Alzheimer's disease (AD) is a growing public health crisis that has no highly effective treatment. Over 5 million Americans currently suffer from AD and this number is expected to increase to 13.5 million by 2050. Even a modest reduction in the risk of AD would impact public health tremendously: delaying the onset of AD by 5 years is predicted to halve the prevalence of the disease. The aggregation of the protein amyloid-? (A?) into extracellular plaques in the brain is a key step in the development of AD pathology and is hypothesized to begin before significant cell and synaptic loss lead to cognitive impairment and dementia. Changes in A? production by 25-40% have been shown to completely protect or cause AD in humans. Recent research has shown that A? levels fluctuate with the sleep-wake cycle in both animal models and humans: A? levels are higher in the fluid around the brain during wakefulness and lower during sleep, i.e. a diurnal A? pattern. In animal models of transgenic mice that develop amyloid deposition, sleep deprivation increased both A? concentrations and plaques in the brain while enhancing sleep with medication reduced both A? concentrations and plaques. These findings have not been translated to humans, leaving a critical gap in our ability to pursue sleep modulation as a preventive strategy for AD. This proof-of-concept study proposes to directly assess in humans if A? levels can be increased by sleep deprivation and decreased by sleep enhancement with medication. Healthy, cognitively normal individuals aged 45-60 years recruited from a longitudinal cohort studying familial AD will have baseline home sleep measured followed by sleep deprivation, sleep enhancement with a medication, or control (i.e. adhere to baseline home sleep schedule). During sleep modification, blood and cerebrospinal fluid will be collected to quantify A? levels as well as kinetics (i.e. production and clearance) using stable isotope labeled amino acids. The proposed study not only will increase our understanding of the pathogenesis of AD, it may suggest innovative AD prevention and treatment approaches that involve sleep therapies and may launch a novel field of research that identifies new targets for AD treatment.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Small Research Grants (R03)
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Special Emphasis Panel (ZAG1)
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Mackiewicz, Miroslaw
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Washington University
Schools of Medicine
Saint Louis
United States
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Lucey, Brendan P; Hicks, Terry J; McLeland, Jennifer S et al. (2018) Effect of sleep on overnight cerebrospinal fluid amyloid ? kinetics. Ann Neurol 83:197-204