Based on the data presented in the current study, administration of AM404 at low dose significantly induced neuroprotection in primary mouse hippocampal neuronal culture incubated with WT/GFX and reduced cognitive deficits associated pathological features, which might be partly through Akt/GSK3β pathway in hyperglycemic 3×Tg-AD mice. This evidence concerns the gene GSK3B and Cognitive impairment.