Epicatechin and brain health: Current evidence with perspectives for integrated multi-omic analytical approaches

Epicatechin, a dietary flavan-3-ol abundant in cocoa and in a variety of fruits and beverages, has attracted increasing attention for its potential role in maintaining brain health. Human studies suggest that epicatechin is highly bioavailable following ingestion, primarily in the form of structurally related phase II and gut microbiota-derived metabolites. Epidemiological evidence suggests positive associations between consumption of epicatechin-rich foods and cognitive performance, while randomized controlled trials provide more robust, although sometimes inconsistent, evidence for benefits on cognitive function. The inconsistencies in results suggest potential interindividual variability in responsiveness, likely driven by differences in metabolism of epicatechin, gut microbiota composition, genetic polymorphism, or health status. Experimental in vivo studies also suggested that epicatechin exerts neuroprotective effects, including neuroinflammation, oxidative stress, or neurodegeneration, with implicated mechanisms involving Nrf2, AMPK, AKT/ CREB, and autophagy-related signaling pathways. Emerging evidence further directs that epicatechin could support brain health by preserving neurovascular function and blood-brain barrier integrity. Recent advances using untargeted transcriptomic and proteomic approaches, as well as integrated multi-omic and bioinformatic analyses, have revealed complex regulatory mechanisms involving both coding and non-coding RNAs, and have identified key pathways related to endothelial function, inflammation, synaptic integrity, and cellular adhesion. This review synthesizes current human and experimental evidence on epicatechin and brain health, the importance of interindividual variability, and highlights the important role of multi-omics technologies in elucidating underlying molecular mechanisms of action. Such integrative approaches are needed for advancing precision nutrition strategies and for evaluating the therapeutic potential of epicatechin in brain health and neurodegenerative disease prevention.