ABSTRACT: Lifestyle-based interventions, including dietary modifications, can reduce dementia risk. In this regard, dietary supplementation with medium-chain triglycerides (MCT) shows promise against Alzheimer’s disease in humans. This effect is 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 classic 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 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 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 Alzheimer’s disease mouse models. However, unlike KD,MCT supplementation did not elevate circulating ketones, suggesting different mechanisms. Indeed, while MCT enhanced the peripheral insulin response of Alzheimer’s disease mice, KD conversely unveiled their latent metabolic vulnerability, increasing their hyperglycemia, 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 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 Alzheimer’s disease improves cognition and systemic metabolism without elevating circulating ketone levels.
