Medium-chain triglycerides improve cognition and systemic metabolism in mouse models of Alzheimer's disease

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 (AD). 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 AD. 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 (KD). 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 KD. Diets were tested in two AD 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 KD 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 signaling in AD mouse models. However, unlike KD, MCT supplementation did not elevate circulating ketones, suggesting different mechanisms. Indeed, MCT enhanced the peripheral insulin response of AD mice, while KD conversely unveiled their latent metabolic vulnerability, increasing their hyperglycaemia, body weight gain, and adiposity. The systemic metabolic disturbances of AD 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 KD, but in distinct ways. Notably, KD selectively triggered hepatic neutral lipid depletion and prominent proinflammatory gene expression while MCT down-regulated expression of cholesterol-related genes. Collectively, these findings reveal that MCT supplementation in the context of AD improves cognition and systemic metabolism without elevating circulating ketone levels. Overall design: Liver 3 months-old mice received for 6 months, either a Control diet (C, 70% carbohydrate, 20% long-chain triglycerides, 10% protein, 4.1 kcal/g, Research Diets), a Control diet enriched with medium-chain triglycerides (MCT or M, 70% carbohydrate, 10% long-chain triglycerides, 10% medium-chain triglycerides (C8:0-C10:0 ratio of 3:2), 10% protein, 4.1 kcal/g, Research Diets) or a carbohydrate-free high fat ketogenic diet (KD or K, 90% long-chain triglycerides, 10% protein, 6.7 kcal/g, Research Diets). WT and 3xTg-AD mice liver were used with a sample size of 4 mice per genotype/diet giving a total of 24 livers (WT-C=4, WT-K=4, WT-M=4, 3xTg-C=4, 3xTg-K=4, 3xTg-M=4).