Scientists at the University of Kentucky have uncovered a new reason why people with Alzheimer's disease often struggle with sleep, long before memory loss begins. The study, led by researchers at the Sanders-Brown Center on Aging, reveals that a protein called tau "hijacks" the brain's energy supply, keeping the brain in a state of overactive excitability that prevents restorative rest.
The research, published in NPJ Dementia, found that tau pathology - protein tangles that disrupt cell communication in the brains of people affected by Alzheimer's - radically changes how the brain uses glucose. Instead of using sugar to create traditional energy, the brain redirects it to produce glutamate, a signaling molecule that stimulates brain activity.
"It's like a petulant toddler who just won't calm down and go to sleep," said Shannon Macauley, Ph.D., an associate professor of physiology and principal investigator on the research study. "The brain is hijacking all your glucose to make glutamate over and over again, keeping the system awake and preventing it from reaching the deep, restorative stages of sleep necessary for recovery and memory formation."
For the thousands of Kentucky families affected by dementia, sleep disruption is often one of the most challenging symptoms. Sleep loss frequently appears decades before a formal diagnosis, causing significant distress for patients and a burden on caregivers.
Macauley explained that the discovery offers a "canary in the coal mine," providing a potential new biomarker to identify Alzheimer's earlier in Kentucky's aging population.
"This project was experimentally complex, and was driven by Riley E. Irmen, who's just a superstar in the lab," said Macauley. Irmen, a graduate student in Macauley's laboratory, served as the paper's first author.
"This work really began around four years ago when I joined Dr. Macauley's lab," said Irmen. "As the project evolved and we began to dig deeper into the mechanisms, we expanded the scope of work by implementing new techniques and building collaborations across the University of Kentucky and Washington University in St. Louis."
Macauley's earlier research laid the groundwork for this discovery by identifying Alzheimer's disease as a state of bioenergetic collapse or energetic failure. Previous work focused on ATP-sensitive potassium (KATP) channels, which act as specialized metabolic sensors that link blood sugar levels directly to brain activity. These sensors were found to be essential for the way fluctuations in glucose drive the buildup of amyloid-beta plaques and disrupt sleep-wake cycles.
This cyclical metabolic process creates a loop: the disease causes sleep disruption, and the sleep disruption worsens the disease.
While previous studies explored how the brain senses and reacts to energy, this new study reveals that the tau protein goes a step further by essentially going rogue with the brain's fuel supply, redirecting it away from traditional energy production and toward a state of constant overdrive. This disruption creates a profound imbalance between stimulatory and calming signals in the brain.
This distinction is critical for Kentuckians living with dementia because it suggests the brain's engine is not necessarily broken but rather misusing its fuel.
"What's really exciting is that it seems some of these phenotypes are reversible," said Macauley. "That means you don't have to grow back neurons or get rid of all the plaques and tangles in your brain to rescue sleep."
Because the researchers identified the specific path the energy takes, they believe existing drugs - such as those used for epilepsy or diabetes - could potentially be used to restore harmony to the brain's metabolism. The hope is that these interventions could reverse sleep-disrupting symptoms and improve quality of life today, even as researchers continue to work toward a long-term cure.
In the meantime, the team encourages actively creating all the right elements for regular, consolidated sleep during nighttime hours to slow the progression of the Alzheimer's and prevent caregiver burnout.
"Until there are more disease-modifying treatments, it is critical to highlight factors, like sleep, that individuals can modify to reduce vulnerability," said Irmen. "Connecting these basic science findings to meaningful public impact is especially important for the community."
The goal now is to take these findings and build upon them.
"Maybe there are ways we can ease symptoms associated with Alzheimer's disease and dementia without having a complete cure," said Macauley. "We're going to get there, but short term, I'll take this as a win."
In addition to Mcauley and Irmen, the paper was co-authored by Macauley Irmen, Sierra M. Turner, J. Andy Snipes, Holden C. Williams, Gopal V. Velmurugan, Jerry B. Hunt Jr., Junyan Li, Patrick G. Sullivan, Daniel C. Lee and Lance A. Johnson at the University of Kentucky and Kaelyn H. Schloss, Xiaodan Wang and Adam Q. Bauer from Washington University in St. Louis.
Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers R01AG068330, R01AG093847, R01AG060056, R01AG062550, R01AG080589 and P30AG072946 and by the National Institute of General Medical Sciences of the National Institutes of Health under Award Numbers P30GM127211 and P20GM148326. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
This work was supported by a $250,000 award from The CART Fund (Coins for Alzheimer's Research Trust).
This work was supported by award numbers ABA-22-972169 and ABA-22-972169-Invite from the Alzheimer's Association.
