Beyond Epilepsy: The Expanding Role of Valproic Acid in Alzheimer’s Disease Therapy – a Review

Valproic acid (VPA), a well-established anticonvulsant and mood stabilizer, has gained significant attention for its potential neuroprotective effects in neurodegenerative diseases, particularly Alzheimer disease (AD). As a histone deacetylase inhibitor, VPA influences gene expression, synaptic plasticity, and neuronal survival, making it a promising candidate for therapeutic intervention. Preclinical studies have demonstrated that VPA reduces β-amyloid accumulation, inhibits tau hyperphosphorylation, modulates oxidative stress, and attenuates neuroinflammation-key pathological hallmarks of AD. Additionally, VPA enhances neurogenesis and supports synaptic function, further contributing to its neuroprotective properties. Despite encouraging in vitro and in vivo findings, clinical trials investigating VPA's efficacy in AD have yielded mixed results. While some studies reported benefits in managing behavioral symptoms, large-scale trials, including the Alzheimer's Disease Cooperative Study Valproate Trial, failed to demonstrate significant cognitive improvement and revealed notable side effects. These findings highlight the need for further research to optimize VPA's clinical application, including targeted drug delivery, combination therapies, and patient-specific approaches. This review explores the molecular mechanisms underlying VPA's neuroprotective effects, evaluates its therapeutic potential in AD and other neurodegenerative disorders, and discusses the challenges that must be addressed before its widespread clinical implementation. SIGNIFICANCE STATEMENT: Valproic acid shows promise for treating Alzheimer disease by targeting key pathological mechanisms. This review highlights valproic acid's neuroprotective potential, summarizes preclinical and clinical findings, and outlines the critical challenges that must be addressed to advance its use in Alzheimer disease therapy.