Mediterranean Diet in Neurodegenerative Diseases: Recent Advances from Gut–Immune–Brain Axis to Multi-Omics Guided Precision Nutrition

Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) are increasingly understood as systemic disorders driven by chronic neuroinflammation, metabolic dysregulation, and barrier dysfunction, which interact dynamically along the gut–immune–brain axis. The Mediterranean diet rich in plant-based foods, olive oil, and fish, is consistently associated with reduced cognitive decline and neurodegeneration risk. This review synthesizes recent advances to present a comprehensive framework illustrating how the Mediterranean diet functions as a systems-level modulator. Mechanistically, the Mediterranean diet remodels the gut microbiota, enhancing the production of bioactive metabolites like SCFA-producing bacteria (SCFAs). These metabolites serve as key signaling mediators that reinforce intestinal barrier integrity, reduce systemic inflammation, and subsequently modulate central processes. Within the central nervous system, diet-derived cues influence neuroinflammation by reprogramming microglial and astrocytic states, support mitochondrial function and proteostasis, and help maintain blood–brain barrier (BBB) stability. Disease-specific insights for AD and PD highlight the diet's role in modulating hallmark pathologies such as Amyloid Beta (Aβ), tau, and α-synuclein aggregation. Emerging multi-omics technologies—including single-cell/spatial transcriptomics and microbiome profiling—are reshaping the field, offering unprecedented resolution to dissect these pleiotropic effects. Ultimately, while the Mediterranean diet presents a promising neuroprotective strategy, individual responses vary based on genetics, microbiome, and metabolic context. The integration of these technologies is pivotal for transitioning from generalized dietary advice to precision nutrition approaches tailored to individual patient profiles, positioning the Mediterranean diet not merely as a diet but as a programmable intervention for neuro-immune and metabolic network modulation. Key challenges remain, including the need for more randomized controlled trials (RCTs) and standardized frameworks for multi-omics integration.