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].
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Overview
Mermaid diagram (expand to render)
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:
Orexin and Amyloid Production: Orexin neuropeptides, produced in the lateral hypothalamus, promote wakefulness and have been shown to increase amyloid-beta production through gamma-secretase modulation[@kang2009]. Blocking orexin signaling may therefore reduce Aβ production.
Sleep and Glymphatic Clearance: During deep sleep, the glymphatic system becomes highly active, clearing metabolic waste products including amyloid-beta from the brain[@betaamyloid2023]. Sleep disruption impairs this clearance mechanism.
Tau Pathology: Sleep deprivation also accelerates tau protein pathology, another key driver of AD neurodegeneration[@feng2023].
Intervention
Drug: Suvorexant (Belsomra®) 20 mg taken nightly
Comparator: Placebo
Duration: 18–24 months of treatment
Suvorexant is a dual orexin receptor antagonist (DORA) that blocks both OX1R and OX2R, promoting sleep initiation and maintenance by inhibiting orexin-mediated arousal signaling[@orexin2022].
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 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
Unknown, Suvorexant for the Prevention of Alzheimer's Disease (SToP-AD) (n.d.)
Unknown, Washington University School of Medicine - SToP-AD Study (n.d.)
[Kang JE, Lim MM, Bateman RJ, et al, Orexin receptor antagonism reduces amyloid-beta production and improves sleep in mouse models of Alzheimer's disease (2009)](https://doi.org/10.1016/j.jneumeth.2009.08.001)
[Ohno Y, Shimizu S, Harada S, et al, Orexin and Alzheimer's disease: a potential therapeutic target (2020)](https://doi.org/10.1016/j.neurobiolaging.2020.03.015)
[Feng Y, Li L, Lin X, et al, Sleep disruption and tau pathology in Alzheimer's disease (2023)](https://doi.org/10.1093/brain/awac467)
[Nedergaard M, Goldman SA, Glymphatic failure and the sleep-dumped amyloid hypothesis of Alzheimer's disease (2023)](https://doi.org/10.1038/s41582-022-00635-8)
[Thompson MD, Xiong W, Ge P, et al, Orexin receptor antagonists for neuroprotection in neurodegenerative disease (2022)](https://doi.org/10.1016/j.jns.2021.119365)