Sleep problems associated with Alzheimer’s may have less to do with the amount of plaque in the brain than scientists previously expected.
Researchers at the University of Kentucky found that Alzheimer’s-related pathology and normal aging affected different sleep stages in mice. They also found that sleep disturbances appeared early and did not worsen in proportion to amyloid plaque accumulation.
The findings point to the brain’s immune cells as an unexpected contributor to sleep loss.
Published in Alzheimer’s & Dementia on June 7, 2026, the study found that experimentally reducing these immune cells restored more than two hours of daily sleep in affected mice without removing amyloid plaques.
Alzheimer’s and Aging Disrupt Different Stages of Sleep
Researchers found that Alzheimer’s-related brain changes primarily affected NREM sleep, while normal aging had a greater effect on REM sleep.
The team studied genetically modified mice that develop amyloid plaques and compared their sleep patterns with those of mice without the genetic changes.
Using recordings of brain activity and muscle movement, researchers monitored changes across different sleep stages.
Mice with amyloid pathology showed reductions in nonrapid eye movement sleep (NREM). Aging, meanwhile, was associated with reduced rapid eye movement sleep, or REM, and changes in recovery after sleep deprivation.
The distinction suggests that examining individual sleep stages may reveal information that total sleep duration alone cannot provide.
However, the findings do not establish whether these differences can identify Alzheimer’s in humans.
Sleep Problems Did Not Worsen as Plaques Accumulated
The researchers found that sleep disturbances emerged around the time amyloid plaques first appeared but remained relatively stable as plaque burden increased.
At three months, when little or no plaque burden was detectable, the genetically modified mice showed relatively normal sleep patterns.
By six months, plaques had developed, accompanied by measurable sleep deficits.
Nicholas J. Constantino, the study’s first author, expected those disturbances to worsen as plaque levels increased.
“I expected that as plaque burden became more severe, sleep disruption would also worsen,” he said in the University of Kentucky announcement.
Instead, plaque burden more than doubled between six and 18 months without a corresponding deterioration in the measured NREM sleep deficit.
The result suggested that plaque accumulation alone could not fully explain the sleep changes, leading researchers to consider another biological process.
Related: Why It Gets Harder to Sleep as You Age, and What’s Really Happening Inside Your Body at Night
Brain Immune Cells Offered an Unexpected Explanation
Image Credit: khwanpisit/123RF
The team identified microglia, immune cells involved in the brain’s response to abnormalities, as important contributors to the disturbances.
Using advanced imaging, researchers found that microglial populations expanded beyond plaque-containing areas into brain networks that regulate sleep and wakefulness.
Shannon L. Macauley, the study’s senior author, explained the finding.
“Basically, we showed that it is not the plaques themselves, or solely dysfunctional neurons, that cause sleep loss but actually microglia.”
To test that connection, researchers administered pexidartinib (PLX3397) for 14 days.
The experimental drug depleted about 87% of microglia, producing substantial improvements in sleep and brain electrical activity.
Crucially, the intervention did not reduce amyloid plaque burden.
The Findings Open Another Direction for Alzheimer’s Research
The discovery suggests that modifying the brain’s immune response could offer a possible approach to addressing Alzheimer’s related sleep disturbances.
The University of Kentucky publicly announced the research on July 16, 2026, after the study was published.
However, broadly removing microglia is not an established clinical treatment. These cells perform important functions, and the experiment did not determine the long-term consequences of substantially depleting them.
The researchers are exploring ways to influence microglial metabolism, including investigating medications such as metformin and stiripentol. Neither was established by this study as an effective treatment for Alzheimer’s related sleep loss.
The findings also did not demonstrate improved memory or slower disease progression in humans.
Still, the research offers a different way to investigate a familiar problem. Rather than focusing exclusively on amyloid deposits, scientists may need to examine how the brain responds to their presence.
What could the brain’s immune response reveal about treating Alzheimer’s related sleep problems without targeting amyloid plaques?
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