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.

Inclusion criteria

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

• 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.
• Participants may be men or women, age 55 - 65 years (inclusive). Enrollment will target equal number of men and women participants.
• 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.
• Participants must have a GDS-15 score of 4 or less.
• Participants must provide an address and phone number where they can be accessible to the Study team for follow up.
• 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:

• 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).
• Participants with a history of significant neurological disease or history of epilepsy.
• Participants with cardiovascular disease or hypertension.
• Participants with diabetes.
• Participants with traumatic brain injury, or serious mental illness including bipolar disorder, schizophrenia, major depressive disorder or post-traumatic stress disorder.
• Participants who have taken in the past 30 days prescribed or over-the-counter (OTC) stimulants, sleeping medications, or psychiatric medications including antidepressants.
• 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.
• 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.
• 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.
• 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.
• Participants who have a pre-planned surgery or medical procedure that would interfere with the conduct of the study.
• Participants with a serious infection requiring medical attention in the past 30 days.
• Any significant neurological impairment in the opinion of the Principal Investigator that would affect the GF Monitor data.
• Participants with a diagnosis of substance use-disorder in the past 2 years.
• Participants with urinary retention or requiring to void several times during the night