A systematic review on the effects of hypercaloric diet in animal models of Alzheimer's disease

Background: According to several published studies, a hypercaloric diet (HD) could be considered a risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). To fully understand the molecular pathways involved, HD has been investigated in several animal models. Objective: The aim of this systematic review (SR) is to provide an overview of recent published data on the effects of HD on animal models of AD to gain insight into the molecular mechanisms potentially involved and to highlight current knowledge gaps for future studies. Methods: Structured bibliographic searches were carried out on PubMed, the Cochrane Library, and ISI Web of Knowledge. The SR was conducted following the Cochrane Handbook and the PRISMA statement. Studies enrolling only wild-type models or not using standard diet (SD) as control were excluded, as were non-original publications. Included studies were assessed for risk of bias using SYRCLE's tool. Results: A total of 77 studies met inclusion criteria. Most reported significant behavioral differences in HD-exposed mice (Morris Water Maze, Open Field, Y-maze), though with considerable variability due to protocol heterogeneity. A significant increase in tau and amyloid deposition was observed after HD exposure, and most studies reported negatively affected learning and memory. However, nearly half found no significant differences between HD and SD groups, likely reflecting heterogeneity in diet duration and type, animal age, and strain susceptibility. Methodological quality varied widely, with many studies omitting randomization, blinding, or sex-stratified analyses. Conclusions: Despite variability, evidence suggests HD worsens behavioral performance and increases tau and amyloid expression in mouse brain, representing a risk factor for dementia. More rigorous, standardized, and sex-balanced preclinical studies are needed, and findings support dietary interventions as early non-pharmacological strategies in AD prevention.