SUMMARY Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting the lives of more than 5 million Americans and their families and is the biggest forthcoming health challenge. AD is a multifactorial disorder manifested clinically by progressive memory loss, decline in cognitive functions and ultimately leading to dementia. Despite being the subject of intense research, there is no cure for AD, therefore, identifying therapies that can reduce disease progression at early stages is critical. Circadian impairment is a major feature of Alzheimer’s disease. Behavioral circadian alterations, known as sundowning, are experienced by more than 80% of patients and represent the leading factor for hospitalization and nursing home placement in AD. New research suggests that circadian disruption occurs early during disease progression and contributes to neurodegeneration. Since circadian rhythms regulate multiple systems in the human body coordinating physiology with the environment, alterations in this system have a profound impact on health, behavior, sleep, and cognition. The proposed work will conduct a preliminary investigation on the beneficial effects of regulating the time of food intake to improve circadian function, on cognition and disease markers in Mild Cognitive Impairment (MCI) or AD patients. One of the most powerful regulators of the circadian system is the daily feed/fast cycle. We recently demonstrated that time-restricted feeding (TRF) improves key disease components including memory, sleep, behavior, disease pathology, and brain transcription in mouse models of AD. Notably, we found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep and hyperactivity, and normalizing transcription of circadian, AD, and neuroinflammation-associated genes in AD mice. Thus, our study unveiled for the first time that circadian modulation through timed feeding has far-reaching effects beyond metabolism and affects the brain as the substrate for neurodegeneration. A similar intervention in human patients may have a profound translational value, addressing the crucial need for accessible approaches to reduce or halt AD progression. We now propose to test the safety, feasibility, and effectiveness of a time-restricted eating (TRE) paradigm in patients with a clinical diagnosis of cognitive impairment due to MCI or AD. We will recruit 40 patients and randomize them into two groups that will follow a TRE model of prolonged fasting during the night (14h without food intake) for 6 or 12 months. We will monitor blood-based markers of health, metabolism, epigenetic aging, and AD pathology; record circadian regulation based on sleep and activity monitoring and evaluate cognitive functions. The data collected will be fundamental to designing a larger clinical trial using TRE to improve circadian function and reduce cognitive and pathology burden in AD. Since this is a ...