Efficacy of antioxidants as a therapy for Alzheimer's disease: a meta-analysis

BACKGROUND: Oxidative stress plays a central role in the pathogenesis of Alzheimer's disease (AD), contributing to neuronal damage, amyloid-beta aggregation, tau hyperphosphorylation, and neuroinflammation. Although antioxidants have been proposed as potential therapeutic agents, clinical trials have yielded inconsistent results. OBJECTIVE: To systematically evaluate the efficacy of various antioxidants-including vitamins, polyphenols, and other antioxidant preparations-on cognitive function, oxidative stress biomarkers, neuropsychiatric symptoms, and disease progression in patients with AD. METHODS: We conducted a systematic search of PubMed, Embase, and Web of Science from inception to October 2, 2025, for randomized controlled trials (RCTs) evaluating antioxidant interventions in AD patients. Study selection, data extraction, and quality assessment were performed independently by multiple reviewers. Meta-analyses were conducted using random-effects models where significant heterogeneity was present (I² > 50%). Outcomes included cognitive function scales (e.g., ADAS-Cog, MMSE), oxidative stress markers, neuropsychiatric symptoms, daily living abilities, neuroimaging measures, and fluid biomarkers. RESULTS: A total of 23 RCTs comprising 10,537 participants were included. Antioxidants showed mixed effects across outcomes. While certain oxidative stress markers (urinary 8-iso-prostaglandin F2α: SMD 0.75, 95% CI 0.12-1.38) and neuropsychiatric symptoms (NPI: SMD -0.85, 95% CI -1.13 to -0.57) improved significantly, core cognitive endpoints such as ADAS-Cog (SMD 0.01, 95% CI -0.21 to 0.23) and MMSE (SMD 0.19, 95% CI -0.17 to 0.56) showed no significant benefit. Fluid biomarkers including Aβ42, p-tau, and t-tau remained unchanged. High heterogeneity was observed across multiple outcomes, reflecting variability in antioxidant types, dosages, and patient populations. CONCLUSION: Antioxidants may improve certain oxidative stress markers and neuropsychiatric symptoms in AD patients but do not consistently enhance core cognitive function or alter AD-specific pathology. Current evidence does not support antioxidants as disease-modifying therapies, though they may serve as adjunctive interventions to improve quality of life and behavioral symptoms. Well-designed RCTs with longer follow-up and standardized protocols are warranted. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420261321660, identifier: CRD420261321660.