SEX- AND DOSE-DEPENDENT CATALASE INCREASE AND ITS CONTRIBUTION TO COGNITIVE IMPROVEMENT IN A BENZOATE DOSE- FINDING CLINICAL TRIAL FOR ALZHEIMER'S DISEASE
Authors: Lane *Hsien-Yuan 
Published: February 2025

Abstract

Background
Current therapies for AD using traditional theories have been insufficiency. Of note, other mechanisms, such as oxidative stress, contribute to the pathogenesis of AD (1). Importantly, there are sex-related differences in oxidative stress during the cognitive modulation and neurodegenerative process. Previous studies found that sodium benzoate was capable of improving cognitive function of patients with mild AD (Lin et al., Biol Psychiatry 2014) or schizophrenia (Lane et al., JAMA Psychiatry 2013). Of interest, benzoate showed efficacy for female patients but not for male patients with dementia (2). Catalase is a crucial endogenous antioxidant that alleviates oxidative stress; and deficiency of catalase is regarded to be related to the pathogenesis of age-related neurodegenerative diseases like AD (3) and schizophrenia (Lin et al., Int J Neuropsychopharmacol 2023). Earlier, sodium benzoate’ s treatment response for schizophrenia was observed to be related with its effect on catalase activity assayed in peripheral blood (Lin et al., Biol Psychiatry 2018). Recently, a randomized, double- blind, dose-comparison (500 mg/day, 750 mg/day, and 1000 mg/day), placebo-controlled trial showed that sodium benzoate performed best at 1000 mg/day in improving cognitive function of the patients with mild AD (4). While both sex and benzoate doses influenced cognitive outcome in patients with dementia, and clinical improvement after benzoate treatment was positively correlated with catalase change in the blood of schizophrenia patients (Lin et al., Biol Psychiatry 2018), whether sex or benzoate doses also affect catalase activity in the benzoate-treated AD patients remain unknown.

Aims & Objectives
The current study aimed to examine the roles of sex and benzoate dosage in the alteration of catalase activity and the clinical impact in the patients with mild AD who received benzoate treatment.

Methods
This secondary analysis used data from a double-blind trial (4), in which 149 AD patients were randomized to receive placebo or one of three benzoate doses (500, 750, or 1000 mg/day) and measured with Alzheimer's disease assessment scale-cognitive subscale. Blood levels of catalase and another two endogenous antioxidants, superoxide dismutase (SOD) (Lin et al., Neuropsychiatr Dis Treat 2020) and glutathione (Lin &Lane, Antioxidants 2021), were assayed before and after treatment. While sodium benzoate is also an inhibitor of D-amino acid oxidase (DAAO) (Lin &Lane, Schizophr Res 2023), blood levels of DAAO were also measured (Lin &Lane, Int J Neuropsychopharmacol 2022).

Results
Higher baseline catalase activity was associated with more cognitive improvement after benzoate treatment among both female and male patients. Benzoate treatment, particularly at 1000 mg/day, increased catalase among female patients, but not among male. The increases in the catalase activity among the benzoate-treated women were correlated with their cognitive improvements. SOD, Glutathione, and DAAO didn’ t affect the cognitive outcome after benzoate or placebo treatment.

Discussion & Conclusion
Supporting the oxidative stress theory and sex difference in AD, the finding suggest that sex (female) and benzoate dose co-determine catalase increase in benzoate-treated AD patients and the catalase increment contributes to cognitive improvement of benzoate-treated women.

References
1. Lane, H. Y., Wang, S. H., &Lin, C. H. (2023). Differential relationships of NMDAR hypofunction and oxidative stress with cognitive decline. Psychiatry Res. 2023;326:115288.
2. Lin, C. H., Chen, P. K., Wang, S. H., &Lane, H. Y. (2021). Effect of Sodium Benzoate on Cognitive Function Among Patients With Behavioral and Psychological Symptoms of Dementia: Secondary Analysis of a Randomized Clinical Trial. JAMA Network Open, 4(4), e216156.
3. Lane, H. Y., &Lin, C. H. (2023). Diagnosing Alzheimer's Disease Specifically and Sensitively With pLG72 and Cystine/Glutamate Antiporter SLC7A11 AS Blood Biomarkers. The International Journal of Neuropsychopharmacology, 26(1), 1-8.
4. Lane, H. Y., Wang, S. H., &Lin, C. H. (2023). Endogenous antioxidants predicted outcome and increased after treatment: A benzoate dose-finding, randomized, double-blind, placebo-controlled trial for Alzheimer's disease. Psychiatry and Clinical Neurosciences, 77(2), 102-109.