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

Abstract

AbstractAimBoth 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.MethodsApoE 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.ResultsT2DM 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.ConclusionWe 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.