How Sleep Loss Was Detected in the Mice
The sleep disruption primarily affected NREM sleep, or non-rapid eye movement sleep. Mice with the APP/PS1 model of the disease spent less time in NREM sleep at six months of age than wild-type mice. Aging did not change this pattern. For the treatment study, six-month-old female mice were fitted with small head implants for electroencephalography and electromyography recordings to measure brain activity and muscle movement, according to the university.
The researchers identified microglia as a causal, reversible driver of amyloid-associated sleep loss and view sleep and EEG measurements as sensitive biomarkers for early, symptom-free Alzheimer's disease.
How the Drug Depleted Microglia
To test whether microglia directly caused the sleep loss, mice were given food containing pexidartinib for 14 days. The drug, originally used in cancer research, blocks a signal that immune cells need to survive. At an estimated dose of 400 milligrams per kilogram of body weight, it reduced microglia by 87 percent. Researchers compared EEG and EMG recordings on day 7 and day 14 of treatment against baseline values.
Why Early Plaques May Be Key
Lead author Nicholas J. Constantino reported that the sleep and brain activity disruptions observed at six months did not worsen by 18 months, despite plaque levels more than doubling. The researchers interpret this as a ceiling effect: sleep loss does not increase proportionally with plaque amount. While normal aging primarily reduced REM sleep, amyloid plaques specifically disrupted NREM sleep. The study also found that aging eliminated the compensatory sleep rebound after sleep deprivation, while amyloid pathology specifically targeted NREM sleep. Study lead Shannon Macauley explained that it was not the plaques themselves or damaged neurons alone that caused sleep loss, but rather microglia responding to plaques, triggering an inflammatory cascade that kept the brain awake.
Bridging the Gap Between Mice and Humans
Benefits have so far been shown only in mice, not humans. Temporary removal of most brain immune cells is neither an established nor practical treatment for Alzheimer's patients. This approach remains experimental. Further research will determine whether it can safely achieve similar benefits in humans. In the animal model, the finding shifts attention from plaques themselves to microglia as a possible, reversible cause of sleep loss in Alzheimer's disease.