How Circadian Rhythm Disruption May Contribute to Alzheimer’s Disease

Alzheimer’s Disease May Disrupt the Brain’s Internal Clock—And Resetting It Could Slow the Disease

Alzheimer’s disease does more than affect memory—it may also interfere with the brain’s natural sense of time. New research suggests that disruptions to the brain’s internal clock can alter gene activity in key brain cells, potentially accelerating the buildup of harmful plaques. Encouragingly, correcting these timing problems may open the door to new treatment strategies.

Sleep Disturbances Offer Early Clues

Changes in sleep patterns are often among the earliest signs of Alzheimer’s disease. Many individuals experience restless nights, frequent awakenings, or excessive daytime sleepiness long before noticeable memory decline. As the disease progresses, some patients develop “sundowning,” a condition marked by confusion, anxiety, and agitation later in the day.

These symptoms point toward a malfunction in the circadian system—the biological clock that regulates sleep, alertness, hormone release, and other essential bodily processes. While scientists have long suspected a link between circadian disruption and Alzheimer’s, the underlying biological mechanisms were not well understood.

How Alzheimer’s Alters Brain Cell Timing

Researchers at Washington University School of Medicine in St. Louis have uncovered new evidence showing that Alzheimer’s disease interferes with circadian rhythms inside specific brain cells. Using mouse models of Alzheimer’s, the team discovered widespread changes in the timing and behavior of hundreds of genes critical for brain health.

Their findings, published in Nature Neuroscience, indicate that restoring normal circadian rhythms could become a promising approach to slowing disease progression.

According to the study’s lead investigator, Dr. Erik S. Musiek, nearly half of the genes known to increase Alzheimer’s risk are regulated by circadian rhythms. In Alzheimer’s models, these genes lost their normal daily activity patterns, potentially impairing vital brain functions. Understanding this connection may help researchers develop therapies that target gene timing rather than the genes themselves.

Why Sleep Problems May Speed Up Alzheimer’s

Sleep disruption is one of the most commonly reported challenges faced by people with Alzheimer’s and their caregivers. Previous research has shown that poor sleep can begin years before cognitive symptoms appear. Beyond reducing quality of life, ongoing sleep disturbances place biological stress on the brain, which may accelerate neurodegeneration.

The circadian clock controls roughly one-fifth of all human genes, determining when they turn on or off throughout the day. These rhythms help regulate immune responses, metabolism, and brain repair processes. When this timing system breaks down, the brain becomes more vulnerable to damage.

A Key Protein Tied to Amyloid Accumulation

Earlier studies by Dr. Musiek’s team identified a protein called YKL-40 that naturally follows a circadian rhythm and helps regulate amyloid levels in the brain. Amyloid plaques are a hallmark of Alzheimer’s disease. When YKL-40 levels rise too high—a condition associated with increased Alzheimer’s risk—amyloid begins to accumulate more rapidly.

This discovery raised an important question: could amyloid itself disrupt the brain’s internal clock?

Amyloid Throws Gene Activity Out of Sync

To investigate further, researchers examined gene activity in the brains of mice with amyloid buildup resembling early-stage Alzheimer’s disease. They compared these patterns with those of healthy young mice and older mice without amyloid accumulation. Brain samples were collected every two hours over a full day to capture changes across the circadian cycle.

The results showed that amyloid significantly disrupted the normal timing of gene activity in microglia and astrocytes—two types of brain cells essential for maintaining neural health. Microglia act as the brain’s immune system, clearing debris and toxins, while astrocytes support neurons and regulate communication between brain cells.

Many of the affected genes are responsible for breaking down waste, including amyloid itself. Although these genes were still active, their timing was misaligned, reducing their effectiveness and allowing amyloid to build up more easily.

New Gene Rhythms Linked to Inflammation

The study also revealed that amyloid triggered abnormal rhythmic activity in hundreds of genes that do not typically follow a circadian pattern. Many of these genes are associated with inflammation, stress responses, and tissue imbalance—processes commonly seen in Alzheimer’s disease.

This combination of lost healthy rhythms and newly activated harmful ones may contribute to ongoing brain damage over time.

A New Direction for Alzheimer’s Treatment

Taken together, the findings suggest that strengthening or correcting circadian rhythms in specific brain cells could help preserve brain function and reduce amyloid accumulation.

While more research is needed, scientists are optimistic that future treatments could focus on adjusting the brain’s internal clock—either enhancing, dampening, or fine-tuning it in targeted cell types. Such approaches may one day help delay or prevent key features of Alzheimer’s disease.

Final Thoughts

This research highlights the importance of biological timing in brain health and disease. By understanding how Alzheimer’s disrupts the brain’s internal clock, scientists may uncover innovative ways to slow cognitive decline and improve quality of life for patients and caregivers alike.