Effect of allopurinol and other xanthine oxidase inhibitors on oxidative stress in Alzheimer’s disease: A systematic review and meta-analysis (2015–2025)

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuropathology. Accumulating evidence implicates oxidative stress in AD pathogenesis. Xanthine oxidase (XO) is a major enzymatic source of reactive oxygen species in purine metabolism. XO inhibitors (e.g., allopurinol, febuxostat, topiroxostat) reduce XO-derived radicals and may thus ameliorate oxidative damage in the brain. We aimed to systematically review preclinical and clinical studies from 2015–2025 examining whether XO inhibition reduces oxidative stress markers, improves cognitive outcomes, or lowers dementia risk in AD. Methods: We searched PubMed, Scopus, Web of Science, and Google Scholar (2015–2025) using keywords combining “Alzheimer OR dementia” with “xanthine oxidase OR allopurinol OR febuxostat OR topiroxostat” and “oxidative stress OR cognitive OR dementia incidence”. Inclusion criteria were English-language studies on AD or related dementia assessing XO inhibitor effects on oxidative stress biomarkers, cognitive performance, or dementia incidence. We included both preclinical (animal in vitro experiments and in vivo models) and clinical (observational or interventional) studies. Screening, data extraction, and bias assessments (SYRCLE for animal studies, Newcastle–Ottawa Scale for observational studies, Cochrane tools for trials) were performed by two independent reviewers (blinded as XX and YY). A PRISMA flow diagram was constructed to map study selection.