Does Disrupting the Brain’s Clock Influence Alzheimer’s?

Jet lag is a drag for any traveler to be sure, but could it also play a role in Alzheimer’s disease? A BrightFocus Alzheimer’s Disease Research-funded study aims to answer that question by investigating how chronic jet lag-induced circadian rhythm disruptions affect Alzheimer’s progression.

Jet lag can throw off your circadian rhythm—the bodily processes that recur on a 24-hour cycle, regulated by a “clock” in a region of the brain—especially when it happens frequently. Led by BrightFocus Alzheimer’s Disease Research grant recipient Ashish Sharma, PhD, a postdoctoral fellow at Washington University in St. Louis, this project will examine how chronic jet lag affects amyloid-beta and tau levels in the brain.

Dr. Sharma’s goal is for his findings to inspire new strategies for treatment and prevention. “On the treatment side, our work aims to uncover the molecular mechanisms linking circadian rhythm disruption to Alzheimer’s,” he said. By identifying the key players in this process, he hopes to discover molecular targets for new therapies.

“Studying subtle changes in circadian rhythms alongside sleep irregularities may improve the accuracy of identifying individuals at risk,” he added. “This approach could help identify those who should undergo further biomarker testing, allowing for earlier diagnosis and more effective interventions.”

Inspiration From Family and Work

Jet lag, which affects people who travel across several time zones, occurs when the body stays synced to a traveler’s original time zone, causing symptoms like daytime fatigue and disrupted sleep. About 45% of people with Alzheimer’s report problems sleeping, and amyloid plaques and tau tangles have been linked to this disrupted sleep.

Shift work—referring to a non-traditional work schedule often taking place overnight—can also mess with your circadian rhythm over time. While working an early job as a shift worker, Dr. Sharma became keenly interested in bad sleep and brain health. “Experiencing the effects of circadian misalignment firsthand sparked my curiosity about how biological processes follow rhythmic patterns and what happens when those rhythms are disrupted,” he said.

As he continued his studies, Dr. Sharma came across research linking circadian rhythm disruptions and Alzheimer’s led by Erik Musiek, MD, PhD, professor of neurology, Washington University School of Medicine. Dr. Musiek established the foundation link between circadian rhythm disruptions and Alzheimer’s disease. “That discovery piqued my interest for this field, driving me to explore how disruptions in our internal clocks might contribute to neurodegeneration,” he said. Dr. Musiek is now Dr. Sharma’s mentor.

Dr. Sharma also found inspiration to improve the treatment and prevention of Alzheimer’s from his family’s experience with the disease. “I watched a family member slowly fade—first losing memories, then words, until even their ability to communicate was gone.”

“That experience left a lasting imprint on me,” he said. “My goal is to uncover the mechanisms behind the disease so we can develop interventions that not only preserve memory but also protect the quality of life of those affected.”

Focusing on the Brain’s Waste-Disposal System

For the study, Dr. Sharma is using multiple mouse models of Alzheimer’s disease and subjecting them to jet lag, applying advanced technologies that allow him to precisely track and analyze changes in the brain, including amyloid and tau pathology.

Dr. Sharma is focusing on immune cells in the brain called microglia, which maintain brain health by clearing waste and regulating inflammation. To determine the role of microglia in circadian rhythm disruption, his team is depleting the cells from the research models.

“This all-or-nothing approach allows us to assess [microglia’s] overall contribution before moving to more precise techniques,” Sharma explained. “If we find a strong connection, we can then target specific microglial populations to better understand their role in circadian disruptions and Alzheimer’s disease.”

Dr. Sharma’s goal is to uncover a microglial signature that could inspire the development of targeted therapies to slow the progression of Alzheimer’s.

Future Directions

Dr. Sharma’s research reflects BrightFocus Foundation’s 360-degree approach to funding Alzheimer’s research. This strategy involves investing in a wide range of innovative science aimed at uncovering new pathways to preventing, treating and ultimately curing Alzheimer’s.

Investigating the role of sleep and circadian rhythm disruption in disease progression is critical to this approach because research has shown that nightly sleep is critical to the brain’s ability to flush the brain of toxins, including the amyloid that’s present in the early stages of the disease.

In the future, Dr. Sharma hopes to extend his research beyond microglia and identify other key cell types involved in Alzheimer’s disease. “By mapping these cellular changes, we can gain a more comprehensive understanding of how circadian disruption contributes to neurodegeneration,” he said.

“If successful, these insights could translate into clinical applications—whether through biomarker development for early detection or identifying therapeutic targets to slow disease progression.”

Dr. Sharma describes the support from BrightFocus Foundation’s Alzheimer’s Disease Research program as pivotal in advancing his team’s understanding of the disease. “In my own work, this support has been invaluable,” he said. “By investing in fundamental research like ours, BrightFocus is not only accelerating scientific breakthroughs but also paving the way for future treatments that could transform patient outcomes.”