Abstract
Lifestyle-based interventions, including dietary modifications, can reduce dementia risk. In this regard, dietary supplementation with medium-chain triglycerides (MCT) has shown potential therapeutic benefits in individuals with Alzheimer's disease. These effects are widely presumed to be mediated by hepatic conversion of MCT into circulating ketones. However, the physiological and cellular mechanisms underlying the benefits of MCT remain understudied, particularly in the context of Alzheimer's disease. Here, we investigated the cellular and molecular changes occurring in the brain and systemically in response to dietary supplementation with MCT versus a ketogenic diet. The experimental design consisted of comparing a 70% carbohydrate control diet to either a control diet supplemented with 10% MCT or a carbohydrate-free high-fat ketogenic diet. Diets were tested in two Alzheimer's disease mouse models, slow-progressing 3xTg-AD mice that model pre-symptomatic/early stages and rapidly progressing 5xFAD mice that model late stages of the disease. We found that MCT supplementation and a ketogenic diet both improved hippocampal-dependent spatial learning and memory, increased dendritic spine density of hippocampal neurons and modulated hippocampal expression of genes associated with mitochondrial functions, synaptic structure and insulin signalling in Alzheimer's disease mouse models. However, unlike the ketogenic diet, MCT supplementation did not elevate circulating ketones, suggesting different mechanisms. Indeed, MCT supplementation enhanced the peripheral insulin response of Alzheimer's disease mice, while the ketogenic diet conversely unveiled their latent metabolic vulnerability, increasing their hyperglycaemia, body weight gain and adiposity. The systemic metabolic disturbances of Alzheimer's disease mice correlated with transcriptomic alterations in hepatic lipid metabolism and ketogenesis genes and increased lipid droplet accumulation. These liver metabolic abnormalities were partially reversed by both MCT supplementation and the ketogenic diet, but in distinct ways. Notably, the ketogenic diet selectively triggered hepatic neutral lipid depletion and prominent proinflammatory gene expression, while MCT downregulated expression of cholesterol-related genes. Collectively, these findings reveal that MCT supplementation in the context of Alzheimer's disease improves cognition and systemic metabolism without elevating circulating ketone levels.