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Zi-Wei Yu,1,&ast; Sheng-Dan Pu,2,&ast; Xiao-Tong Sun,2 Xi-Chang Wang,1 Xin-Yuan Gao,2 Zhong-Yan Shan1 1Department of Endocrinology and Metabolism and the Institute of Endocrinology, The NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, First Hospital of China Medical University, Shenyang, 110001, People’s Republic of China; 2Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhong-Yan Shan; Xin-Yuan Gao, Tel +8613804905018 ; +8613904517001, Email cmushanzhongyan@163.com; m15124768260@163.comPurpose: The prevalence of mild cognitive impairment (MCI) in patients with type 2 diabetes (T2D) is rapidly increasing. Thyroid hormones are key regulators of cognitive function in adults. The purpose of this study was to investigate the relationship between thyroid hormone sensitivity and MCI in euthyroid T2D patients.Patients and Methods: A total of 400 euthyroid T2D patients were enrolled in this cross-sectional study, including 218 patients with normal cognition and 182 MCI patients. The Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive function. The free triiodothyronine to free thyroxine (FT3/FT4) ratio was calculated as a measure of peripheral sensitivity to thyroid hormones; the thyroid-stimulating hormone index (TSHI), thyrotrophic thyroxine resistance index (TT4RI) and thyroid feedback quantile-based index (TFQI) were calculated as measures of central sensitivity to thyroid hormones. Linear regression analysis and logistic regression analysis were performed to explore the relationships between these indices of thyroid hormone sensitivity and the MoCA score and MCI, respectively.Results: Compared with the normal cognitive function group, patients in the MCI group had higher TSHI, TT4RI and TFQI but a lower FT3/FT4 ratio (P< 0.05). The MoCA score was positively correlated with the FT3/FT4 ratio but negatively correlated with TSHI, TT4RI and TFQI (P< 0.05). Multivariate logistic regression analysis showed that a low FT3/FT4 ratio and high TSHI, TT4RI and TFQI were independently associated with MCI (P< 0.05). After adjustment for confounding factors, the odds ratio (OR) for the association between MCI and the highest tertile of the FT3/FT4 was 0.455 (95% CI: 0.264– 0.785), for the highest tertile of TSHI, the OR was 2.380 (95% CI: 1.376– 4.119), for the highest tertile of TT4RI, the OR was 2.342 (95% CI:1.353– 4.054), and for the highest tertile of TFQI, the OR was 2.536 (95% CI: 1.466– 4.387) (P< 0.05).Conclusion: Impaired sensitivity to thyroid hormones is associated with MCI in euthyroid T2D patients.Keywords: type 2 diabetes, mild cognitive impairment, thyroid hormones, sensitivity to thyroid hormones