Diet, Metabolism and Synaptic Function: Integrating Evidence Across Models in Neurodegeneration Research

The brain has a higher energy demand per unit weight than any other organ in the body; however, links between metabolism, diet and neurological function have historically been underexplored. This partly stems from early assumptions that brain metabolism is primarily dependent on glucose and ketone bodies, whereas more recent evidence indicates broader metabolic flexibility and complex cell-type specialisation. In the past few decades, brain metabolism has become increasingly recognised as relevant to neurological and mental health, and many neurodegenerative disorders are accompanied by changes in brain energy utilisation. In parallel, epidemiological studies associate hypercaloric dietary patterns and metabolic disorders-particularly type-2 diabetes mellitus-with increased risk of later cognitive decline and sporadic Alzheimer's disease, although causal pathways remain difficult to establish in humans. In this narrative review, we summarise selected findings linking "unhealthy" diets to synaptic function, focusing on synaptic plasticity, neuroinflammation and adult hippocampal neurogenesis, and we distinguish between evidence from human observational studies and mechanistic insights from animal and cellular models. We also discuss candidate mechanisms-including insulin resistance-linked signalling changes, lipid-driven inflammatory amplification, oxidative stress, and altered lipid handling-that may contribute to synaptic vulnerability. Finally, we outline translational considerations and key knowledge gaps (including physiological exposure levels and heterogeneity of experimental paradigms) that currently limit inference from preclinical models to clinical intervention.