Pharmacological Enhancement of Glymphatic Function in Humans

The Effect of Dexmedetomidine on Glymphatic Function in the Human Brain

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.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Other: Placebo; Drug: Dexmedetomidine; Drug: Dexmedetomidine and Midodrine

Detailed Description

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
• Enrollment (Actual): 31
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University Medical Center
  • Washington
    • Spokane, Washington, United States, 99164
      • Washington State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Potential participants must satisfy the following criteria to be enrolled in the study:

1. In the opinion of the Principal Investigator, participants must be fluent in English and be able to understand the informed consent form approved by the Institutional Review Board (IRB). All participants must sign the study informed consent document indicating that they understand the purpose of procedures required for the study and are willing to participate in the study prior to any study procedures being performed.
2. Participants may be men or women, age 55 - 65 years (inclusive). Enrollment will target equal number of men and women participants.
3. Participants must have a MoCA score at least 26 for in-person assessment or 19 for over-the-phone assessment, unless waived by decision of the PI.
4. Participants must have a GDS-15 score of 4 or less.
5. Participants must provide an address and phone number where they can be accessible to the Study team for follow up.
6. Participants must agree to wear the GF Monitor per the Study Phase under baseline and dexmedetomidine infusion and be willing to complete all other aspects of the protocol.

Exclusion Criteria:

• Potential participants who meet any of the following criteria will be excluded from participating in the study:

  1. Participants with a formal diagnosis of any sleep disorder (e.g., sleep apnea on PAP therapy, insomnia, restless leg syndrome, circadian rhythm sleep disorder, parasomnia).
  2. Participants with a history of significant neurological disease or history of epilepsy.
  3. Participants with cardiovascular disease or hypertension.
  4. Participants with diabetes.
  5. Participants with traumatic brain injury, or serious mental illness including bipolar disorder, schizophrenia, major depressive disorder or post-traumatic stress disorder.
  6. Participants who have taken in the past 30 days prescribed or over-the-counter (OTC) stimulants, sleeping medications, or psychiatric medications including antidepressants.
  7. Participants who consume more than 400 mg/day of caffeine. Participants will be required to not consume caffeine on the day-of the sleep study.
  8. Female Participants who consume more than 3 alcoholic drinks on any day or more than 7 drinks per week. Male participants who consume more than 4 alcoholic drinks on any day or more than 14 drinks per week.
  9. Participants who are enrolled in other research studies and are receiving an investigational drug within 30 days of the planned start date for visit 1.
  10. Participants who have any condition that, in the opinion of the Principal Investigator, would compromise the well-being of the participant or the study or prevent the participant from meeting or performing study requirements.
  11. Participants who have a pre-planned surgery or medical procedure that would interfere with the conduct of the study.
  12. Participants with a serious infection requiring medical attention in the past 30 days.
  13. Any significant neurological impairment in the opinion of the Principal Investigator that would affect the GF Monitor data.
  14. Participants with a diagnosis of substance use-disorder in the past 2 years.
  15. Participants with urinary retention or requiring to void several times during the night

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Dexmedetomidine Cross-Over Placebo	Other: Placebo; Placebo
Active Comparator: Dexmedetomidine Cross-Over Treatment	Drug: Dexmedetomidine; Treatment
Active Comparator: Dexmedetomidine & Midodrine Cross-Over Treatment	Drug: Dexmedetomidine and Midodrine; Treatment
Placebo Comparator: Dexmedetomidine & Midodrine Cross-Over Placebo	Other: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean change from baseline in plasma Aβ42/Aβ40 ratio following dexmedetomidine treatment	Measured with mass spectrometry	Pre/post 4-hour sleep period
Mean change from baseline in plasma Aβ42/Aβ40 ratio following dexmedetomidine and midodrine treatment	Measured with mass spectrometry	Pre/post 4-hour sleep period
Mean change from baseline in plasma %p-tau217 following dexmedetomidine treatment	Measured with mass spectroscopy	Pre/post 4-hour sleep period
Mean change from baseline in plasma %p-tau217 following dexmedetomidine and midodrine treatment	Measured with mass spectroscopy	Pre/post 4-hour sleep period

Collaborators and Investigators

• Sponsor: Applied Cognition
• Collaborators: Washington State University; Stanford University
• Investigators: Study Director: Paul Dagum, MD PhD, Applied Cognition; Principal Investigator: Albert Cheung, MD, Stanford Hospital; Principal Investigator: Brieann C Satterfield, PhD, Washington State University

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2023
• Primary Completion (Actual): September 13, 2024
• Study Completion (Actual): September 13, 2024

Study Registration Dates

• First Submitted: February 15, 2026
• First Submitted That Met QC Criteria: February 19, 2026
• First Posted (Actual): February 25, 2026

Study Record Updates

• Last Update Posted (Actual): February 25, 2026
• Last Update Submitted That Met QC Criteria: February 19, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: drug; clearance; increase; glymphatic
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Imidazoles; Amines; Alcohols; Amino Alcohols; Ethanolamines; Dexmedetomidine; Midodrine
• Other Study ID Numbers: AC.2023.01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No