Targeting sleep physiology to modulate glymphatic brain clearance

Sleep has been postulated to play an important role in the removal of potentially neurotoxic molecules, such as amyloid-β, from the brain via the glymphatic system. Disturbed sleep, on the other hand, may contribute to accumulation of neurotoxins in brain tissue, ultimately leading to neuronal death. A bidirectional relationship has been proposed between impaired sleep and neurodegenerative processes, which start years before the onset of clinical symptoms associated with conditions like Alzheimer’s and Parkinson’s disease. Given their heavy burden on society, it is imperative to develop interventions that promote efficient brain clearance and thereby could aid in preventing or slowing down neurodegeneration.In this review, we explore whether the metabolic clearance function of sleep can be enhanced through sensory (e.g., auditory, vestibular) or transcranial (e.g., magnetic, ultrasound, infra-red light) stimulation, as well as pharmacological (e.g., antiepileptics) and behavioral (e.g., sleeping position, physical exercise, cognitive intervention) modulation of sleep physiology. A particular focus will be placed on strategies to enhance slow-wave activity during non-rapid eye movement sleep as a driver of glymphatic brain clearance. Overall, the review provides a comprehensive overview on the potential preventative and therapeutic applications of sleep interventions in combating neurodegeneration, cognitive decline, and dementia.