Imagine a small fire breaking out in a corner of your kitchen. With the right fire extinguisher, you might be able to put it out quickly. Instead, the sprinkler system is triggered and floods the entire house, turning a localized problem into widespread damage. According to researchers, something similar could be happening in the brains of people with Alzheimer’s disease. Amyloid plaques—sticky protein clumps that accumulate in the brain—are like the fire. Microglia, the brain’s resident immune cells, act like the sprinklers. Their response is intended to protect the brain, but it can ultimately make the situation worse. A team at the University of Kentucky has now identified this harmful process for the first time and demonstrated a way to stop it.

Immune Cells in the Brain Are Linked to Sleep Loss in Alzheimer’s

In a study published in the journal Alzheimer’s & Dementia, researchers led by Dr. Shannon L. Macauley, associate professor of physiology at the UK College of Medicine, and first author Dr. Nicholas J. Constantino, a recent PhD graduate from UK, found that microglia are the primary cause of sleep loss in an animal model of Alzheimer’s.

When the researchers used a drug to temporarily eliminate the majority of these cells, the animals regained more than two hours of sleep per day. The finding points to a potential new treatment target for the disease, which Macauley described as a “paradigm shift.” Until now, scientists had attributed the sleep loss associated with Alzheimer’s primarily to damaged nerve cells or the presence of amyloid plaques. The new findings suggest that the disorder may instead stem from a much more widespread immune response, similar to a “whole-house reaction.”

“Essentially, we’ve shown that it’s not the plaques themselves or solely dysfunctional neurons that cause the sleep loss, but actually the microglia,” said Macauley. “Microglia are immune cells that, when they react to plaques, set off this complex inflammatory cascade—as if the microglia were partying all night long and keeping the brain awake.”

Measuring Sleep and Brain Activity

To distinguish Alzheimer’s-related changes from those caused by normal aging, the researchers studied two groups of mice. One group had a genetic predisposition to form amyloid plaques, while the other consisted of “wild-type” mice that aged normally. The animals were examined at six months of age, when plaques first appear, and again at 18 months, a stage representing advanced disease.

The team used several state-of-the-art instruments to closely monitor changes in sleep and brain activity. The mice wore small devices attached to their heads that recorded electroencephalograms (EEG) and electromyograms (EMG). An EEG captures patterns of electrical activity and oscillations in the brain’s networks, creating what could be described as the brain’s electrical fingerprint. An EMG measures muscle activity. Together, these two methods enabled the researchers to determine exactly when the animals were awake, in deep, restorative sleep, or dreaming.

To locate the immune cells that, as Macauley described it, “partied all night long,” the researchers also used a technique called light-sheet microscopy. In this method, the brain tissue is made transparent, and a detailed digital 3D image is then created using a thin laser beam. This approach gave the team a comprehensive overview of both the amyloid plaques and the immune cells throughout the brain.

Temporary Removal of Microglia

To test whether the microglia were actually causing the sleep disorder, the scientists used a drug called pexidartinib (PLX3397). The drug was originally developed for cancer research and blocks a signaling pathway that microglia rely on for survival. After the mice received the drug for 14 days, approximately 87% of the immune cells in the brain were temporarily eliminated. The researchers were then able to determine whether sleep improved in their absence.

The team also used a mathematical method called “Fitting Oscillations and One Over Frequency” to classify the brain’s electrical activity into two categories: periodic activity (the rhythmic waves we commonly refer to as brain waves) and aperiodic activity (the electrical background noise). Using a car analogy, the researchers essentially tested whether the brain’s engine continued to run at an unusually high RPM even while the animals were at rest.

Early Plaques Trigger a Persistent Sleep Deficit

Macauley described the results as “staggering and unexpected.” The findings showed that plaque accumulation and sleep disturbances did not worsen together in a steady decline. “I had expected that sleep disturbances would also worsen as plaque burden increased,” said Constantino. “The disturbances in sleep and cortical EEG activity that emerged after six months, when the plaques first appeared, had not worsened after 18 months, even though plaque burden had more than doubled.”

The team referred to this pattern as the “ceiling effect.” Although plaque concentration more than doubled, the extent of sleep loss remained roughly the same. This finding suggests that the initial wave of immune activity triggered by early plaques may be sufficient to account for the sleep problem. Additional plaques may not lead to a proportional increase in sleep disturbances.

Alzheimer’s Attacks Restorative Sleep

The study also helped distinguish the effects of the normal aging process from those associated with Alzheimer’s pathology. Normal aging primarily led to a reduction in REM (Rapid Eye Movement) sleep, the sleep phase associated with dreaming and memory consolidation. In contrast, amyloid pathology selectively reduced NREM (non-rapid eye movement) sleep, the deep, restorative sleep phase.

“This restorative sleep is extremely important for physical recovery, learning, and memory, as well as for clearing away the day’s toxins,” said Macauley. “When Alzheimer’s patients lose this phase, they lose their brain’s primary cleanup cycle, creating a feedback loop that can promote further damage.” The loss of this restorative phase could therefore set off a harmful cycle. Poor sleep can impair the brain’s ability to clear waste products, which could contribute to further damage and even more severe sleep disturbances.

More Than Two Hours of Sleep Restored

The most striking result emerged after the researchers removed the microglia. Mice with Alzheimer’s-like pathology regained more than two hours of sleep per night after the majority of their immune cells in the brain had been removed. Their periods of restorative NREM sleep also became longer, giving them more opportunities to enter healthy REM sleep, which supports the formation of new memories. Importantly, this improvement occurred even though the amount of amyloid plaques in the brain remained unchanged.

This finding suggests that the inflammatory response to the plaques could be a reversible cause of sleep loss and might potentially be treated separately from the plaques themselves. This also raises an important question for future research: Could restoring this essential sleep in humans help break the positive feedback loop associated with Alzheimer’s disease?

The discovery was made within the research environment of Macauley’s lab at the Institute of Physiology at the Sanders-Brown Center on Aging. Macauley attributed the progress to a “wonderful partnership” between herself, her students, and other trainees. She encourages her team members to become “calculated risk-takers” and has hung a quote from Wayne Gretzky in her office: “You miss 100% of the shots you don’t take.”

Wearable EEG Could Aid in Earlier Detection

The overarching goal of the research is to develop affordable and noninvasive tools for people affected by Alzheimer’s disease. The current findings provide several avenues for future work. The researchers identified patterns of electrical brain activity that appear to distinguish Alzheimer’s-related changes from the normal aging process. They believe that EEG technology could ultimately serve as “an easily accessible, affordable, and longitudinal biomarker for Alzheimer’s disease.”

“With wearable EEG systems, we could monitor people in their home environments and potentially screen them for changes associated with Alzheimer’s disease without initially requiring expensive or invasive tests,” said Macauley. Such devices could enable local clinics throughout Kentucky to screen at-risk patients before they have to travel long distances to large hospitals to undergo more specialized testing.

Calming Microglia Without Removing Them

Macauley’s lab is currently investigating ways to reduce microglial overactivity without completely eliminating the cells. The team is testing safe medications already in use, including the diabetes drug metformin and the antiepileptic drug stiripentol. The researchers aim to determine whether these drugs can alter the energy metabolism of microglia and reduce their tendency toward overactivity. By preventing immune cells from keeping the brain’s “engine” in a state of heightened activity, the team hopes to restore healthy sleep and improve quality of life years before noticeable memory loss sets in.

“If we can specifically target this process, it could improve quality of life, attention, cognitive abilities, and reduce confusion,” said Macauley. The search for effective solutions begins with identifying both the cause of the problem and the right tool to combat it. Macauley’s team is making progress on both fronts.