From plate to brain: role of mediators and moderators on the impact of diet on Alzheimer's disease.

Diet represents one of the most clinically accessible modifiable risk factors for Alzheimer's disease (AD), with potential to influence disease onset and progression through multiple biological pathways. Emerging evidence from observational studies suggests that adherence to specific dietary patterns, including the Mediterranean (MedDiet) and Mediterranean-DASH intervention for neurodegenerative delay (MIND) diets, is associated with reduced AD risk and slower cognitive decline. However, the mechanistic pathways underpinning these associations remain incompletely understood, and evidence from randomized controlled trials has been less consistent. A critical but frequently overlooked distinction lies between mediators, defined as the biological mechanisms linking diet to AD outcomes, and moderators, which are individual or contextual factors that influence the magnitude and direction of these associations. Integrating mediators and moderators within a unified analytical framework is increasingly recognized as essential for advancing precision nutrition approaches to AD prevention (with multiple recent publications explicitly calling for this approach and providing empirical examples of its implementation). This mini-review, developed as the conceptual foundation for a planned meta-analysis, synthesizes current evidence on key mediating pathways, including neuroinflammation, brain insulin resistance, oxidative stress, blood-brain barrier dysfunction, hyperhomocysteinaemia, and gut-brain axis dysregulation. We further examine major moderating factors such as apolipoprotein E (APOE) ε4 genotype, biological sex, age, disease stage, and socioeconomic context that may determine who benefits from dietary interventions and under what conditions.