University of Kentucky researchers have made a breakthrough in Alzheimer’s research, restoring more than two hours of sleep per day in mice without removing the amyloid plaques long considered the hallmark of the disease.
The study, published in the journal Alzheimer’s & Dementia, found that the brain’s own immune cells — microglia — are the main drivers of sleep loss in 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, even though the plaques remained unchanged.
The result points to a potential new treatment target for the disease, which lead researcher Shannon L. Macauley, Ph.D., called “paradigm shifting.”
The ‘Sprinkler System’ Problem
Scientists had previously attributed Alzheimer’s-related sleep loss mainly to damaged neurons or the physical presence of amyloid plaques. The new findings suggest the disruption may instead come from a much broader immune reaction.
“Basically, we showed that it is not the plaques themselves, or solely dysfunctional neurons, that cause sleep loss but actually microglia,” said Macauley, an associate professor of physiology in the UK College of Medicine.
“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.”
The Study
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, representing advanced disease.
The team used EEG and EMG to monitor sleep and brain activity, and light sheet microscopy to create 3D images of plaques and immune cells throughout the brain.
To test whether microglia were causing the sleep disruption, the scientists used a drug called Pexidartinib (PLX3397), which blocks a signaling pathway that microglia depend on for survival. After 14 days, about 87% of the brain’s immune cells were temporarily removed.
The Results
The findings were “mind-blowing and unexpected,” Macauley said. Plaque accumulation and sleep disruption did not worsen together in a steady decline. Even though plaque levels more than doubled by 18 months, the amount of lost sleep remained about the same.
The most striking result: mice with Alzheimer’s pathology gained more than two hours of sleep per night once microglia were depleted. Their periods of restorative non-REM sleep also became longer, giving them more opportunities to enter healthy dreaming sleep.
Importantly, the improvement occurred even though the amount of amyloid plaque in the brain did not change.
Why It Matters
The study also helped distinguish normal aging from Alzheimer’s pathology. Normal aging primarily reduced REM sleep, while amyloid pathology selectively reduced non-REM sleep — the deeply restorative stage.
“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.”
What’s Next
Macauley’s lab is now studying ways to reduce microglial overactivity without eliminating the cells completely. The team is examining safe medications already in use, including the diabetes drug Metformin and the antiseizure drug Stiripentol.
The broader goal is to develop affordable and noninvasive tools. The researchers identified patterns of electrical brain activity that appear to distinguish Alzheimer’s-related changes from normal aging, suggesting EEG 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 Alzheimer’s disease,” Macauley said.
The Bottom Line
University of Kentucky researchers have restored more than two hours of sleep per day in Alzheimer’s mice by temporarily removing overactive immune cells, without clearing amyloid plaques. The study found that microglia — the brain’s immune cells — are the main drivers of sleep loss in Alzheimer’s, triggering inflammation that keeps the brain awake. The findings point to a potential new treatment target for the disease, separate from the plaques themselves.
