Abstract

Intermittent fasting (IF) is suggested to mitigate cognitive impairment in Alzheimers disease (AD). We detailed the effects of IF in AD development and assessed the contribution of the gut microbiota-metabolite-brain axis in promoting the effects of fasting. A 16-week IF regimen significantly improved spatial memory and cognitive function in AD transgenic mice; this improvement was accompanied by decreased A{beta} accumulation and suppression of neuroinflammation. IF reshaped the microbiota and beneficially altered the microbial metabolites related to cognitive function. Multi-OMICs integration demonstrated a strong connection between IF induced changes in hippocampus gene expression, the composition of the gut microbes, and the serum metabolites beneficial for cognitive function. Removal of gut microbes with antibiotics abolished the neuroprotective effects of IF. These findings suggest new avenues for therapy and nutritional intervention to prevent the development of AD and other neurodegenerative diseases.