Alzheimer’s Disease: Disrupted Internal Clock Linked to Plaque Buildup, Mouse Study Reveals
A new study published October 23, 2025, suggests a critical link between Alzheimer’s disease and disruptions in the body’s natural circadian rhythms, offering potential new avenues for treatment and prevention. Researchers have discovered that the disease interferes with the daily activity of genes within brain cells, impacting their ability to clear harmful amyloid plaques – a hallmark of the neurodegenerative condition.
Alzheimer’s disease is well-known for its impact on memory and cognitive function, but emerging research highlights the importance of the body’s internal clock – the circadian rhythm – in the disease’s progression. Now, a team from Washington University School of Medicine in St. Louis has demonstrated in mice that Alzheimer’s disrupts the circadian rhythms within specific brain cells, altering the regulation of hundreds of genes crucial for brain function. The findings, appearing in Nature Neuroscience, indicate that restoring or controlling these rhythms could represent a promising therapeutic strategy.
“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,” explained a senior researcher involved in the study. “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.”
Changes in sleep patterns are frequently reported by caregivers of Alzheimer’s patients, and previous research from the team showed these changes can begin years before noticeable memory loss. These disrupted sleep patterns not only burden patients and caregivers but also create biological and psychological stress that can accelerate disease progression. Identifying the root cause of this disruption is thus paramount. The body’s circadian clock influences approximately 20% of all genes in the human genome, controlling when they are activated or deactivated to manage essential processes like digestion, the immune system, and the sleep-wake cycle.
researchers had previously identified a protein, YKL-40, that fluctuates with the circadian cycle and regulates amyloid protein levels in the brain. Elevated levels of YKL-40, linked to Alzheimer’s risk in humans, were found to contribute to amyloid buildup.Recognizing that the cyclic nature of Alzheimer’s symptoms suggested other circadian-regulated proteins were involved, the team expanded their examination.
In this latest study,scientists analyzed gene expression in the brains of mice exhibiting amyloid accumulations mirroring early-stage Alzheimer’s,comparing them to healthy young mice and aged mice without amyloid.By collecting tissue samples every two hours over a 24-hour period, they mapped gene activity throughout the circadian cycle.
The analysis revealed that amyloid accumulations disrupted the daily rhythms of hundreds of genes within brain cells called microglia and astrocytes – in ways distinct from the effects of aging alone. Microglia function as the brain’s immune response, clearing away toxic materials and dead cells, while astrocytes support neuronal communication. The affected genes are primarily involved in enabling microglial cells to break down waste, including amyloid. While the circadian disruption didn’t completely halt gene activity, it transformed an orderly process into a chaotic one, perhaps hindering the optimal functioning of brain cells, including amyloid clearance.
Moreover, the presence of amyloid appeared to generate new rhythms in hundreds of genes not typically governed by the circadian cycle. many of these genes are involved in the brain’s inflammatory response to imbalances like amyloid plaque buildup. These findings collectively suggest that therapies targeting circadian cycles in microglia and astrocytes could support healthy brain function.
“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,” the lead researcher stated. “Ultimately, we hope to learn how to optimize the circadian system to prevent amyloid accumulation and other aspects of Alzheimer’s disease.”
More information: A glial circadian gene expression atlas reveals cell type and disease-specific reprogramming in response to amyloid pathology or aging,Nature Neuroscience (2025). DOI: 10.1038/s41593-025-02067-1.
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