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This study investigates the therapeutic potential of flavonols\u2014quercetin, kaempferol, myricetin, and fisetin\u2014in targeting A\u03b2 aggregation and mitigating AD pathology through diverse molecular mechanisms. Our findings reveal that flavonols effectively inhibit A\u03b2 oligomerization and fibril formation, reduce oxidative stress via Nrf2\/HO\u20101 pathway activation, and suppress neuroinflammation by modulating microglial polarization. Additionally, these compounds enhance mitochondrial function, promote autophagy\u2010mediated clearance of A\u03b2 aggregates, and regulate key enzymes such as \u03b2\u2010secretase (BACE1) and \u03b1\u2010secretases (ADAM10\/17), favoring non\u2010amyloidogenic pathways. Quercetin demonstrated neuroprotective effects by activating TrkB signaling, reducing tau phosphorylation, and enhancing synaptic plasticity. Kaempferol prevented A\u03b2\u2010induced apoptosis via the ER\/ERK\/MAPK pathway and inhibited acetylcholinesterase activity, improving cognitive outcomes. Myricetin ameliorated mitochondrial dysfunction and oxidative damage through GSK3\u03b2\/ERK2 signaling modulation and showed enhanced brain bioavailability when delivered via nanostructured lipid carriers. Fisetin reduced A\u03b2 burden by upregulating neprilysin expression, suppressed neuroinflammation, and improved synaptic function by restoring synaptic protein levels. Overall, flavonols exhibit multi\u2010targeted therapeutic potential against AD by addressing its complex pathogenesis. Their ability to cross the blood\u2013brain barrier and low toxicity profiles position them as promising candidates for further clinical development. This study underscores the potential of flavonols as natural agents for AD treatment and highlights their role in advancing multi\u2010mechanistic therapeutic strategies.<\/jats:p>","DOI":"10.1002\/biof.70047","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T09:26:23Z","timestamp":1756891583000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The Therapeutic Potential of Flavonols in Alzheimer's Disease: Inhibiting Amyloid\u2010\u03b2, Oxidative Stress, and Neuroinflammation"],"prefix":"10.1002","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0944-0320","authenticated-orcid":false,"given":"Mohammad Yasin","family":"Zamanian","sequence":"first","affiliation":[{"name":"Neurophysiology Research Center Hamadan University of Medical Sciences  Hamadan Iran"},{"name":"Department of Pharmacology and Toxicology, School of Pharmacy Hamadan University of Medical Sciences  Hamadan Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lusine G.","family":"Khachatryan","sequence":"additional","affiliation":[{"name":"Department of Pediatric Diseases N.F. 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