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 the accumulation of neurotoxins in brain tissue, eventually 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 the heavy burden these conditions place on society, it is imperative to develop interventions that promote efficient brain clearance, thereby potentially aiding in the prevention or slowing of 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 is placed on strategies to enhance slow-wave activity during non-rapid eye movement sleep as a driver of glymphatic brain clearance. Overall, this review provides a comprehensive overview on the potential preventative and therapeutic applications of sleep interventions in combating neurodegeneration, cognitive decline, and dementia.