Disrupted Circadian Rhythms Linked to Alzheimer’s Progression

Alzheimer’s disease has long been associated with disruptions in daily rhythms, leading to significant challenges for patients and caregivers alike. Recent research from the Washington University School of Medicine in St. Louis reveals that these disturbances may be linked to changes in the brain’s circadian rhythms, specifically in glial cells. The study, published on October 23, 2023, in Nature Neuroscience, highlights how these disruptions can alter gene regulation and potentially influence the progression of the disease.

The research team, led by Erik S. Musiek, MD, PhD, observed that in mice models of Alzheimer’s disease, the daily activity patterns of numerous genes were significantly altered. This change is particularly concerning given that approximately half of the 82 genes associated with Alzheimer’s risk are regulated by circadian rhythms. Musiek noted, “Knowing that a lot of these Alzheimer’s genes are being regulated by the circadian rhythm gives us the opportunity to find ways to identify therapeutic treatments to manipulate them and prevent the progression of the disease.”

In the early stages of Alzheimer’s, patients often experience disrupted sleep, which can lead to increased daytime napping and confusion during the evening, a phenomenon known as sundowning. Musiek explained that these symptoms frequently escalate the burden on caregivers and contribute to the disease’s advancement. The study’s findings suggest that addressing these circadian disruptions may offer new avenues for treatment.

Understanding Circadian Impact on Gene Regulation

The body’s circadian clock influences about 20% of all human genes, controlling vital functions such as digestion, immune response, and the sleep-wake cycle. Musiek and his team focused on the effects of amyloid protein accumulations—characteristic of Alzheimer’s disease—on gene expression in the brains of mice. They found that amyloid not only disrupted the daily rhythms of numerous genes but also created new patterns of activity in genes that typically do not exhibit circadian rhythms.

The researchers collected brain tissue samples at two-hour intervals over a 24-hour period to analyze gene activity. Their findings revealed that the disruption caused by amyloid accumulations affected microglia and astrocytes—two types of glial cells crucial for brain health. Microglia are responsible for clearing toxic materials and dead cells, while astrocytes support neuronal communication.

Musiek remarked that the altered gene activity turned the usual orderly function of these cells into a chaotic process, hindering their ability to effectively clear amyloid deposits from the brain. This dysfunction could exacerbate the symptoms of Alzheimer’s disease, creating a detrimental feedback loop that accelerates its progression.

Future Directions for Therapeutic Interventions

The implications of this research are significant. Musiek emphasized the need to further explore therapies that target circadian cycles within glial cells to enhance brain function. “We have a lot of things we still need to understand, but where the rubber meets the road is trying to manipulate the clock in some way,” he stated. The goal is to find ways to strengthen, weaken, or regulate circadian rhythms to optimize brain health and potentially prevent amyloid accumulation.

This study was funded by the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, and the National Institutes of Health. As researchers continue to unravel the intricate connections between circadian rhythms and Alzheimer’s disease, the hope is to develop innovative strategies that can alter the disease’s trajectory and improve the quality of life for those affected.

The findings represent a promising step in understanding the biological mechanisms underlying Alzheimer’s disease, paving the way for future research and potential treatments aimed at restoring normal circadian function in patients.