Effect of Sodium Benzoate on Cognitive Function Among Patients With Behavioral and Psychological Symptoms of Dementia: Secondary Analysis of a Randomized Clinical Trial

IMPORTANCE: Female gender is a major risk factor for dementia; however, gender has not yet been adequately addressed by clinical trials. A recent study demonstrated that sodium benzoate, a D-amino acid oxidase inhibitor, improved cognitive function in early-phase Alzheimer disease. OBJECTIVE: To examine the potential gender difference in the effects of benzoate treatment on the behavioral and psychological symptoms of dementia (BPSD). DESIGN, SETTING, AND PARTICIPANTS: This post hoc secondary analysis used data from a randomized, double-masked, placebo-controlled trial conducted in 3 major medical centers in Taiwan and enrolled 97 patients with BPSD. Data were analyzed between February 2014 and November 2017. INTERVENTIONS: Six weeks of treatment of 250 to 1500 mg/d of sodium benzoate or placebo. MAIN OUTCOMES AND MEASURES: The primary outcome measures were Alzheimer disease assessment scale–cognitive subscale (ADAS-cog) and Behavioral Pathology in Alzheimer Disease Rating Scale (BEHAVE-AD) scores. RESULTS: Among 97 total participants (62 [64%] women; mean [SD] age, 75.4 [7.7] years), 49 patients (30 women and 19 men) were randomized to sodium benzoate, and 48 (32 women and 16 men) were randomized to placebo. Among 62 women, 6-week benzoate treatment significantly surpassed placebo in the effects on ADAS-cog performance (mean [SD] difference in score between baseline and end point, −3.1 [6.4] points vs 0 [4.5] points; Cohen d = 0.56; P = .04) but not BEHAVE-AD performance. In contrast, among 35 men, the 2 treatment groups did not differ significantly in both ADAS-cog and BEHAVE-AD scores. Compared with placebo, benzoate treatment also increased estradiol to follicle-stimulating hormone ratios among women (mean [SD] difference between baseline and end point, 0 [0.2] vs −0.1 [0.3]; P = .03). CONCLUSIONS AND RELEVANCE: These findings suggest that benzoate treatment may improve cognitive function in women with later-phase dementia. In the future, longer dose-finding trials are warranted to further clarify the efficacy of benzoate for later-phase dementia and investigate the role of sex hormones and other factors in the pathogenesis of dementia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02103673