GSK-3β Activation Mediates Apolipoprotein E4-Assocaited Cognitive Impairment in Type 2 Diabetes Mellitus: A Multicenter, Cross-Sectional Study

Background: Both glycogen synthase kinase-3β (GSK-3β) activation and ApoE ε4 genotype contribute to the cognitive decline in patients with type 2 diabetes mellitus (T2DM), which shows a high incidence of developing into Alzheimer’s disease (AD). However, the relationship between ApoE ε4 and GSK-3β in the cognitive impairment in T2DM patients remains unclear.Methods: ApoE genotypes and platelet GSK-3β were measured in 1139 T2DM patients recruited from five medical centers. Cognitive functions were assessed by Mini-Mental State Examination (MMSE). The association and the relationships of ApoE genotypes, GSK-3β activity and cognitive function were analyzed by regression and mediating effect analyses, respectively.Findings: Using ApoE ε3 as standard, ApoE ε4 but not ApoE ε2 haplotype T2DM patients show poorer cognitive function and elevated platelet GSK-3β activity. Besides, the elevation of GSK-3β activity was positively correlated with the diabetes duration, HbA1c and plasma glucose levels. Further analysis revealed significant pairwise correlations among ApoE gene polymorphism, cognitive function and GSK-3β activity, respectively. Lastly, the Baron Kenny model unveiled a mediative role of GSK-3β between ApoE ε4 and cognitive impairment.Interpretation: We reported the novel associations that insulin resistance-induced GSK-3β upregulation mediates ApoE ε4-enhanced cognitive impairment in T2DM patients. Therefore, modulating GSK-3β should be promising in preserving the cognitive function in T2DM patients, especially to those with ApoE ε4 genotype.Funding Information: This study was supported in parts by the Natural Science Foundation of China (91949205, 31730035, 81721005, 81901107), the National Key R&D Program of China (2016YFC1305800), the Hubei Province scientific research project (2018ACA142, WJ2021M041), the Wuhan Health Science Foundation (WX20Q04), the Guangdong Provincial Key S&T Program (018B030336001) and the Science and Technology Program of Guizhou Province (Qiankehe zhicheng [2021] yiban 423).Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: The study protocol was approved by Tongji Medical School Ethics Committee in accordance with the principles of the Helsinki Declaration II. All participants have provided written informed consent.