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.

The authors have declared no competing interest.

Research reported on this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers R01AG054073, R01AG058533, R01AG070862, P41EB015922, and U19AG078109.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Procedures contributing to this work were all compliant with the Helsinki Declaration of 1975, as revised in 2013, and with the ethical standards of the relevant national and institutional committees on human experimentation. Ethical approval was obtained from the local institutional review board (University of North Texas Health Science Center). Written informed consent was obtained from every participant. The current research consists of a secondary analysis of anonymized data.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

↵* HABS-HD MPIs: Sid E O’Bryant, Kristine Yaffe, Arthur Toga, Robert Rissman, & Leigh Johnson; and the HABS-HD Investigators: 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 and Rocky Vig.