Purpose of the Study: Diabetes mellitus (DM) is characterized by chronic hyperglycemia and diabetic complications. Exacerbated cortical neuronal degeneration were observed in Alzheimer’s disease (AD) patients with DM. DM is considered a risk factor of AD, as DM-induced activation of stress responses in central nervous system (CNS) such as oxidative stress and neuroinflammation may lead to various neurodegenerative disorders. Abnormal accumulation of methylglyoxal (MG), one of the most reactive advanced glycation end-product (AGE) precursors, is found in the serum of diabetic patients. As MG is reported to induce brain cells impairment, like neuronal cell death, in CNS, and increased levels of AGEs have also been observed in brains of AD patients, hence the effect of MG leading to subsequent symptoms of AD was investigated. Methods: C57BL/6 mice were treated with MG solution (60mg/kg) or saline (100μl of 0.9% saline as sham control) by intraperitoneal injection for 9 weeks. The Morris water maze (MWM) was used to examine the spatial learning ability and cognition of mice. Footprint, escape latency and time spent in the target quadrant were measured and recorded. Summary of the Results: Significantly longer escape latency was observed in the MG-treated mice than that of the control group starting from Day 3. The mean escape latency of the MG-treated group was 13.41sec. while that of the control group was 5.450sec. in Day 5. It was also demonstrated in the probe trial that there was a significant reduction of the percentage time spent in the target quadrant of the MG-treated mice (44.07 ± 2.720) than that of the control group (58.29 ± 4.324). Conclusions: MG could induce AD symptoms causing spatial learning ability impairment and cognition decline in mice. MG may therefore play a role in the dysfunction of brain cells and dysregulation of CNS resulting in Alzheimer’s disease. Disclosure W. Li: None. S. Wu: None. F. Lee: None. K. Yue: None.