Alzheimer's disease is linked in part to the buildup of harmful proteins in the brain, including amyloid and tau. Most current treatments aim to remove these proteins directly. This study explores a different approach: helping the brain clear waste more effectively during sleep. The investigators will test whether certain medications can safely boost the brain's natural "cleaning system," known as the glymphatic system, in healthy older adults. Participants will receive controlled sleep treatments and blood tests to measure protein clearance. If successful, this strategy could support new therapies that work alongside existing Alzheimer's treatments.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
31
Stanford University Medical Center
Stanford, California, United States
Washington State University
Spokane, Washington, United States
Mean change from baseline in plasma Aβ42/Aβ40 ratio following dexmedetomidine treatment
Measured with mass spectrometry
Time frame: Pre/post 4-hour sleep period
Mean change from baseline in plasma Aβ42/Aβ40 ratio following dexmedetomidine and midodrine treatment
Measured with mass spectrometry
Time frame: Pre/post 4-hour sleep period
Mean change from baseline in plasma %p-tau217 following dexmedetomidine treatment
Measured with mass spectroscopy
Time frame: Pre/post 4-hour sleep period
Mean change from baseline in plasma %p-tau217 following dexmedetomidine and midodrine treatment
Measured with mass spectroscopy
Time frame: Pre/post 4-hour sleep period
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