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. The gene discussed is GSK3B; the disease is Cognitive impairment.