Pharmacological Enhancement of Glymphatic Function in Humans

Alzheimer's disease (AD) is driven in part by impaired clearance of aggregation-prone proteins, including amyloid-β (Aβ) and tau. Although current disease-modifying therapies primarily target direct protein sequestration, restoration of endogenous waste clearance represents a complementary and underexplored therapeutic strategy. Investigators propose a prospective, interventional study to evaluate whether pharmacologic modulation of sleep-associated glymphatic function enhances clearance of AD-relevant proteins in humans. In this crossover study, healthy older adults will undergo controlled sleep interventions and receive either a single-agent therapy that suppresses central noradrenergic tone or a fixed-dose combination therapy designed to suppress central noradrenergic tone while stabilizing systemic vascular dynamics. The primary endpoint will be the change in plasma mass-balance indices of Aβ and tau clearance during a standardized overnight intervention. Investigators hypothesize that coordinated modulation of central noradrenergic signaling and vascular stability will enhance sleep-associated, glymphatic-linked clearance of amyloid and tau. If confirmed, these findings would establish glymphatic modulation as a tractable and druggable systems pathway in humans and support further evaluation of clearance-augmenting strategies as complementary approaches to existing disease-modifying therapies for Alzheimer's disease and related proteinopathies.