The relationship between sleep architecture and brain waste clearance has become one of the most consequential frontiers in dementia prevention. If a single approved medication could both restore normal sleep and simultaneously reduce the accumulation of the proteins that define Alzheimer's and Parkinson's disease, it would fundamentally reframe how clinicians approach both sleep disorders and neurodegeneration in aging populations.
This narrative review in Current Neuropharmacology synthesizes preclinical and early clinical evidence around suvorexant, an FDA-approved dual orexin receptor antagonist (blocking OX1R and OX2R), examining its potential to interrupt the chain of pathological events that links chronic sleep loss to neurodegeneration. The mechanistic argument centers on the glymphatic system — the brain's overnight waste-clearance network — which operates predominantly during slow-wave sleep. Cumulative sleep deprivation impairs glymphatic flow, allowing amyloid-β to accumulate and tau hyperphosphorylation to proceed unchecked. Preclinical models cited in the review show suvorexant normalizing sleep architecture, which correlates with measurable reductions in amyloid plaque burden and tau phosphorylation, two hallmark pathologies of Alzheimer's disease. The review also extends the argument to Parkinson's disease and broader tauopathies, where disrupted orexin signaling has been documented independently.
Several important caveats constrain enthusiasm. This is a narrative review — not a meta-analysis or clinical trial — meaning selection bias in the literature surveyed cannot be ruled out. The bulk of mechanistic evidence remains preclinical, with robust human randomized-controlled trial data still sparse. Suvorexant's favorable side-effect profile compared to benzodiazepines or z-drugs is well established, but whether that tolerability advantage translates into long-term neuroprotection in humans remains an open question. The orexin system also plays roles in metabolism, cardiovascular tone, and mood regulation, meaning chronic antagonism carries systemic implications not yet fully characterized. For now, this review is best read as a sophisticated mechanistic hypothesis — incremental but intellectually coherent — that positions suvorexant as a candidate warranting properly powered longitudinal trials in at-risk populations.
