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Even with tremendous progress in modern neuroscience, a permanent remedy or cure for this crippling disease is still unattainable. Polyphenols are a group of naturally occurring potent compounds that can modulate the neurodegenerative processes typical of AD. The present comprehensive study has been conducted to find out the preclinical and clinical potential of polyphenols and elucidate their possible mechanisms in managing AD. Additionally, we have reviewed different clinical studies investigating polyphenols as single compounds or cotherapies, including those currently recruiting, completed, terminated, withdrawn, or suspended in AD treatment. Natural polyphenols were systematically screened and identified through electronic databases including Google Scholar, PubMed, and Scopus based on in vitro cell line studies and preclinical data demonstrating their potential for neuroprotection. A total of 63 significant polyphenols were identified. A multimechanistic pathway for polyphenol's mode of action has been proposed in the study. Out of 63, four potent polyphenols have been identified as promising potential candidates, based on their reported clinical efficacy. Polyphenols hold tremendous scope for the development of a future drug molecule as a phytopharmaceutical that may be incorporated as an adjuvant to the therapeutic regime. However, more high\u2010quality studies with novel delivery methods and combinatorial approaches are required to overcome obstacles such as bioavailability and blood\u2013brain barrier crossing to underscore the therapeutic potential of these compounds in AD management.<\/jats:p>","DOI":"10.1002\/ptr.8344","type":"journal-article","created":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T02:18:26Z","timestamp":1730773106000},"page":"25-50","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Therapeutic Potential of Polyphenols in Cellular Reversal of Patho\u2010Mechanisms of Alzheimer's Disease Using In Vitro and In Vivo Models: A Comprehensive Review"],"prefix":"10.1002","volume":"39","author":[{"given":"Monalisha","family":"Samal","sequence":"first","affiliation":[{"name":"Centre of Excellence in Unani Medicine, Bioactive Natural Product Laboratory, Department of Pharmacognosy and Phytochemistry School of 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