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Summary: Alzheimer’s disease not only damages memory but also distorts the brain’s internal clock, altering the daily rhythms of hundreds of genes related to brain health. The researchers found that in mice with amyloid buildup, normal circadian gene activity in microglia and astrocytes (the brain’s immune and support cells) became erratic.
This alteration affected genes that regulate waste removal and inflammation, which could accelerate neurodegeneration. By identifying how Alzheimer’s rewires circadian genetic cycles, scientists hope to develop treatments that reset the rhythm and slow disease progression.
Key facts
Circadian disruption: Amyloid accumulation in Alzheimer’s disrupts normal day-night genetic cycles in microglia and astrocytes. Genetic reprogramming: More than half of the known genes related to Alzheimer’s are controlled and rhythmically altered in disease models. Therapeutic goal: Restoring or strengthening circadian rhythms can reduce amyloid buildup and inflammation.
Source: WUSTL
Alzheimer’s disease is known for disrupting patients’ daily rhythms. Restless nights with little sleep and increased daytime naps are early indicators of the onset of the disease, while sundowning or confusion later in the day are typical of the later stages of the disease.
These symptoms suggest a link between disease progression and the circadian system (the body’s internal clock that controls our sleep-wake cycle), but scientists did not know the full nature of the connection.
Researchers at Washington University School of Medicine in St. Louis have now shown in mice that circadian rhythms within certain brain cells are altered in Alzheimer’s disease in ways that change how and when hundreds of genes regulate key functions in the brain.
The findings, published Oct. 23 in Nature Neuroscience, suggest that controlling or correcting these circadian rhythms could be a potential way to treat the disease.
“There are 82 genes that have been associated with the risk of Alzheimer’s disease, and we found that the circadian rhythm controls the activity of about half of them,” said Erik S. Musiek, MD, PhD, Charlotte & Paul Hagemann Professor of Neurology at WashU Medicine, who led the study. In mice that modeled Alzheimer’s disease, the typical patterns of daily activity of those genes were altered.
“Knowing that many of these Alzheimer’s genes are regulated by the circadian rhythm gives us the opportunity to find ways to identify therapeutic treatments to manipulate them and prevent disease progression.”
Musiek, co-director of the Center on Biological Rhythms and Sleep (COBRAS) at WashU Medicine and a neurologist specializing in aging and dementia, said changes in sleep patterns are among the most common concerns reported to him by caregivers of Alzheimer’s patients.
He and his colleagues have previously shown that these changes begin in Alzheimer’s disease years before memory loss becomes evident. He noted that in addition to creating burdens for caregivers and patients, altered sleep patterns generate biological and psychological stresses that accelerate disease progression.
To break this feedback cycle it is necessary to identify its origins. The body’s circadian clock is thought to act on 20% of all genes in the human genome, controlling when they are turned on or off to manage processes including digestion, the immune system and our sleep-wake cycle.
Musiek had previously identified a specific protein, YKL-40, that fluctuates throughout the circadian cycle and regulates normal levels of amyloid protein in the brain.
He found that an excess of YKL-40, which is linked to Alzheimer’s risk in humans, leads to the buildup of amyloid, a buildup that is a hallmark of the neurodegenerative disease.
Amyloid alters the rhythmic functions of the brain
The cyclical nature of Alzheimer’s symptoms suggests that there are more proteins regulated by the circadian rhythm and their associated genes involved beyond YKL-40.
So in this latest study, Musiek and his colleagues examined gene expression in the brains of mice with accumulations of amyloid proteins that mimic the early stages of Alzheimer’s, as well as those of healthy young animals and old mice without amyloid accumulations.
The scientists collected tissue at 2-hour intervals for 24 hours and then performed an analysis of which genes were active during particular phases of the circadian cycle.
They found that amyloid accumulations altered the daily rhythms of hundreds of genes in brain cells known as microglia and astrocytes in different ways than aging alone.
Microglia are part of the brain’s immune response, removing toxic materials and dead cells, while astrocytes play roles in supporting and maintaining communication between neurons.
The affected genes are usually involved in helping microglial cells break down brain waste material, including amyloid.
While the circadian disruption did not completely shut down the genes in question, it turned an ordered sequence of events into a scattered affair that could degrade the optimal synchronicity of brain cell functions, such as amyloid clearance.
Additionally, the researchers found that the presence of amyloid appeared to create new rhythms in hundreds of genes that normally do not have a circadian pattern of activity. Many of the genes are involved in the brain’s inflammatory response to infections or imbalances such as amyloid plaque buildup.
Musiek said that together, the findings point to exploring therapies that target circadian cycles in microglia and astrocytes to support healthy brain function.
“We still have a lot of things to understand, but the difficult part is trying to manipulate the clock in some way, making it stronger, weaker or turning it off in certain types of cells,” he said.
“Ultimately, we hope to learn how to optimize the circadian system to prevent amyloid buildup and other aspects of Alzheimer’s disease.”
Sheehan PW, Fass S, Sapkota D, Kang S, Hollis HC, Lawrence JH, Anafi RC, Dougherty JD, Fryer JD, Musiek ES. An atlas of glial circadian gene expression reveals cell type and disease-specific reprogramming in response to amyloid pathology or aging. Nature neuroscience. October 23, 2025. DOI: 10.1038/s41593-025-02067-1.
Funding: This study was funded by the National Institute on Aging (R01AG054517, T32AG058518), the National Institute of Neurological Disorders and Stroke (R01NS102272), and the National Institutes of Health (R00AG061231). The content is the sole responsibility of the authors and does not necessarily represent the official views of the NIH.
Key questions answered:
A: It alters the rhythmic expression of hundreds of genes in glial cells, altering the rhythm of essential brain functions such as immune responses and waste removal.
A: Microglia and astrocytes, which manage immune defense and neuronal support, experience significant alterations in their daily patterns of gene activity.
A: Correcting or strengthening the brain’s internal clock could improve gene regulation related to amyloid clearance and inflammation control, which could slow disease progression.
About this news on research into Alzheimer’s disease, genetics and circadian rhythm
Author: Abeeha Shamshad
Source: WUSTL
Contact: Abeeha Shamshad – WUSTL
Image: Image is credited to Neuroscience News.
Original research: Open access.
“A Glial Circadian Gene Expression Atlas Reveals Cell Type and Disease-Specific Reprogramming in Response to Amyloid Pathology or Aging” by Erik S. Musiek et al. Nature Neuroscience
Abstract
An atlas of glial circadian gene expression reveals cell type and disease-specific reprogramming in response to amyloid pathology or aging
Although disruption of the circadian rhythm can promote neurodegenerative diseases, the impact of aging and neurodegenerative pathology on circadian gene expression patterns in different brain cell types is still unknown.
Here we use translational ribosome affinity purification to identify circadian translatomes of astrocytes, microglia, and bulk tissue in healthy mouse cortex and in settings of β-amyloid plaque pathology or aging.
We show that glial circadian translatomes are highly cell type specific and exhibit profound, context-dependent reprogramming in response to amyloid pathology or aging.
Transcripts involved in glial reactivity, immunometabolism and proteostasis, as well as in almost half of all Alzheimer’s disease risk genes, showed circadian oscillations, many of which were altered by pathology.
Microglial oxidative stress and amyloid phagocytosis showed temporal variation in gene expression and function.
Therefore, circadian rhythms in gene expression are cell- and context-dependent and provide important information about glial function in health, Alzheimer’s disease, and aging.
