Alzheimer’s breakthrough: Scientists restore two hours of sleep without clearing brain plaques

Researchers say something similar may happen in the brains of people with Alzheimer's disease. Amyloid plaques, sticky clumps of protein that accumulate in the brain, are like the fire. Microglia, the brain's resident immune cells, act like the sprinklers. Their response is meant to protect the brain, but it may ultimately make the situation worse.

A team at the University of Kentucky has now identified this damaging process for the first time and demonstrated a way to shut it down.

Brain Immune Cells Linked to Alzheimer's Sleep Loss

In a study published in the journal Alzheimer's & Dementia, researchers led by Shannon L. Macauley, Ph.D., an associate professor of physiology in the UK College of Medicine, and first author Nicholas J. Constantino, Ph.D., a recent UK doctoral graduate, found that microglia are the main drivers of sleep loss in an animal model of Alzheimer's.

When the researchers used a drug to temporarily eliminate most of these cells, the animals regained more than two hours of sleep each day. The result points to a potential new treatment target for the disease, which Macauley called "paradigm shifting."

Scientists had previously attributed Alzheimer's related sleep loss mainly to damaged neurons or the physical presence of amyloid plaques. The new findings suggest that the disruption may instead come from a much broader immune reaction, similar to a "whole house response."

"Basically, we showed that it is not the plaques themselves, or solely dysfunctional neurons, that cause sleep loss but actually microglia," said Macauley. "Microglia are immune cells that, when they respond to plaques, kick off this elaborate cascade of inflammation, as if the microglia are partying all night, and keeping the brain awake."

Tracking Sleep and Brain Activity

To separate Alzheimer's related changes from those caused by normal aging, the researchers studied two groups of mice. One group had a genetic tendency to develop amyloid plaques, while the other consisted of "wild-type" mice that aged normally.

The animals were examined at six months of age, when plaques begin to appear, and again at 18 months, a stage representing advanced disease.

The team used several advanced tools to closely monitor changes in sleep and brain activity. The mice wore small head mounted devices that recorded electroencephalography (EEG) and electromyography (EMG).

An EEG captures patterns of electrical activity and oscillations across brain networks, creating what can be thought of as an electrical fingerprint of the brain. An EMG measures muscle activity. Together, the two methods allowed researchers to determine precisely when the animals were awake, in deep restorative sleep or in dreaming sleep.

To locate the immune cells that were "partying all night," as Macauley described them, the researchers also used a technique called light sheet microscopy. The method makes brain tissue transparent, then uses a thin plane of laser light to build a detailed 3D digital image.

This approach gave the team a full view of both amyloid plaques and immune cells throughout the brain.

Temporarily Removing Microglia

To test whether microglia were actually causing the sleep disruption, the scientists used a drug called Pexidartinib (PLX3397). The medication was first developed for cancer research and blocks a signaling pathway that microglia depend on for survival.

After the mice received the drug for 14 days, about 87% of the brain's immune cells were temporarily removed. The researchers could then determine whether sleep improved in their absence.

The team also used a mathematical method called Fitting Oscillations and One Over Frequency to divide the brain's electrical activity into two categories: periodic activity (the rhythmic waves we usually think of as brain waves) and aperiodic activity (the background electrical noise).

Using a car comparison, the researchers were effectively testing whether the brain's engine continued to run at an unusually high speed even while the animals were resting.

Early Plaques Trigger a Lasting Sleep Deficit

Macauley called the results "mind-blowing and unexpected." The findings showed that plaque accumulation and sleep disruption did not worsen together in a steady decline.

"I expected that as plaque burden became more severe, sleep disruption would also worsen," said Constantino. "The disruptions in sleep and cortical EEG activity that occur at six months, when plaques first emerge, did not worsen by 18 months, despite more than double the amount of plaque burden."

The team described this pattern as a ceiling effect. Even though plaque levels more than doubled, the amount of lost sleep remained about the same.

That result suggests that the first wave of immune activity triggered by early plaques may be enough to establish the sleep problem. Additional plaques may not produce a proportional increase in sleep disruption.

Alzheimer's Targets Restorative Sleep

The study also helped distinguish the effects of normal aging from those linked to Alzheimer's pathology.

Normal aging primarily reduced rapid eye movement (REM) sleep, the stage associated with dreaming and memory consolidation. In contrast, amyloid pathology selectively reduced nonrapid eye movement (NREM) sleep, the deeply restorative stage of sleep.

"That restorative sleep is super important for physical repair, learning and memory and washing out the toxins of the day," Macauley said. "When Alzheimer's patients lose this stage, they lose their brain's primary cleaning cycle, creating a feed-forward loop that may drive further damage."

The loss of this restorative period could therefore create a harmful cycle. Poor sleep may reduce the brain's ability to clear waste, which could contribute to further damage and even more sleep disruption.

More Than Two Hours of Sleep Restored

The most striking result came after the researchers depleted the microglia.

Mice with Alzheimer's related pathology gained more than two hours of sleep per night once most of their brain immune cells had been removed. Their periods of restorative NREM sleep also became longer, giving them more opportunities to enter healthy dreaming sleep that supports the formation of new memories.

Importantly, the improvement occurred even though the amount of amyloid plaque in the brain did not change.

This finding suggests that the inflammatory response to plaques may be a reversible cause of sleep loss and could potentially be treated separately from the plaques themselves.

It also raises a major question for future research: could restoring this essential sleep in people help interrupt the feed-forward loop associated with Alzheimer's disease?

A Collaborative Lab Culture

The discovery grew out of the research environment in Macauley's laboratory in the Department of Physiology at the Sanders-Brown Center on Aging. Macauley credited the progress to a "beautiful partnership" between herself, her students and other trainees.

"I love people who take initiative, find their passion are curious and keep pushing to find an answer," Macauley said.

She encourages members of her team to become "calculated risk-takers," and keeps a Wayne Gretzky quote in her office: "You miss 100% of the shots you don't take."

Constantino, who recently defended his doctorate at UK, said that this atmosphere gave him the confidence to pursue challenging questions that crossed multiple fields.

"Dr. Macauley has also taught me to embrace uncertainty and failure as part of the scientific process," Constantino said. "Some of the most interesting studies I have been a part of emerged because our original hypothesis was wrong."

When experiments encounter obstacles, Macauley encourages the team to keep investigating rather than stop.

"Follow the data, ask better questions and figure out what is actually happening."

That approach helped the researchers move beyond the field's traditional focus on neurons and investigate whether microglia could be a treatment target.

Portable EEG Could Aid Earlier Detection

The broader goal of the research is to develop affordable and noninvasive tools for people affected by Alzheimer's disease. The current findings provide several directions for future work.

The researchers identified patterns of electrical brain activity that appear to distinguish Alzheimer's related changes from normal aging. They believe EEG technology could eventually serve as a "readily accessible, affordable and longitudinal biomarker of Alzheimer's disease."

"Portable EEG systems could allow us to monitor people in their home environments and potentially screen for changes associated with an Alzheimer's disease, without the initial need for expensive or invasive tests," Macauley said.

Such devices could potentially allow local clinics across Kentucky to screen people at risk before requiring them to travel long distances to major hospitals for more specialized testing.

Calming Microglia Without Removing Them

Macauley's laboratory is now studying ways to reduce microglial overactivity without eliminating the cells completely.

The team is examining safe medications that are already in use, including the diabetes drug Metformin and the antiseizure drug Stiripentol. Researchers want to determine whether these medicines can change how microglia process energy and reduce their tendency to become overactive.

By preventing immune cells from keeping the brain's engine in a heightened state, the team hopes to restore healthy sleep and improve quality of life years before noticeable memory loss develops.

"If we can target that process, it might help with quality of life, attention, cognition and confusion," Macauley said.

Finding effective solutions begins with identifying both the source of the problem and the right tool to address it. Macauley's team is making progress on both fronts.

Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers R01AG068330, R01AG093847 and P30AG072946, and by the National Institute of General Medical Sciences of the National Institutes of Health under Award Numbers P30GM127211 and P20GM148326. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

This work was supported by a $287,236 award from the Cure Alzheimer's Fund.

This work was supported by a $250,000 award from The CART Fund (Coins for Alzheimer's Research Trust).