R01AG080551

Effect of Suvorexant on Alzheimer's Disease Biomarkers - 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 approximately 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 (p-tau181) to unphosphorylated tau-181 (tau181) 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 p-tau181/tau181 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. Two hundred cognitively normal, amyloid-positive adults with symptomatic insomnia aged 65 years or older 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 p-tau181/tau181, 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.

Washington University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Missouri United States

State-Wide

Early and Late Stage Clinical Trials for the Spectrum of Alzheimers Disease/Alzheimers Related Dementias and Age-Related Cognitive Decline (R01 Clinical Trial Optional) (PAR-21-359)

Amendment Since initial award the End Date has been extended from 03/31/28 to 03/31/29 and the total obligations have increased 94% from $1,595,468 to $3,099,927.