Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-β (Aβ) deposition, tau hyperphosphorylation, oxidative stress, and chronic neuroinflammation. Growing evidence highlights neuroinflammation-driven by microglial activation and pro-inflammatory cytokine release-as a key contributor to AD pathogenesis and progression. In the absence of effective disease-modifying therapies, attention has turned to natural compounds with multi-target potential. Flavonoids, a diverse class of plant-derived polyphenols, have demonstrated neuroprotective properties through antioxidant activity, modulation of neuroinflammatory pathways, and interference with both Aβ aggregation and tau pathology. This narrative review provides an integrative overview of current findings on the mechanisms of action of key flavonoids-such as quercetin, luteolin, and apigenin-in both preclinical and clinical models. Emphasis is placed on their effects on microglial polarization, oxidative stress reduction, mitochondrial support, and synaptic function enhancement. Moreover, flavonoids show synergistic potential when combined with standard pharmacotherapies, such as acetylcholinesterase inhibitors, and may offer broader cognitive benefits in patients with mild cognitive impairment (MCI). Despite these promising findings, significant challenges persist, including poor bioavailability, inter-individual variability, and limited long-term clinical data. This review identifies critical gaps in knowledge and outlines future directions, including targeted drug delivery systems, biomarker-guided personalization, and long-duration trials. Flavonoids thus emerge not only as promising neuroprotective agents but also as complementary candidates in the development of future multi-modal strategies for AD treatment.