Pharmacological enhancement of glymphatic function in humans increases the clearance of Alzheimer’s disease-related proteins

ABSTRACT Alzheimer’s disease (AD) is characterized by the mis-aggregation of amyloid β (Aβ) and tau, which is proposed to be driven by impaired Aβ and tau clearance. While sleep-active glymphatic transport contributes to the clearance of Aβ and tau in humans, studies have yet to demonstrate that it is possible to enhance glymphatic transport in humans and that augmenting glymphatic transport improves the clearance of Aβ and tau from the human brain. In two cross-over clinical trials in healthy older adults, we demonstrated that a fixed-dose combination therapy of intravenous dexmedetomidine (0.7 μg/kg/h) and 10 mg oral midodrine (ACX-02), that suppressed central noradrenergic tone while maintaining systemic arterial pressure, increased EEG slow waves, enhanced cerebrovascular pulsatility, and reduced parenchymal resistance to perivascular fluid flow, that have shown to be key determinants of glymphatic transport. Dynamic shifts in plasma mass balance indices of clearance within the brain demonstrated that pharmacological enhancement of glymphatic transport increased Aβ and tau clearance by approximately 9%–10% during a single 4h 15min sleep opportunity. Bayesian mediation analysis demonstrated that increasing EEG slow waves and declining parenchymal resistance were key mediators, and cerebrovascular compliance was a moderator, of the effect of ACX-02 on plasma AD biomarker dynamics. These findings demonstrate that pharmacologic enhancement of glymphatic transport increased brain-to-blood clearance of Aβ and tau in human participants. This suggests that enhancement of Aβ and tau clearance may serve as a complementary approach to existing disease-modifying therapies, and as a therapeutic approach in AD and AD-related proteinopathies.