Over 5 million Americans currently suffer from Alzheimer Disease (AD), a number predicted to increase as the population ages. Sleep disturbances are associated with brain changes of AD, even before cognitive problems. In mouse models, sleep deprivation leads to acceleration of amyloid plaque deposition, a key pathological feature of AD. The proposed project will translate this finding to humans. The overarching hypothesis for this human study is that sleep disturbance leads to decreased deep sleep or slow wave sleep (SWS), leading to relatively increased neuronal synaptic activity, leading to relatively increased monomeric amyloid-beta (A beta) release into the interstitial space, leading to chronically elevated A beta levels, leading to increased risk of aggregation of A beta into amyloid plaques, and eventually leading to increased risk of symptomatic AD. This project will test the first portion of this hypothetical cascade by examining the relationship of SWS and A beta levels using two different models: 1) An experimental model in which SWS is disrupted in normal individuals and, 2) a clinical model in which people with obstructive sleep apnea, a common sleep disorder that disrupts sleep, will have SWS and A beta levels tested before and after treatment. The long-term objective of this line of research is to determine whether sleep can be modified or improved with the goal of reducing risk of AD. The research team for this project combines expertise in sleep medicine, AD, and electrophysiology. In addition to training in the techniques and novel protocols proposed for the research experiments, the Principal Investigator will obtain formal didactic education in signal processing over the course of the award. A Safety Advisory Panel will supervise the proposed study to ensure it is completed in a safe and ethical manner, and will buttress ongoing education in the responsible conduct of research. The multidisciplinary team of world-class mentors and collaborators, and the extensive intellectual and physical resources available at Washington University, will optimize the training experience and the likelihood for successful transition to independent research. The technical, research, and career skills obtained during this award will facilitate the Principal Investigator in launching a successful career as a physician-scientist investigating the intersection of sleep and neurodegenerative diseases.

Public Health Relevance

Sleep disturbances are associated with Alzheimer Disease, the most common cause of dementia and a major public health problem. This project will investigate the relationship between deep sleep (slow wave sleep) and amyloid-beta, a substance important in the brain changes of Alzheimer Disease. If this study is successful, modulating sleep may become a prime target for attempting to delay or prevent Alzheimer Disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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NST-2 Subcommittee (NST)
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Corriveau, Roderick A
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Washington University
Schools of Medicine
Saint Louis
United States
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Musiek, Erik S; Bhimasani, Meghana; Zangrilli, Margaret A et al. (2018) Circadian Rest-Activity Pattern Changes in Aging and Preclinical Alzheimer Disease. JAMA Neurol 75:582-590
Ju, Yo-El S; Ooms, Sharon J; Sutphen, Courtney et al. (2017) Slow wave sleep disruption increases cerebrospinal fluid amyloid-? levels. Brain 140:2104-2111
Molano, Jennifer R V; Roe, Catherine M; Ju, Yo-El S (2017) The interaction of sleep and amyloid deposition on cognitive performance. J Sleep Res 26:288-292
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Ju, Yo-El S; Finn, Mary Beth; Sutphen, Courtney L et al. (2016) Obstructive sleep apnea decreases central nervous system-derived proteins in the cerebrospinal fluid. Ann Neurol 80:154-9
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