Aim: Type 2 diabetes mellitus (DM) increases the risk of dementia. We aimed to elucidate the dynamics of blood biomarkers according to the severity of cognitive impairment in patients with DM and to identify useful biomarkers for diabetes-related dementia. Methods: This was a cross-sectional, nested case-control study of 121 Japanese diabetic and nondiabetic patients with different levels of cognitive functioning. We evaluated participants' cognitive functions, blood biomarkers related to Alzheimer's disease, and soluble triggering receptors expressed on myeloid cells 2 (sTREM2). We then compared these biomarkers between the DM and non-DM groups and across the different cognitive strata. Results: Significantly lower levels of serum sTREM2 were observed in the DM than in the non-DM patients. This was true across all the cognitive strata of the two groups, including those with normal cognition. We also found that plasma levels of phosphorylated tau 181 (p-tau181) increased with increasing levels of cognitive decline in both the DM and non-DM groups. However, this was accompanied by a decrease in plasma amyloid-β(Aβ)42/Aβ40 ratios in non-DM patients only. Conclusion: This study revealed novel characteristic trajectories of dementia-related blood biomarkers in diabetes-related dementia, suggesting the pathological involvement of molecular cascades initiated by impaired microglial activation. This results in decreased serum sTREM2, followed by tauopathy without substantial amyloid plaques, reflected by plasma p-tau elevation with no decrease in the Aβ42/Aβ40 ratio. Our results warrant further research into this molecular cascade to elucidate pathogenetic mechanisms of diabetes-related dementia and establish useful biomarkers.

The authors have declared no competing interest.

This work was supported in part by Grant-in-Aid for Scientific Research (B) to N.S-A. (JP18H02737 and 21H02835), (C) to H.Y. (JP19K07905 and JP22K11720), and M.T. (JP22K07456), and by Grant-in-Aid for Exploratory Research to N.S-A. (JP18K19769) from Japan Society for the Promotion of Science. This study was also supported in part by a grant from Smoking Research Foundation to N.S-A. (2019T004), a grand from Takeda Medical Research Foundation to N.S-A., and a grant from the Japan Agency for Medical Research and Development to T.T. (AMED, JP21dk0207055h0001 and JP21ae0101077003). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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The study was approved by the Kyoto Dementia Center Research Ethics Committee.

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