Circadian Rhythm Controls Alzheimer's Disease Risk Genes in Brain Cells

The daily pattern of genetic activity differs between cell types according to their state of health, a new study has shown, shedding light on the connection between Alzheimer's disease and the brain's working routine.

Known as the circadian rhythm, this cycle signals when we should wake up and sleep, while also ensuring numerous internal biological functions operate on schedule during every 24-hour period.

Circadian rhythm and Alzheimer's disease risk genes

Disturbed sleep has previously been associated with Alzheimer's. Researchers led by a team at Washington University School of Medicine (WashU Medicine) therefore examined more closely the circadian rhythms of genes connected with risk factors for the disease.

The team compared the brains of healthy mice of different ages with those of mice carrying an Alzheimer's-like condition. They assessed the expression of important genes in two particular cell types: astrocytes, which support neurones, and immune cells known as microglia. The findings were subsequently verified in human tissue.

"There are 82 genes that have been associated with Alzheimer's disease risk, and we found that the circadian rhythm is controlling the activity of about half of those," says neurologist Erik Musiek, from WashU Medicine.

"Knowing that a lot of these Alzheimer's genes are being regulated by the circadian rhythm gives us the opportunity to find ways to identify therapeutic treatments to manipulate them and prevent the progression of the disease."

Put simply, the cellular clocks governing cell behaviour exert a substantial effect on several genes associated with Alzheimer's pathology. This influence could interfere with normal brain function, particularly the brain's capacity to remove toxic waste.

Plaques, cellular clocks and brain function

The Alzheimer's mice had been genetically modified to form amyloid-beta protein plaques in their brains, which occur alongside the disease. It remains uncertain whether these deposits disturb the rhythm, or whether a disrupted cycle causes plaques to form. However, the researchers believe altered circadian clocks may be a concern.

That fits with existing knowledge of Alzheimer's, which is known to interfere with the body's daily routines. There is even a name for the heightened confusion that can emerge in the late afternoon or early evening: sundowning.

"Circadian rhythms in gene expression are cell-dependent and context dependent, and provide important insights into glial function in health, Alzheimer's disease and aging," write the researchers in their published paper.

Resetting the body's clocks

Scientists estimate that roughly one fifth of genes in the human genome alter their expression in response to the body's clocks, affecting functions including digestion, sleep and bodily repair.

As evidence points to daily fluctuations in brain cells affected by neurodegeneration, researchers can explore methods to offset the consequences of pathology. Resetting the clock of genes essential to brain function could offer a means of protecting against Alzheimer's.

"We have a lot of things we still need to understand, but where the rubber meets the road is trying to manipulate the clock in some way, make it stronger, make it weaker or turn it off in certain cell types," says Musiek.

"Ultimately, we hope to learn how to optimize the circadian system to prevent amyloid accumulation and other aspects of Alzheimer's disease."

The research was published in Nature Neuroscience.