Summary: Alzheimer’s disease does more than impair memory — it disturbs the brain’s internal clock, altering the daily rhythms of hundreds of genes that support brain health. In mouse models with amyloid accumulation, researchers found that normal circadian gene activity in microglia and astrocytes — the brain’s immune and support cells — becomes irregular, affecting processes such as waste clearance and inflammation.
These circadian changes may accelerate neurodegeneration. By mapping how Alzheimer’s pathology rewires daily gene cycles, scientists aim to develop therapies that restore healthy rhythms and slow disease progression.
Key Facts
- Circadian disruption: Amyloid accumulation in Alzheimer’s alters normal day–night gene cycles in microglia and astrocytes.
- Gene reprogramming: Roughly half of the genes linked to Alzheimer’s risk show circadian control, and many of these rhythms are disturbed in disease models.
- Therapeutic potential: Strengthening or correcting circadian rhythms could improve amyloid clearance and reduce inflammatory responses.
Source: WUSTL
Alzheimer’s disease is well known for disturbing daily routines. Early on, patients often experience fragmented sleep and daytime drowsiness; in later stages, sundowning — increased confusion in the late afternoon and evening — is common. These symptoms point to a link between disease progression and the circadian system, the internal clock that governs sleep–wake cycles and daily patterns of gene activity.
Until now, the precise nature of that link was unclear. Researchers at Washington University School of Medicine in St. Louis analyzed circadian gene expression in specific brain cell types and discovered that Alzheimer’s-related amyloid pathology markedly disrupts the timing of gene activity in glial cells. Their study, published October 23 in Nature Neuroscience, suggests that interventions targeting these clock disruptions could offer a new approach to treatment.
“There are 82 genes associated with Alzheimer’s risk, and we found that circadian rhythms regulate about half of them,” said Erik S. Musiek, MD, PhD, the Charlotte & Paul Hagemann Professor of Neurology at WashU Medicine and lead author of the study. In mouse models of Alzheimer’s, the normal daily activity patterns of those genes were altered, indicating disease-driven reprogramming of circadian control.
Musiek, co-director of the Center on Biological Rhythms and Sleep (COBRAS) and a neurologist who treats dementia, noted that caregivers frequently report changes in sleep long before memory decline appears. Those sleep disruptions not only burden caregivers and patients, they also produce biological and psychological stressors that can accelerate disease progression.
Amyloid disrupts rhythmic brain functions
To explore how amyloid affects circadian regulation, the team compared gene expression across the day in three groups of mice: those that model early amyloid accumulation, healthy young mice, and aged mice without amyloid deposits. They collected brain tissue every two hours over a 24-hour period and profiled which genes were active at different times.
Their analysis showed that amyloid accumulation disturbed the daily rhythms of hundreds of genes specifically in microglia and astrocytes, producing changes distinct from aging alone. Microglia are the brain’s immune cells responsible for clearing debris, while astrocytes support neurons and help regulate neural communication. Many of the disrupted genes are involved in waste processing, immune signaling and responses necessary for clearing amyloid.
Rather than switching genes off entirely, amyloid-induced circadian disruption scrambled the timing and coordination of gene activity. This loss of temporal order could reduce the effectiveness of synchronized processes, such as phagocytosis of amyloid by microglia. In addition, amyloid pathology gave rise to new daily rhythms in hundreds of genes that are not normally circadian, many of which relate to inflammatory responses.
Taken together, these findings point to therapeutic strategies that target glial circadian cycles. “We need to understand whether manipulating the clock — strengthening it, dampening it, or selectively altering it in certain cell types — can support brain function,” Musiek said. “Ultimately, the goal is to optimize circadian regulation to prevent amyloid buildup and mitigate other harmful processes in Alzheimer’s disease.”
Reference: Sheehan PW, Fass S, Sapkota D, Kang S, Hollis HC, Lawrence JH, Anafi RC, Dougherty JD, Fryer JD, Musiek ES. A glial circadian gene expression atlas 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 research was supported 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 authors’ responsibility and does not necessarily reflect the official views of the NIH.
Key Questions Answered:
A: It disrupts the rhythmic expression of hundreds of genes in glial cells, altering the timing of essential brain functions including immune responses and waste clearance.
A: Microglia and astrocytes show the most pronounced changes, with altered daily gene activity that can impact their roles in inflammation control and neuronal support.
A: Restoring or reinforcing the brain’s internal clock could improve the timing of gene networks responsible for amyloid removal and inflammatory balance, potentially slowing disease progression.
About this research on Alzheimer’s, genetics, and circadian rhythm
Author: Abeeha Shamshad
Source: WUSTL
Contact: Abeeha Shamshad – WUSTL
Image: Image 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
A glial circadian gene expression atlas reveals cell type and disease-specific reprogramming in response to amyloid pathology or aging
Circadian rhythm disruption may promote neurodegeneration, but how aging and disease pathology reshape circadian gene patterns across brain cell types has been unclear. Using translating ribosome affinity purification, the study profiled circadian translatomes of astrocytes, microglia and bulk cortex in healthy mice and in models of amyloid-β plaque pathology or aging.
The authors report that glial circadian translatomes are highly cell-type-specific and undergo profound, context-dependent reprogramming in response to amyloid pathology or aging. Transcripts tied to glial reactivity, immunometabolism and proteostasis — and nearly half of known Alzheimer’s risk genes — showed circadian oscillations, many of which were altered by pathology. Microglial oxidative stress and amyloid phagocytosis displayed time-of-day variation in gene expression and function. These results show that circadian gene rhythms are both cell- and context-dependent, offering insight into glial roles in health, aging and Alzheimer’s disease.