Resveratrol's Multifaceted Potential in Alzheimer’s Disease: Insights from Preclinical and Clinical Evidence

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs), and neuroinflammation, leading to progressive cognitive decline. Research has increasingly emphasized the importance of a nutritious diet rich in phytochemicals that promotes brain health and potentially mitigates the risk or progression of neurodegenerative diseases, such as AD. Resveratrol (RSV), a natural polyphenol with known anti-inflammatory, antioxidant, antiapoptotic, and neuroprotective properties, has thus garnered significant attention. This review examines the potential of RSV in modulating AD pathophysiology, drawing from preclinical and clinical investigations. Preclinical studies demonstrate RSV reduces Aβ accumulation by modulating BACE1, enhancing neprilysin activity, inhibiting aggregation, and promoting clearance. RSV also attenuates Tau phosphorylation in animal models, suggesting its potential to target both hallmark AD pathologies. Furthermore, RSV exhibits anti-inflammatory properties by reducing microglial activation and proinflammatory markers. Clinical trials indicate that RSV may attenuate declines in CSF Aβ40 levels and reduce CSF MMP9 levels, indicating potential benefits in Aβ pathology and neuroinflammation in select studies. However, its impact on tau remains inconclusive. Some clinical studies have shown trends toward cognitive benefits, particularly in functional measures such as ADCS-ADL; however, these findings are inconsistent across different cognitive assessments (e.g., MMSE and ADAS-cog). Due to limited and inconsistent clinical evidence, RSV’s therapeutic efficacy for AD or mild cognitive impairment (MCI) remains unproven, necessitating larger, well-powered clinical trials in diverse populations to evaluate its potential benefits. RSV holds promise as a potential therapeutic agent. Still, challenges such as poor bioavailability and rapid metabolism require optimized delivery systems and further research to establish clinical efficacy and optimal dosing.