Endogenous antioxidants predicted outcome and increased after treatment: A benzoate dose‐finding, randomized, double‐blind, placebo‐controlled trial for Alzheimer's disease

Abstract

Aim Previous pilot studies suggest that sodium benzoate may be a potential cognitive enhancer for patients with Alzheimer's disease (AD), schizophrenia, or late‐life depression. Especially for AD treatment, a confirmatory trial with predictive biomarkers is urgently needed. This study aimed to confirm benzoate as a novel treatment for AD and to discover its optimal dose and biomarkers. Methods A 24‐week, dose‐finding, randomized, double‐blind, placebo‐controlled trial, with clinical measurements at weeks 0, 8, 16, and 24, was conducted in three major medical centers in Taiwan. Among 154 patients screened for AD, 149 were eligible and randomized to one of the four treatments: (i) benzoate 500 group (fixed 500 mg/day); (ii) benzoate 750 (500 mg/day for the first 4 weeks, 750 mg/day from the 5th week); (iii) benzoate 1000 (500 mg/day for the first 4 weeks, 1000 mg/day from the 5th week); and (iv) placebo. The primary outcome measure was AD assessment scale‐cognitive subscale (ADAS‐cog). Results The benzoate 1000 group performed best in improving ADAS‐cog (P = 0.026 at week 24), with female advantage. Higher plasma catalase at baseline predicted better outcome. Benzoate receivers tended to have higher catalase and glutathione than placebo recipients after treatment. The four intervention groups showed similar safety profiles. Conclusions By enhancing two vital endogenous antioxidants, catalase and glutathione, sodium benzoate therapy improved cognition of patients with AD, with higher baseline catalase predicting better response. Supporting the oxidative stress theory, the results show promise for benzoate as a novel treatment for AD.

Elucidating the Mechanisms of Sodium Benzoate in Alzheimer Disease: Insights from Quantitative Proteomics Analysis of Serum Samples

“…As an NMDAR enhancer, sodium benzoate has been reported to improve the cognitive function of patients with AD in randomized, double-blind, placebo-controlled trials ( Lin et al, 2014 ; Lane et al, 2023 ). The study explored the potential mechanisms of sodium benzoate in treating AD using label-free quantitative proteomics with a small sample size.…”

“…In addition, it may play a neuroprotective role by reducing oxidative stress, altering sex hormones, and having other routes ( Xu et al, 2019 ; Lin et al, 2021 ). Sodium benzoate has been reported to improve the cognitive function of patients with AD in randomized, double-blind, placebo-controlled trials ( Lin et al, 2014 ; Lane et al, 2023 ). In addition to the role of an NMDAR enhancer, other possible mechanisms of sodium benzoate in improving AD deserve further study.…”

Mapping new pharmacological interventions for cognitive function in Alzheimer’s disease: a systematic review of randomized clinical trials

“…However, human studies have been limited ( Ekert et al, 2018 ). Sodium benzoate has been shown to be a cognitive enhancer in patients with AD, schizophrenia, or late-life depression ( Lane et al, 2022 ). On the other hand, estrogen has been shown to delay disease progression and minimize cognitive decline in AD patients, especially in women.…”

Differential Impacts of Endogenous Antioxidants on Clinical Symptoms and Cognitive Function in Acute and Chronic Schizophrenia Patients

“…Three endogenous antioxidants in peripheral blood were measured using commercially available kits, as previously described ( Lane et al, 2023 ).…”