Time-restricted feeding mitigates Alzheimer's disease-associated cognitive impairments via a -propionic acid-FFAR3 axis.

Time-restricted feeding (TRF) holds promise for alleviating cognitive decline in aging, albeit the precise mechanism via the gut-brain axis remains elusive. In a clinical trial, we observed, for the first time, that a 4-month TRF ameliorated cognitive impairments among Alzheimer's disease (AD) patients. Experiments in 5xFAD mice corroborated the gut microbiota-dependent effect of TRF on mitigating cognitive dysfunction, amyloid-beta deposition, and neuroinflammation. Multi-omics integration linked () and propionic acid (PA) with key genes in AD pathogenesis. Oral supplementation of or PA mimicked TRF's protective effects. Positron emission tomography imaging confirmed PA's blood-brain barrier penetration, while knockdown of the free fatty acid receptor 3 (FFAR3) diminished TRF's cognitive benefits. Notably, we observed a positive correlation between fecal PA and improved cognitive function in an AD cohort, further indicating that TRF enhanced PA production. These findings highlight the microbiota-metabolites-brain axis as pivotal in TRF's cognitive benefits, proposing or PA as potential AD therapies.