Exploring the Impact of Circadian Rhythms on Glial Function and Alzheimer Disease

Erik Musiek, MD, PhD

Early within the first year of birth, activity and sleep cycles synchronize to the 24-h rotation of the Earth on its axis. In recent years, there has been a vested interest and greater understanding of the influence of biological cellular clocks on vital parts of central nervous system development in humans. Circadian rhythms affect multiple aspects of cognitive functions, particularly those needed for effort-intensive cognitive tasks, which require top-down executive control.

At the 2024 American Neurological Association (ANA) Annual Meeting, held September 14-17 in Orlando, Florida, one presentation, given by Erik Musiek, MD, PhD, focused on circadian regulation of glial activation and neuroinflammation in Alzheimer disease (AD). The presentation was part of a larger session that focused on the role of compartmentalized inflammation in different neurological diseases, focusing on targets like microglia, oligodendrocytes, and astrocytes.

Musiek, a professor of neurology at Washington University in St. Louis, sat down at the meeting to discuss his presentation and the topic at hand. He highlighted the growing understanding of how disrupted circadian rhythms, often seen in patients with AD, contribute to disease progression. In addition, he delved into the role of glial cells, particularly micoglia, in regulating inflammation and clearing amyloid and tau in the brain. Furthermore, Musiek emphasized the potential for circadian dysfunction, such as light exposure at night, to increase the risk of AD and other diseases.

NeurologyLive: Why was this a topic of interest for you?

Erik Musiek, MD, PhD: Well, my lab has been interested in this for a while—why our normal 24-hour rhythms, our circadian rhythms, seem to break down when people have Alzheimer's disease and other neurodegenerative diseases. We’re interested in understanding what impact that has. We're also looking at how in healthy people, poor sleep patterns or poor circadian function—like staying up late looking at your TV—can increase the risk of Alzheimer's and other degenerative diseases. We want to understand the molecular details of how these things happen.

What do we currently know about the role of glial activation and neuroinflammation in AD?

Well, I think over the past 10 years, there’s been an explosion in the amount of work on glial cells. Everyone used to be focused on neurons—how they make amyloid beta, tau, and whatnot. But the big discovery was the identification of the gene TREM2, which is a microglial gene and a risk factor for Alzheimer's. Several genetic risk factors for Alzheimer’s seem to involve glial genes, and we now appreciate how important these cells are in the brain. They regulate inflammation and help clear things like amyloid and tau from the brain.

We’re particularly excited because we think sleep and circadian rhythms have a big impact on glial cells—probably more so than on neurons. Some colleagues at WashU and elsewhere have shown that sleep deprivation affects microglia and their function. We’re more focused on how the circadian clock in each cell affects glial function. Disrupting that clock, or the animal’s exposure to light, can have profound effects. Interestingly, not all effects are as expected. Sometimes, disrupting the clock makes the pathology worse, but in certain cell types, it can make the pathology better. So, we see this as an opportunity to develop new therapeutic ideas.

In terms of drug development, is it feasible to include aspects of glial function when considering patient demographics for clinical trials? Should this be something to monitor when screening participants?

I think for sure. We have some biomarkers in blood and spinal fluid that can tell us about glial activation. For example, GFAP is a biomarker for Alzheimer’s that we can detect in blood or spinal fluid, and soluble TREM2 is a microglial marker that people measure in CSF. These aren’t widely used in clinical practice yet—they’re mostly in research studies—but integrating these biomarkers could help us select patients who may respond better to certain therapies.

With the new anti-amyloid immunotherapies, they seem to slow the disease down, but they could be more effective. There are also risks related to inflammation in the brain, like microhemorrhages or swelling. It’s possible that markers of glial activation or inflammation might affect your risk of side effects from these drugs, but we don’t know that yet. So, I do think they could eventually be integrated into clinical practice, starting with research.

What are some of the downstream effects of circadian dysfunction? Are there any ways to prevent or curb the incidence of circadian dysfunction?

Circadian dysfunction comes in many forms. The most common in our society is light exposure at night. With phones, TVs, and streetlights, we often disrupt our sleep-wake cycles and circadian clocks, making us misaligned with normal daily routines. There’s evidence this increases the risk of diseases like cancer, cardiovascular disease, and diabetes. There’s some data suggesting it might increase the risk of Alzheimer’s, but it hasn’t been studied as much. We do see that when we disrupt circadian rhythms in animals, they develop amyloid plaques faster and have more brain inflammation, so it seems to be a problem.

There are steps individuals can take—like practicing good sleep hygiene. This means avoiding bright light late at night, turning off your phone, and sleeping in a dark room. It’s easier said than done in our world. There’s also the issue of light pollution. City lights, especially modern LED lights, are brighter and more blue, and blue light is what triggers the circadian system. We could reduce this exposure by using less blue light or dimming lights at night.

A recent study suggested areas with higher light pollution have higher rates of dementia. It’s a complicated study, but it suggests that reducing blue light exposure at night may be helpful.

Are there any last comments pertinent to the discussion?

Actually, one thing I should mention—light exposure is the main issue with circadian rhythms, but eating patterns are also important. There’s a field called time-restricted feeding, where people eat during the day and avoid eating at night. That’s another personal intervention one can make, like avoiding big meals late at night to align your circadian rhythms.

Transcript edited for clarity.