Alzheimer’s disease is a debilitating neurodegenerative disorder affecting millions of individuals and their families worldwide. With no cure in sight, researchers are continually exploring innovative approaches to alleviate the symptoms and slow the progression of this devastating disease. One emerging avenue of investigation involves addressing the disruption of circadian rhythms, the body’s internal biological clock, which plays a crucial role in regulating various physiological processes. Recent research published in Cell Metabolism has shed light on the potential of time-restricted feeding to correct circadian disruptions in Alzheimer’s disease.
Many individuals living with Alzheimer’s disease experience circadian rhythm disturbances. These disruptions manifest as changes in sleep patterns, increased cognitive impairment during the evening, and difficulties falling and staying asleep. The new research explored a novel approach to address circadian disruptions in Alzheimer’s disease – time-restricted feeding (TRF). TRF is a form of intermittent fasting that limits the daily eating window without reducing the overall food intake.
“Our laboratory is primarily interested in deciphering alterations in how the genes are expressed in the brain and how these mechanisms contribute to neuronal dysfunction and neurodegeneration,” explained study author Paula Desplats, an associate professor of neuroscience at the University of California San Diego.
“Precise knowledge of disease pathways can identify novel therapeutics for disorders such as Alzheimer’s disease. A major regulator of gene transcription is the circadian clock. Loss of circadian rhythmicity is a major hallmark of neurodegenerative disease and is experienced by more than 80% of Alzheimer’s patients in the form of disrupted sleep patterns and impaired cognition in the evening (sundowning). We therefore sought to determine whether modulation of circadian rhythmicity via time-restricted feeding is able to correct Alzheimer’s pathology.”
For their study, the researchers used mice with Alzheimer’s disease-like conditions as their experimental subjects. These mice were divided into two groups: one group adhered to the time-restricted feeding (TRF) schedule, and the other group served as the control, with unrestricted access to food at all hours.
The mice in the TRF group were subjected to a daily eating window of six hours, followed by a 14-hour fasting period. This TRF schedule was designed to align with the natural circadian rhythms and emulate a more typical eating pattern.
Throughout the study, the researchers conducted various behavioral assessments on the mice to evaluate changes in memory, hyperactivity at night, adherence to a regular sleep schedule, and disruptions during sleep. These assessments provided insights into the behavioral impact of TRF.
In addition to behavioral assessments, Desplats and her colleagues performed molecular analyses on both groups of mice. They examined gene expression patterns associated with Alzheimer’s disease and neuroinflammation. Additionally, they measured the levels of amyloid protein in the brains of the mice, as amyloid deposits are a well-known feature of Alzheimer’s.
The mice subjected to the TRF regimen demonstrated significant behavioral improvements compared to the control group. They exhibited better memory, reduced hyperactivity during nighttime hours, adhered to a more regular sleep schedule, and experienced fewer sleep disruptions. Overall, these behavioral assessments indicated that TRF mitigated the behavioral symptoms of Alzheimer’s disease in the mice.
At a molecular level, the researchers found notable differences in gene expression patterns between the two groups. Multiple genes associated with Alzheimer’s disease and neuroinflammation were expressed differently in the TRF group, suggesting that TRF had an impact on the molecular mechanisms underlying the disease. Additionally, the TRF regimen effectively reduced the accumulation of amyloid protein in the brains of the mice.
“The take-home message of our study is that restricting the amount of time allowed for daily feeding, but not the amount of food consumed, rescued brain transcriptional rhythms and significantly ameliorated both neuropathology and cognitive deficits in rodent models of Alzheimer’s disease,” Desplats told PsyPost. “This study has yet to be translated into human patients, but our work provides support for the importance of future investigations of the therapeutic potential of time-restricted eating as a powerful circadian modulator of Alzheimer’s disease in humans, which we hope to lead.”
The researchers found that TRF affected certain genes and proteins related to Alzheimer’s disease. One important discovery was a protein called Bmi1, which when lacking in mice, led to Alzheimer’s-like changes in the brain. TRF helped restore normal Bmi1 levels.
“We conducted this study mainly focused on the regulation of gene expression in the brain by the circadian clock,” Desplats explained. “While we expected to see a positive impact on neuropathology, we were surprised by the extent of the improvements in multiple measures of Alzheimer’s pathology in response to time-restricted feeding. Another interesting finding was the identification of a Bmi1 as a potential mediator of these effects, as this molecule is involved in the control of cellular senescence and DNA-damage responses, associated with aging.”
Mouse models of Alzheimer’s disease play a pivotal role in advancing our understanding of the disease’s mechanisms and in preclinical testing of potential therapies. These models provide a controlled environment to investigate genetic and environmental factors contributing to Alzheimer’s. However, they also have an inherent limitation — the differences between mouse and human brain physiology.
“There are many limitations to using mouse models of Alzheimer’s disease, as they do not always replicate what is seen during human pathology,” Desplats said. “Thus, we now seek to determine whether the positive effects of time-restricted eating on Alzheimer’s pathology can be reproduced in humans. We are also carrying out additional experiments in mice to understand the specific biological processes that control these outcomes and identify druggable targets for the treatment of the disease.
“Our findings, in concordance with a growing body of evidence, indicate that Alzheimer’s disease must be treated in a manner that reflects its complex etiology and pathology,” Desplats added. “Time-restricted eating is a lifestyle change that can be easily and immediately integrated into our daily routines. This dietary approach could complement pharmaceutical interventions and be an effective way to markedly improve the lives of people affected by the disease.”
The study, “Circadian modulation by time-restricted feeding rescues brain pathology and improves memory in mouse models of Alzheimer’s disease“, was authored by Daniel S. Whittaker, Laila Akhmetova, Daniel Carlin, Haylie Romero, David K. Welsh, Christopher S. Colwell, and Paula Desplats.
