Background and Objective: Obesity has been associated with cognitive deficits and even dementia. The purpose of this study was to identify the beneficial effects of anti-diabetic agent, alogliptin benzoate (ALG), dipeptidyl peptidase-4 inhibitor to cognition deficits, antidepressive state and metabolic abnormality. Materials and Methods: Three months oral administration of ALG (30 mg kg(-1)/day) were performed in ApoE-/- mice with high-fat diet (HFA, n = 15). The non-treated mice with high-fat diet (HFD, n = 15) became obese. Mice were fed from the age of 8 weeks until 20 weeks. As a control, non-exercised mice without high-fat diet (NOR, n = 15) were prepared. Morris water maze test as spatial learning and novel object recognition test as recognition memory were performed. Forced swimming test as depressive state was also performed. Histopathological analysis was performed in the hippocampus and the liver of three groups. Comparisons among groups were performed using two-way ANOVA followed by Fisher's least significant difference analysis (p<0.05). Results: Mice in HFD showed cognition deficits, depressive condition and metabolic abnormality. The ALG treatment did not reduce the body weight compared with untreated mice with high-fat diet. The liver weight/body weight ratio was significantly (p<0.05) reduced in HFA compared with HFD. The circulating levels of liver enzyme and lipids were significantly (p<0.05) lower in HFA compared with HFD. Both of Morris water maze test and novel object recognition test were significantly (p<0.05) recovered in HFA compared with HFD. The forced swimming test was also better in HFA compared with HFD. The ALG treatment significantly (p<0.05) induced brain-derived neurotrophic factor (BDNF) mRNA and reduced calcineurin 1 regulator (RCAN1) mRNA in hippocampus. Histopathological analysis showed reduced pyknotic neurons of the hippocampus and steatosis of the liver by the ALG treatment. Conclusion: These findings suggest that ALG treatment could attenuate cognitive deficit and depressive function in the association with metabolic advantages, through the protection of pyknotic neurons in the hippocampus and steatosis in the liver.