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[Preprint]. 2025 May 7:2025.05.06.25327092.
doi: 10.1101/2025.05.06.25327092.

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

Asma Hallab  1   2   3   4 ; Health and Aging Brain Study (HABS-HD) Study Team
Affiliations

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

Asma Hallab et al. medRxiv. .

Update in

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 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.

Keywords: Cognition; aging; brain; cytokine; insulin resistance; neuroinflammation.

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Conflict of interest statement

Declarations Conflicts of interest: The authors have no conflict of interest, neither financial nor non-financial.

Figures

Figure 1:
Figure 1:. Interleukin-6 levels in the study population and associations with different metabolic biomarkers.
1.a) Interleukin-6 (IL-6) in the study population. 1.b) & 1.c) Serum Glucose levels. 1.d) & 1.e) Glycated Hemoglobin (HbA1c). 1.f) & 1.g) Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). 1.h) & 1.i) Body Mass Index (BMI). Interactions between Interleukin-6 and diabetes are visualized
Figure 2:
Figure 2:. Association between Interleukin-6 levels and different cognitive biomarkers.
Interactions between Interleukin-6 and diabetes are visualized. 2.a) Hippocampus volume. 2.b) Amyloid ß40. 2.c) Amyloid ß42. 3.d) Amyloid ß42/40 ratio. 4.e) Total Tau. 2.f) Phosphorylated (p-)Tau181. 3.g) Neurofilament Chain. Amyloid, Tau, and Neurofilament models are adjusted for renal function. Hippocampus models are adjusted for intracranial volume and scanner type.
Figure 3:
Figure 3:. Mediation analysis – Cross-sectional design.
Only statistically significant results are visualized. 3.a) Amyloid ß40. 3.b) Amyloid ß42. 3.c) Trails-Making-Test B. 4.d) Total Tau. 3.e) Neurofilament Chain. 3.f) Hippocampus volume. ACME: Mediated Effect, ADE: Direct Effect. Amyloid, Tau, and Neurofilament models are adjusted for renal function. Hippocampus models are adjusted for intracranial volume and scanner type.
Figure 4:
Figure 4:. Mediation analysis – Longitudinal design.
Only statistically significant results are visualized. 4.a) Amyloid ß40. 4.b) Amyloid ß42. 4.c) Total Tau. 4.d) Neurofilament Chain. 4.e) Hippocampus volume. ACME: Mediated Effect, ADE: Direct Effect. Amyloid, Tau, and Neurofilament models are adjusted for renal function. Hippocampus models are adjusted for intracranial volume and scanner type.
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