Fractured sleep, daytime sleepiness, and other signs of disturbance in one’s circadian rhythm are common complaints of people with Alzheimer’s disease, and the problems only get worse as the disease progresses.
But the reason for the link between Alzheimer’s and circadian dysfunction is not well understood.
In a new study, researchers found that a clue may lie in the brain protein YKL-40.
They found that YKL-40 is both regulated by clock genes and involved in clearing away potentially toxic buildup of Alzheimer’s proteins in the brain.
Moreover, Alzheimer’s patients who carry a genetic variant that reduces YKL-40 levels maintain their cognitive faculties longer than people without the variant.
The findings suggest that YKL-40 is a possible link between circadian rhythm dysfunction and Alzheimer’s and that therapies targeting the protein may slow the course of the disease.
The research was conducted by a team at Washington University School of Medicine in St. Louis.
Our daily rhythms are set by a master clock in the brain that is driven by the day and night cycle. Each cell also maintains its own internal clock, pegged to the master clock.
A surprisingly broad array of biological processes—from sugar absorption to body temperature to immune and inflammatory responses—vary by time of day.
Although circadian dysfunction affects many aspects of health and disease, it is most easily detected as sleep disturbances, such as difficulty falling asleep or staying asleep at night and increased sleepiness during the day.
Such problems are common in people with Alzheimer’s, even those in the earliest stage of the disease when amyloid plaques have begun forming but cognitive symptoms have not yet appeared.
Previous studies had discovered that high levels of YKL-40 in the cerebrospinal fluid are a sign of Alzheimer’s.
Subsequent research revealed that YKL-40 levels rise with normal aging and as Alzheimer’s progresses.
In the study, the team took Alzheimer’s mouse models prone to developing amyloid plaques and crossed them with genetically modified mice that lack the gene for YKL-40, or with unmodified mice for comparison.
Once the mice were eight months old—elderly, by mouse standards—the researchers examined the animals’ brains.
The amyloid-prone mice without YKL-40 had about half as much amyloid as those that carried the gene.
Amyloid plaques normally are surrounded by immune cells called microglia that help keep the plaques from spreading.
In the mice that lacked YKL-40, the microglia were more plentiful and more primed to consume and remove amyloid.
This jibes with data from studies in people. The team analyzed genetic data from 778 people.
About a quarter (26%) of them carried a genetic variant that reduces levels of YKL-40. Cognitive skills declined 16% more slowly in the people with the variant.
These findings suggest that in Alzheimer’s, it’s bad. People who have less of it fare better.
If scientists could design a therapy to lower YKL-40, it might help the microglia remove more amyloid and maybe slow the progression of the disease.
One author of the study is Erik Musiek, MD, Ph.D., an associate professor of neurology.
The study is published in Science Translational Medicine.
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