GSK-3β activation mediates apolipoprotein E4-associated cognitive impairment in type 2 diabetes mellitus: A multicenter, cross-sectional study.

AIM:Both the activation of glycogen synthase kinase-3β (GSK-3β) and the presence of ApoE ε4 genotype have been found to respectively correlate with cognitive decline in patients with type 2 diabetes mellitus (T2DM), who further show a high incidence of developing Alzheimer's disease. However, the relationship between ApoE ε4 and GSK-3β in the cognitive impairment of T2DM patients remains unclear. METHODS:ApoE genotypes and platelet GSK-3β level were measured in 1139 T2DM patients recruited from five medical centers in Wuhan, China. Cognitive functions were assessed by Mini-Mental State Examination (MMSE). The association and the relationships among apolipoprotein E (ApoE) genotypes, GSK-3β activity and cognitive function were analyzed by regression and mediating effect analyses, respectively. RESULTS:T2DM patients with ApoE ε4 but not ApoE ε2 haplotype showed poorer cognitive function and elevated platelet GSK-3β activity, when using ApoE ε3 as reference. The elevation of GSK-3β activity was positively correlated the diabetes duration, as well as plasma glycated hemoglobin (HbA1c) and glucose levels. Moreover, correlation and regression analysis also revealed significant pairwise correlations among GSK-3β activity, ApoE gene polymorphism and cognitive function. Lastly, using Baron and Kenny modeling, we unveiled a mediative role of GSK-3β activity between ApoE ε4 and cognitive impairment. CONCLUSION:We reported here that the upregulation of GSK-3β activity mediates the exacerbation of cognitive impairment by ApoE ε4-enhanced cognitive impairment in T2DM patients, suggesting GSK-3β inhibitors as promising drugs for preserving cognitive function in T2DM patients, especially to those with ApoE ε4 genotype.