Modifiable glymphatic-related brain clearance physiology in humans: a critical narrative review of interventional evidence

The glymphatic model proposes that cerebrospinal fluid exchanges with interstitial fluid along perivascular pathways, potentially facilitating brain solute clearance. Interest in whether this physiology can be modified has prompted human studies of sleep, exercise, respiratory manipulation, circadian interventions, and neuromodulation, but these studies use endpoints that differ substantially in biological directness. This critical narrative review evaluates human interventional and longitudinal evidence for modifiable glymphatic-related brain-clearance physiology and distinguishes altered neurofluid dynamics from evidence of solute transport. Sleep provides the most convincing convergent evidence: total sleep deprivation impairs intrathecal tracer clearance, whereas normal sleep increases the overnight appearance of amyloid-β and tau in plasma. Sustained aerobic exercise modifies contrast-based brain influx and meningeal lymphatic measures, although evidence remains preliminary. Slow deep breathing and intermittent hypercapnia alter cerebrospinal fluid dynamics; hypercapnia also increases several plasma brain-protein concentrations, but enhanced clearance is unconfirmed. Bright light therapy and transcranial magnetic stimulation modify diffusion-based perivascular imaging proxies that remain indirect and biologically nonspecific. Human neurofluid physiology may therefore be modifiable, but changes in fluid motion or surrogate imaging signals should not be equated with enhanced solute clearance. Clinically meaningful modulation will require controlled studies linking mechanistic target engagement to direct solute transport and neurological outcomes.