M'Bra, P. E. H.; Hamilton, L. K.; Moquin-Beaudry, G.; Aubin, M.; Lyn-Mangahas, C.; Pratesi, F.; Brunet, E.; Castonguay, A.; Mailloux, S.; Galoppin, M.; Bernier, M.; Turri, M.; Vachon, A.; Mayhue, M.; Aumont, A.; Tetreault, M.; Plourde, M.; Fernandes, K. J. L.

Lifestyle factors modulate dementia risk. We investigated mechanisms of dementia risk reduction by emerging dietary ketogenic interventions. We show that distinct interventions, a medium-chain triglycerides (MCT)-enriched diet and a carbohydrate-free, high-fat diet (CFHF), improve cognition and dendritic spine density of memory-associated hippocampal neurons in two mouse models of Alzheimer disease (AD). Only the CFHF diet drove increased circulating ketones, suggesting distinct underlying mechanisms. AD mice exhibited baseline and diet-induced susceptibility to peripheral metabolic disturbances that were improved by MCT and exacerbated by CFHF diets. Prominent AD-associated dysregulation of the liver transcriptome was largely restored by both interventions, but MCT also downregulated lipogenic enzymes and did not trigger a CFHF-like inflammatory signature. Novel AD- and diet-induced plasmatic changes in hormones and lipid species were identified. Thus, different ketogenic interventions yield cognitive benefits in AD models while showing intervention-specific modulation of peripheral metabolic defects, with implications for design of therapeutic ketogenic strategies.