SCOPE: Alzheimer's disease (AD) is the most prevalent form of dementia, lack of effective therapeutic interventions. In this study, we investigate the impact of intermittent fasting (IF), an alternative strategy of calorie restriction, on cognitive functions and AD-like pathology in a transgenic mouse model of AD. METHODS AND RESULTS: APP/PS1 mice at 6 months were randomly allocated to two dietary groups: one receiving ad libitum (AL) feeding and the other undergoing IF for 1 month. Y maze, Barnes maze, western blotting, and immunofluorescence were employed. Behavioral assessments revealed that the APP/PS1-IF group demonstrated notable improvements in cognitive function compared to the AL group. Further analysis showed that microglia in the APP/PS1-IF mice exhibited enhanced phagocytic activity, characterized by prominent enlargement of soma and reduced complexity of their processes. Importantly, IF significantly decreased the accumulation of lipid droplets (LDs) within microglia. These microglia with less LDs may contribute to enhanced β-amyloid (Aβ) phagocytosis, thereby ameliorating Aβ deposition in the brains of APP/PS1-IF mice. CONCLUSION: Our findings demonstrate that IF ameliorates amyloid deposition and cognitive deficits in the AD model mice, which is associated with the reduction of LDs within microglia, providing support for the use of the dietary intervention against AD pathology.