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Current treatments, such as acetylcholinesterase (AChE) inhibitors, offer limited symptomatic relief and can have side effects. With growing interest in functional foods that have fewer side effects, pomegranate (<jats:italic>Punica granatum<\/jats:italic> L.) has gained attention because of its rich antioxidant content. The present study aims to evaluate the antioxidant and neuroprotective effects of four pomegranate cultivars: \u2018Wonderful\u2019, \u2018Phoenicia\u2019, \u2018Azadi\u2019 and \u2018Eversweet\u2019. Additionally, it investigates their metabolite profiles and predicts potential bioactive compounds that could help prevent AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>The \u2018Wonderful\u2019 cultivar demonstrated the highest levels of total phenolic content, total flavonoid content, total anthocyanin content and radical scavenging activities. The AChE and butyrylcholinesterase (BuChE) inhibition rates were highest in \u2018Phoenicia\u2019 and \u2018Wonderful\u2019 cultivars, suggesting potential neuroprotective effects. PC12 cell assays indicated that these cultivars significantly improved cell viability, reduced reactive oxygen species and malondialdehyde levels, and also enhanced catalase activity. Metabolomics analysis identified 141 metabolites, with the \u2018Wonderful\u2019 cultivar showing the highest metabolite abundance. Molecular docking studies indicated that some metabolites, such as taxifolin, demonstrated strong binding affinities for AChE and BuChE, suggesting potential for AD treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p>The \u2018Wonderful\u2019 and \u2018Phoenicia\u2019 cultivars demonstrated the most promising antioxidant and neuroprotective effects among the evaluated pomegranates, likely because of their high taxifolin content. These findings suggest that these cultivars could be valuable for developing functional foods aimed at AD prevention and treatment. \u00a9 2025 Society of Chemical Industry.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jsfa.14176","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T06:53:19Z","timestamp":1738911199000},"page":"4359-4368","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Evaluation of metabolite profiles and neuroprotective potential in four pomegranate cultivars for Alzheimer's disease prevention"],"prefix":"10.1002","volume":"105","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4059-4195","authenticated-orcid":false,"given":"Hana","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Food Science and Human Nutrition, Citrus Research and Education Center University of Florida  Lake Alfred FL 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