SToP-AD: Suvorexant for Alzheimer's Disease Prevention

Overview

The Suvorexant Trial for the Prevention of Alzheimer's Disease (SToP-AD) is a Phase 2 randomized, double-blind, placebo-controlled clinical trial investigating whether suvorexant—a dual orexin receptor antagonist (DORA)—can slow the accumulation of amyloid-beta (Abeta) plaques in cognitively normal older adults at risk for Alzheimer's disease (AD)[@clinicaltrialsgov].

Overview

The Suvorexant Trial for the Prevention of Alzheimer's Disease (SToP-AD) is a Phase 2 randomized, double-blind, placebo-controlled clinical trial investigating whether suvorexant—a dual orexin receptor antagonist (DORA)—can slow the accumulation of amyloid-beta (Abeta) plaques in cognitively normal older adults at risk for Alzheimer's disease (AD)[@clinicaltrialsgov].

This trial represents a paradigm-shifting approach to AD prevention by targeting sleep disruption, a modifiable risk factor that has been increasingly linked to amyloid accumulation and subsequent neurodegeneration["@betaamyloid2023"]. By using suvorexant to improve sleep quality, researchers hypothesize that glymphatic clearance of toxic proteins may be enhanced, potentially reducing amyloid burden in the brain["@kang2009"].

Study Information

| Field | Details |
|-------|---------|
| ClinicalTrials.gov ID | NCT04629547 |
| Official Title | Suvorexant for the Prevention of Alzheimer's Disease (SToP-AD) |
| Phase | Phase 2 |
| Status | Recruiting |
| Enrollment | 200 participants (estimated) |
| Duration | 18–24 months |
| Sponsor | Washington University School of Medicine |
| Collaborators | Good Ventures, Merck Sharp & Dohme LLC |

Study Design and Methodology

Rationale

The scientific rationale for SToP-AD rests on several interconnected mechanisms:

Intervention

• Drug: Suvorexant (Belsomra®) 20 mg taken nightly
• Comparator: Placebo
• Duration: 18–24 months of treatment

Primary and Secondary Outcomes

Primary Outcome

| Outcome | Measure |
|---------|---------|
| Change in amyloid-β accumulation | Plasma pT217/T217 ratio |

The primary endpoint uses plasma phosphorylated tau 217 (p-tau217) as a biomarker of amyloid accumulation. This blood-based biomarker has shown high accuracy for detecting early amyloid changes in preclinical AD[@ohno2020].

Secondary Outcomes

• Change in plasma amyloid-beta (Aβ42/40 ratio)
• Change in CSF amyloid-beta, tau, and p-tau
• Change in cognitive performance measures
• Transcriptomic, metabolomic, and proteomic profiling
• Gut microbiome composition

Eligibility Criteria

Inclusion Criteria

• Age ≥65 years
• Clinical Dementia Rating (CDR) score of 0 (no dementia)
• Documented poor sleep quality or sleep disorder

Key Exclusion Criteria

• Restless legs syndrome
• Untreated sleep apnea
• Plasma p-tau217 ≤1.19 (low amyloid risk)
• History of stroke
• Chronic kidney disease
• Hepatic impairment
• HIV/AIDS
• Active substance abuse
• Current tobacco use
• Use of sedating medications
• Various other medical/psychiatric conditions

Study Locations

| Site | Contact |
|------|---------|
| Washington University School of Medicine, St. Louis, Missouri | Cristina Toedebusch (toedebuschc@wustl.edu, 314-747-0646) |

Scientific Significance

The SToP-AD trial addresses a critical gap in AD prevention research by testing a novel approach: improving sleep to reduce AD pathology. Unlike previous anti-amyloid therapies that target amyloid directly, this trial targets a modifiable lifestyle factor that influences amyloid metabolism.

Connection to Existing Knowledge

This trial builds upon preclinical findings that orexin receptor antagonism reduces amyloid production in animal models[@kang2009]. It also aligns with human observational data linking sleep disturbance to increased AD risk.

The trial leverages:

• [Orexin signaling mechanisms](/mechanisms/orexin-signaling-neurodegeneration)
• [Glymphatic system function](/entities/glymphatic-system)
• [Sleep-wake cycle regulation](/mechanisms/sleep-wake-cycle)
• [Amyloid-beta metabolism](/proteins/amyloid-beta)

Biomarker Innovation

The use of plasma pT217/T217 as the primary endpoint represents a significant advancement in AD clinical trials. This blood-based biomarker is less invasive than PET imaging and CSF collection, potentially enabling larger and more inclusive prevention trials.

Timeline and Anticipated Results

The trial is actively recruiting with an estimated completion date in the late 2020s. Results will inform whether:

• Orexin receptor antagonism can slow amyloid accumulation in humans
• Sleep improvement translates to disease-modifying effects in preclinical AD
• Blood-based biomarkers can serve as primary endpoints in prevention trials

Related Pages

• [Suvorexant for Neurodegeneration](/therapeutics/suvorexant)
• [Orexin Signaling in Neurodegeneration](/mechanisms/orexin-signaling-neurodegeneration)
• [Sleep Disruption and Neurodegeneration](/mechanisms/sleep-disruption-neurodegeneration)
• [Glymphatic System](/entities/glymphatic-system)
• [Clinical Trials in Alzheimer's Disease](/clinical-trials/alzheimers-disease)
• [Promising Clinical Trials in Neurodegeneration](/therapeutics/promising-clinical-trials-neurodegeneration)

References