Intermittent Fasting Improves Alzheimer’s Pathology, Possibly Breaks New Ground for Future Research

Published on August 21 in the journal Cell Metabolism, researchers at the University of California San Diego (UCSD) School of Medicine recently found that time-restricted feeding (TRF) may help correct Alzheimer’s disease-related disruption of the circadian rhythm (more commonly referred to as “biological clock”) in a mouse model. Also, mice on time-restricted feeding showed reduced amyloid accumulation in the brain, together with better memory and cognitive performance than a control group that had free access to food at all times.

The UCSD team stated that time-restricted feeding is a strategy that people can easily and efficiently integrate into their lives. It is hoped that these results, if successfully reproduced in humans, will lead to a significant improvement in the quality of life for Alzheimer’s patients and their caregivers.

Related article: Scientists Unlocked the Secret of Genetic Impact of Time-restricted Eating in Mice

Close Link Between Alzheimer’s Disease and Circadian Rhythm Disruption

Alzheimer’s disease (AD), which predominantly affects people over the age of 65, may become a major global health challenge in the face of population aging. For instance, the Alzheimer’s Association estimates that as of March 2023, there are 6.7 million people living with AD in the United States. By 2060, the number is expected to double to approximately 13.8 million. In addition, the 2023 healthcare costs related to AD or other dementias were estimated at US$345 billion and the amount could soar to over US$1 trillion by 2050,  indicating that the impact of AD on the future society is indeed an issue to be reckoned with. 

Apart from the common symptoms of memory loss, cognitive impairment, worsening cognitive judgment, and reduced communication and motor skills, nearly 80% of people with AD suffer from a variety of disruptions to their circadian rhythms, including difficulty in falling asleep, reduced sleep quality, and increased cognitive impairment and confusion in the evenings. Unfortunately, there are no existing treatments that target this aspect of the disease. 

Dr. Paula Desplats, senior author of the study and a professor in the Department of Neurosciences of UCSD’s School of Medicine, said, “For many years, we assumed that the circadian disruptions seen in people with Alzheimer’s are a result of neurodegeneration, but we’re now learning it may be the other way around — circadian disruption may be one of the main drivers of Alzheimer’s pathology.” 

In fact, as mentioned in the article, there is new evidence that circadian alterations in AD occurs in the preclinical period, and that weakened circadian activity patterns increase the risk of dementia and precede cognitive impairment by several years. Dr. Desplats suggested that regulating the circadian rhythm may represent a new approach, possibly helping to slow down the progression of the disease and leading to new therapeutic options.

TRF Brings About Memory Improvement and Reduced Aβ Accumulation in Mice

Time-restricted feeding (or intermittent fasting), as the name suggests, means eating only for a specific period of time (about 8-10 hours) daily, and not eating anything with calories at all during the rest of the day, thus establishing a fixed pattern of caloric intake, and keeping the eating pattern in line with the biological clock of nutrient metabolism. In this study, researchers used a transgenic mouse model of AD for their study, assigning AD mice to either ad libitum feeding (ALF) or time-restricted feeding (TRF), with a feeding window that aligned with the middle of the active period, 6 hours of feeding and 18 hours of fasting. The equivalent in human terms would be approximately 14 hours of fasting per day. The team assessed a number of different aspects of the two groups of mice, including circadian function, cognitive function, quality of sleep, gene expression, and accumulation of amyloid beta peptide (Aβ) in the brain.

Compared with the ALF group, researchers found that mice in the TRF group achieved a higher total sleep time, slept more regularly with fewer interruptions, and were less hyperactive at night. In addition, the mice in the TRF group performed significantly better than the ALF group in assessments of memory and cognitive functions. These results suggest that intermittent fasting may help alleviate the behavioral symptoms of AD. At the cellular and molecular biology level, the team observed significant differences in gene expression in the hippocampus between the mice in the TRF group and those in the ALF group. A number of genes involved in autophagy, lipid processing, neuroinflammation, and pathological changes in AD could be restored to a normal pattern of transcription through TRF.

Regarding the deposition of amyloid proteins, which has been one of the main focuses of AD research for many years, UCSD researchers found that the mice in the TRF group exhibited an increased clearance of Aβ from the brain and reduced Aβ deposition compared to the ALF group. Overall, the effects of TRF on AD mice go beyond metabolism, demonstrating benefits in adjusting the circadian rhythm, ameliorating neurodegeneration, and regulating gene expressions. 

A Potential AD Management Strategy with More Convenience and Less Drug Reliance

The mechanisms through which TRF conveys the above-mentioned benefits are not well understood and are likely pleiotropic. The alterations brought about by TRF may result from changes in the metabolite interactions, bioenergetic pathway responses, modulation of circadian rhythm timing and strength, epigenetic modifications, and effects on food-anticipatory activity and reward circuits in the brain.

The UCSD team has expressed optimism about the future development as TRF could be a new treatment strategy based on lifestyle changes rather than relying on drugs, which would be relatively easier for clinical implementation and quicker to incorporate into the daily lives of AD patients. They also expect that these findings will one day be translated into human clinical trials.

“Circadian disruptions in Alzheimer’s are the leading cause of nursing home placement,” said Desplats. “Anything we can do to help patients restore their circadian rhythm will make a huge difference in how we manage Alzheimer’s in the clinic and how caregivers help patients manage the disease at home.” She also stressed that intermittent fasting has the potential to be a convenient method of dramatically improving the quality of life for Alzheimer’s patients and their caregivers if these results can be reproduced in humans.

Author

Richard Chau