Exploring the Role of Sleep in Preventing Alzheimer's Disease

In a recent discourse at the 2025 SLEEP Annual Meeting in Seattle, Andrew Varga, MD, PhD, a prominent neuroscientist affiliated with Mount Sinai, presented compelling insights into the controversial topic of whether sleep-dependent brain cleansing plays a pivotal role in preventing Alzheimer’s disease (AD). The session, held from June 8-11, featured a debate with fellow clinician Jeffrey Iliff, PhD, who together examined the intricate relationship between sleep, brain clearance, and neurodegenerative diseases.

The term 'brain cleansing' refers to the brain's natural process of removing metabolic waste and neurotoxic proteins during sleep, primarily facilitated by the glymphatic system. This system utilizes cerebrospinal fluid to flush out harmful substances like beta-amyloid and tau proteins, which are associated with Alzheimer’s and other neurodegenerative conditions. Varga emphasized the historical consensus that sleep is critical for this clearance, positing that disruptions in sleep could lead to an accumulation of these toxic proteins, thereby increasing Alzheimer’s risk.

However, emerging evidence has sparked debate regarding whether wakefulness might actually enhance brain cleansing more so than sleep. Notably, a paper published by researchers at Stanford University in 2024 suggested that the brain's clearance mechanisms may be more active during periods of wakefulness, challenging the long-held belief that sleep is the primary phase for such processes. This shift in understanding has significant implications for how clinicians might approach the prevention and treatment of Alzheimer’s disease.

During his presentation, Dr. Varga discussed the challenges of measuring brain clearance in humans compared to animal models, where researchers can directly observe these processes. In humans, techniques such as lumbar punctures are invasive and not widely used in clinical practice, which complicates the assessment of glymphatic function. Nevertheless, Varga highlighted the potential of developing non-invasive markers that could revolutionize how clinicians monitor brain health and Alzheimer’s risk.

Varga also touched upon emerging therapeutic strategies aimed at enhancing glymphatic function. These include pharmacological interventions that promote slow-wave sleep, which is believed to be crucial for effective brain cleansing. Certain medications, particularly dual orexin receptor antagonists (DORAs), are already showing promise in improving sleep quality and potentially offering neuroprotective effects against Alzheimer’s.

In addition to pharmacological approaches, technological innovations such as transcranial magnetic stimulation and closed-loop acoustic stimulation are being explored to enhance sleep architecture. Other novel interventions include devices aimed at regulating body temperature during sleep, which may alter sleep dynamics in beneficial ways.

Despite the advancements, significant questions remain unanswered regarding the glymphatic system and its relationship to Alzheimer’s disease. Varga pointed out the importance of further research to elucidate the precise mechanisms linking sleep disruption to Alzheimer’s progression. Among the theories under consideration is the role of neural activity during sleep, particularly in regions associated with wakefulness, which may influence tau protein production. Additionally, the relationship between sleep disruption, inflammation, and immune function is another area ripe for exploration.

The implications of these findings are profound, as they challenge existing paradigms and open new avenues for research and therapeutic intervention. The ongoing discourse within the scientific community reflects a growing recognition of the complex interplay between sleep, brain health, and neurodegenerative disorders. As research continues to evolve, the hope is to develop targeted strategies that could mitigate Alzheimer’s risk and improve overall cognitive health through better sleep management.

In conclusion, as Dr. Varga noted, enhancing understanding of the glymphatic system and its function during different states of wakefulness and sleep will be crucial in addressing Alzheimer’s disease. The quest for effective interventions continues, underscoring the critical need for collaboration across various disciplines in neuroscience, psychology, and medicine to tackle this pressing public health issue.