Sodium benzoate, a D-amino acid oxidase inhibitor, improved short-term memory in patients with mild cognitive impairment in a randomized, double-blind, placebo-controlled clinical trial.

Background: Previous studies have found that sodium benzoate (the pivotal D-amino acid oxidase [DAO] inhibitor) improved cognitive function in patients with mild Alzheimer disease; however, its efficacy for mild cognitive impairment (MCI) (especially its core feature, impaired short-term memory) remains uncertain. The aim of this study was to evaluate the efficacy and safety of sodium benzoate in treating amnestic MCI (aMCI).

Methods: This study was a randomized, double-blind, placebo-controlled clinical trial conducted in a major medical center in Taiwan. Eighty-two patients with aMCI were recruited for 24-week treatment of 250 to 1500 mg/day of sodium benzoate or placebo. Overall, cognitive function was measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), and short-term memory was evaluated by the 'recall of test instructions' item in the ADAS-cog. The generalized estimating equation was applied to compare the two groups in efficacy.

Results: Compared with placebo, sodium benzoate therapy, displayed a trend, albeit statistically insignificant, in improving overall cognitive function (P = 0.082), and significantly improved short-term memory (P = 0.044). Both benzoate and placebo were well tolerated and benzoate therapy produced no additional side effect.

Conclusions: With the moderate sample size of the current study, treatment using sodium benzoate, a DAO inhibitor, showed promise in improving cognition, especially short-term memory, in patients with aMCI. Of note, while the ADAS-cog total score has been regarded as insensitive in measuring aMCI, its 'recall of test instructions' item may be a more sensitive and clinically feasible tool. Further larger studies are warranted to confirm the preliminary finding.

Trial registration: ClinicalTrials.gov Identifier. NCT04736355.