Novel Biomarkers of Alzheimer's Disease: Based Upon N-methyl-D-aspartate Receptor Hypoactivation and Oxidative Stress

Early detection and prevention of Alzheimer's disease (AD) is important. The current treatment for early AD is acetylcholine esterase inhibitors (AChEIs); however, the efficacy is poor. Besides, AChEI did not show efficacy in mild cognitive impairment (MCI). Beta-amyloid (A.) deposits have been regarded to be highly related to the pathogenesis of AD. However, many clinical trials aiming at the clearance of A. deposits failed to improve the cognitive decline of AD, even at its early phase. There should be other important mechanisms unproven in the course of AD and MCI. Feasible biomarkers for the diagnosis and treatment response of AD are lacking to date. The N-methyl-D-aspartate receptor (NMDAR) activation plays an important role in learning and memory. On the other hand, oxidative stress has been regarded to contribute to aging with the assumption that free radicals damage cell constituents and connective tissues. Our recent study found that an NMDAR enhancer, sodium benzoate (the pivotal inhibitor of D-amino acid oxidase [DAAO]), improved the cognitive and global function of patients with early-phase AD. Further, we found that peripheral DAAO levels were higher in patients with MCI and AD than healthy controls. We also found that sodium benzoate was able to change the activity of antioxidant. These pieces of evidence suggest that the NMDAR function is associated with anti-oxidation, and have potential to be biomarkers for the diagnosis and treatment response of AD.