Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and remains a major public health challenge. Current drug treatments, including cholinesterase inhibitors and memantine, provide symptomatic relief but do not halt disease progression. Recently, food-derived polyphenols found in fruits, vegetables, tea, coffee, and wine have been identified as potential therapeutic agents due to their antioxidant, anti-inflammatory, and neuroprotective properties, with their ability to target key pathological mechanisms of AD.
Polyphenols exert multiple molecular effects relevant to AD. They can reduce oxidative stress, modulate neuroinflammation, inhibit the aggregation of amyloid-beta (Aβ), and impact tau hyperphosphorylation. For instance, resveratrol, a stilbene found in grapes and red wine, exhibits potent antioxidant activity and improves mitochondrial function.
Epigallocatechin gallate (EGCG), the predominant catechin in green tea, inhibits amyloid beta (Aβ) fibril formation and reduces toxicity. Curcumin, the bioactive polyphenol in turmeric, mitigates oxidative stress while inhibiting both Aβ aggregation and tau pathology. Quercetin, widely found in onions and apples, primarily exerts its neuroprotective effects through anti-inflammatory pathways.
Preclinical studies provide robust evidence of polyphenol efficacy. In animal models, resveratrol has been shown to improve memory performance and reduce the Aβ plaque burden. EGCG mitigated synaptic plasticity impairments and cognitive deficits. Compared with untreated controls, curcumin reduced Aβ deposits and tau hyperphosphorylation. Quercetin treatment improved spatial memory while reducing neuroinflammation. Collectively, these findings illustrate the numerous and unique mechanisms through which polyphenols may slow or counteract the progression of AD.
Recent developments in computational biology have further strengthened the case for polyphenols. In silico investigations have demonstrated that compounds such as resveratrol, EGCG, and curcumin directly interact with amyloidogenic proteins, preventing aggregation and stabilizing non-toxic forms. Additional molecular docking simulations indicated that these polyphenols also effectively bind to key sites on Aβ and tau proteins, therefore interrupting pathological cascades. These studies are providing important information that can be applied to rational drug design and the planning of combination therapies.
While laboratory and computational studies have yielded promising data, considerable barriers remain in translating polyphenols into effective clinical treatments. The most significant barrier is bioavailability. Many polyphenols have rapid metabolism and poor absorption, resulting in low therapeutic concentrations that can reach the brain. For example, resveratrol taken orally has poor systemic availability, and curcumin has poor solubility and rapid clearance. To address these limitations, strategies such as nanoparticle formulations, liposomal carriers, and structural modifications are being explored to enhance stability, absorption, and penetration across the blood–brain barrier.
Future research must prioritize well-designed clinical trials to analyze their efficacy in humans. Although small-scale clinical trials with resveratrol and curcumin have demonstrated cognitive benefits, results remain inconsistent due to variations in dosing, formulation, and study design. Experts recommend a multi-targeted approach, combining polyphenols with standard therapies or a synergistic compound combination. Precision medicine approaches could also enhance therapeutic efficacy by incorporating genetic risk factors, such as the APOE genotype.
In conclusion, polyphenols represent a promising class of disease-modifying agents in the treatment of AD. Their distinctive multi-target capabilities, addressing oxidative stress, inflammation, amyloid aggregation, and tau pathology, set them apart from traditional single-target drugs. While challenges related to bioavailability and clinical translation remain, innovations in delivery systems and trial methodologies are paving the way for their integration into therapeutic practice. As research on medical practice continues, polyphenols may evolve from dietary supplements to valuable components of a therapeutic toolkit against AD.
References: Chen G, Su Y, Chen S, Lin T, Lin X. Polyphenols and Alzheimer’s disease: A review on molecular and therapeutic insights with in silico support. Food Sci Nutr. 2025;13:e70496. doi:10.1002/fsn3.70496
