From Antioxidants to Multi-Target Therapeutics: Preclinical and Emerging Evidence for Flavonoid Neuroprotection in Neurodegenerative Diseases

Flavonoids are plant-derived polyphenols found in fruits, vegetables, tea and other dietary sources. Global dementia prevalence is projected to rise sharply, and current disease-modifying therapies remain limited in efficacy. This gap has contributed to growing interest in dietary flavonoids as multi-target neuroprotective agents. This review draws together mechanistic, preclinical, and early clinical evidence for six flavonoid subclasses (flavanones, flavonols, flavones, flavanols, anthocyanins, isoflavones) across five neuroprotective mechanisms: antioxidant defense, suppression of neuroinflammation, inhibition of pathogenic protein aggregation, promotion of neurogenesis and synaptic density, and preservation of blood–brain barrier integrity. We also summarize proposed structure–activity relationships linking substitution patterns (catechol groups, hydroxylation, glycosylation) to these mechanisms. Most of this evidence comes from in vitro and rodent models. Longitudinal cohorts do link dietary intake to slower cognitive decline, but clinical trials remain few, early-phase, and inconsistent; some report negligible change on clinical metrics such as the UPDRS scale. Certain flavonoid metabolites are detected in rodent brain tissue after oral dosing, though whether humans achieve pharmacologically meaningful brain exposure at dietary or supplemental doses is still unresolved. Translation faces substantial barriers: limited oral bioavailability, extensive first-pass metabolism, inconsistent blood–brain barrier penetration, and wide inter-individual variability in metabolism, gut microbiome composition, and trial design. We close by outlining strategies, including nanoparticle delivery, prodrug design, and precision nutrition approaches, that could move flavonoids closer to clinical relevance.