# Effect of Suvorexant on Alzheimer's Disease Biomarkers

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $1,504,459

## Abstract

PROJECT SUMMARY
Sleep disturbances are increasingly recognized as a risk factor for Alzheimer’s disease (AD) and a marker for
Alzheimer’s disease pathology. The sleep-wake cycle affects the cerebrospinal fluid (CSF) concentrations of
proteins critical to Alzheimer’s disease pathogenesis. We recently reported that overnight sleep disruption
increases CSF amyloid-β (Aβ) levels by ~30% via increased production/release. Orexins (also called
hypocretins) are wake-promoting neuropeptides. Chronic administration of a dual orexin receptor antagonist
(DORA) to increase sleep in amyloid precursor protein (APP) transgenic mice decreased both the soluble
concentration of Aβ in interstitial fluid and amyloid plaque formation. Our preliminary data shows that a DORA,
suvorexant, acutely decreases the ratio of phosphorylated tau-181 (pT181) to unphosphorylated tau-181
(T181) in CSF. Although previous studies examined sleep-mediated changes in CSF Aβ and tau over hours, it
is unknown how chronic administration of DORAs affect plasma and CSF tau, phosphorylated tau (p-tau), Aβ,
and other Alzheimer’s disease fluid biomarkers in individuals with Alzheimer’s pathology. In this project, we will
test the hypothesis that chronic treatment with suvorexant for 6 months will decrease CSF pT181/T181 and
other CSF and plasma AD biomarkers. In this project, we will use an innovative adaptive trial design to test the
potential of chronic treatment with suvorexant for secondary prevention of Alzheimer’s disease. 200 cognitively
normal, amyloid-positive adults with symptomatic insomnia age ≥65 years will be randomized to receive
placebo or suvorexant for 6 months. Each participant will undergo polysomnography as well as lumbar and
venous puncture to sample CSF and blood at baseline, 3 months, and 6 months. We will test the hypothesis
that chronic treatment with suvorexant will decrease CSF pT181/T181 as well as determine the effect on CSF
plasma Aβ, CSF and plasma tau, other forms of CSF and plasma p-tau, and CSF markers for immune
response (microglial function), synaptic function, and non-tau measures of neuronal degeneration. Optimal trial
design is essential prior to launching a full secondary prevention trial with a maximum chance of success. This
study will provide critical information for designing Alzheimer’s disease secondary prevention trial using
suvorexant obtaining data on pharmacokinetics, safety, and chronic effects of suvorexant on multiple soluble
Alzheimer’s disease biomarkers.

## Key facts

- **NIH application ID:** 10819600
- **Project number:** 5R01AG080551-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Brendan Patrick Lucey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,504,459
- **Award type:** 5
- **Project period:** 2023-04-15 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10819600

## Citation

> US National Institutes of Health, RePORTER application 10819600, Effect of Suvorexant on Alzheimer's Disease Biomarkers (5R01AG080551-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10819600. Licensed CC0.

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