonkwo, Raul Vintimilla, Zhengyang Zhou, Michael Donohue, Rema Raman, Matthew Borzage, Michelle Mielke, Beau Ances, Ganesh Babulal, Jorge Llibre-Guerra, Carl Hill, Rocky Vig
Format: Article
Language:English
Published: Elsevier 2025-08-01
Series:Brain, Behavior, & Immunity - Health
Subjects:
Cognition
Insulin resistance
Aging
Brain
Cytokine
Neuroinflammation
Online Access:http://www.sciencedirect.com/science/article/pii/S2666354625000894
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Summary: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.
ISSN:2666-3546

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