Circadian modulation by time-restricted feeding rescues brain pathology and improves memory in mouse models of Alzheimer’s disease

Circadian disruptions impact nearly all people with Alzheimer’s disease (AD), emphasizing both their potential role in pathology and the critical need to investigate the therapeutic potential of circadian-modulating interventions. Here, we show that time-restricted feeding (TRF) without caloric restriction improved key disease components including behavioral timing, disease pathology, hippocampal transcription, and memory in two transgenic (TG) mouse models of AD. We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep and memory, and normalizing daily transcription patterns of multiple genes, including those associated with AD and neuroinflammation. Thus, our study unveils for the first time the pleiotropic nature of timed feeding on AD, which has far-reaching effects beyond metabolism, ameliorating neurodegeneration and the misalignment of circadian rhythmicity. Since TRF can substantially modify disease trajectory, this intervention has immediate translational potential, addressing the urgent demand for accessible approaches to reduce or halt AD progression. [Display omitted] •AD mice present circadian deregulation and aberrant time-of-day brain transcription•TRF modulates hippocampal gene expression and pathways related to AD and inflammation•Increased Aβ clearance and reduced amyloid deposition mediate TRF benefits•Time-restricted feeding recovers sleep and activity rhythms and improves cognition Circadian alterations are prevalent in patients with Alzheimer’s disease (AD). Whittaker et al. report circadian disruptions, which emerge at early pathology stages, in AD mouse models. The application of a time-restricted feeding strategy efficiently restored brain transcription, slowed amyloid deposition, and improved memory deficits in AD mice.