Mice bred to develop Alzheimer’s-like amyloid plaques slept more than two hours a day longer after most of their microglia, the brain’s resident immune cells, were temporarily removed. The plaques themselves were still there when the sleep came back.
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The finding comes from a University of Kentucky team led by Shannon Macauley, an associate professor of physiology in the College of Medicine and a researcher at the Sanders-Brown Center on Aging. It points at an overreacting immune response, rather than the plaques or failing neurons, as a driver of the sleep loss that often accompanies the disease.
Microglia, not plaques, behind the lost sleep
According to a ScienceDaily report dated Oct. 19, the experiment compared mice genetically predisposed to build amyloid plaques with normally aging wild-type mice at two ages: six months, when plaques first appear in the model, and 18 months, when pathology is far more advanced. Each animal wore a small head device recording brain activity and muscle activity, which together reveal sleep stages. Sleep disruption showed up early, at six months, and did not get worse by 18 months even though the plaque burden had more than doubled. The authors describe that pattern as a ceiling effect, and it is one reason they suspect an early immune reaction rather than accumulating plaque is doing the damage.
Macauley put the conclusion bluntly in the university’s account, saying it is “not the plaques themselves, or solely dysfunctional neurons, that cause sleep loss but actually microglia.” She also called the result “mind-blowing and unexpected.”
The research, published in the journal Alzheimer’s & Dementia in a paper titled “Early microglial response to amyloid plaques drives sleep loss in Alzheimer’s disease,” was written up in the University of Kentucky’s own release and is catalogued under DOI 10.1002/alz.71579. Nicholas Constantino, a recent doctoral graduate, is the first author. The release frames the work as a breakthrough, a characterization worth treating with some caution given that every result so far comes from rodents.
Pexidartinib and the 14-day depletion
To remove the cells, the researchers put the drug pexidartinib, also known as PLX3397 and originally developed in cancer research, into the animals’ food for 14 days. That cleared about 87 percent of the microglia. Treated mice spent longer in deep non-REM sleep and had more opportunities to move into REM sleep, and the recovered sleep amounted to more than two hours per day. The effect was described as temporary, which fits the design: microglia are needed for ordinary brain housekeeping, so a diet that strips most of them away is a research tool, not something proposed for patients.
Plaque levels did not change at all. The report’s own subheading says the two hours were restored “without clearing brain plaques,” which separates the sleep problem from the plaque load and suggests the inflammatory reaction might be targeted on its own.
Aging versus Alzheimer’s sleep signatures
The comparison with wild-type animals also showed that the two kinds of sleep loss are not the same. Ordinary aging mainly cut REM sleep, whereas the amyloid pathology selectively disrupted non-REM sleep, the deep stage associated with physical and mental restoration. The team analyzed the recordings with a method that separates rhythmic brain activity from the aperiodic background signal, and used light-sheet microscopy to make tissue transparent and map plaques and microglia in three dimensions.
That difference in patterns is the basis for a second idea. Macauley described EEG as a potentially “readily accessible, affordable and longitudinal biomarker of Alzheimer’s disease,” one that could in principle be run with portable equipment at home or in rural clinics. The proposal has not been validated in people.
What is still unproven in people
Whether the same mechanism operates in human patients is the open question, and the work offers no treatment. The lab is now studying metformin and stiripentol, two drugs that might adjust how microglia use energy so the cells calm down without being eliminated, but no results for those compounds are reported. The funding came from the National Institute on Aging and the National Institute of General Medical Sciences, along with $287,236 from the Cure Alzheimer’s Fund and $250,000 from the Coins for Alzheimer’s Research Trust Fund.
Sleep and dementia have been linked in human research for years, and the National Institute on Aging has covered the evidence on whether poor sleep raises the risk of Alzheimer’s disease as well as work suggesting a disrupted sleep-wake cycle might be a measure of preclinical disease. The mouse result adds a candidate cellular explanation for why those two things travel together: immune cells reacting early to plaque, then sustaining a sleep disturbance that appears before the worst of the pathology.
For families, the practical message is modest. Nothing in the study changes how sleep problems in dementia are managed today, and a drug that wipes out most immune cells in the brain is not a candidate therapy. What the experiment does is move the target. If the sleep loss belongs to the microglial response and not to the plaques, then treatments that gently retune those cells, rather than only clearing amyloid, become a more interesting direction to test.
This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.
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