Alzheimer's disease (AD) is a common neurodegenerative disease characterized by the accumulation of amyloid plaques and neurofibrillary tangles. Recent studies support the hypothesis that amyloid beta (A) dynamics in the brain are influenced by the sleep-wake cycle, with increases in the production of soluble A during wakefulness and decreases during slow wave sleep (SWS). In this model, prior to amyloid deposition, brain soluble A levels may be relatively increased in the elderly primarily due to loss of total sleep time and slow wave sleep (SWS) that occur with normal aging and/or secondarily, due to sleep disturbances such as Sleep Disordered Breathing (SDB) or insomnia that are common in late life. We have preliminary evidence showing that: a) SDB advances cognitive decline in normal elderly; b) SDB increases cerebrospinal fluid (CSF) A42 levels in middle age adults; and, c) increased CSF A42 is associated with reduced SWS in normal elderly. Our goal is to test this hypothesis in 20 cognitively normal elderly with no SDB or brain amyloid (Aim 1), and a group of 22 middle age adults with severe SDB treated with therapeutic continuous positive airway pressure (CPAP) and good treatment compliance (Aim 2). In the elderly group, we will evaluate the relationship between SWS and CSF A42/A40 ratio in the absence of SDB or amyloid burden (measured with a 18F-florbetaben PET scan). In the middle age group, we will disrupt sleep by withdrawing CPAP on one night and allow participants to sleep with therapeutic CPAP on a second night. A morning lumbar puncture will be performed in both visits to evaluate the effect of disrupting sleep by acute CPAP withdrawal on CSF A42 levels. This project will be the first to explore the protective effect of SWS on A42 dynamics in a group of elderly subjects as well as the effect of acute sleep disruption by CPAP withdrawal on CSF A42 levels in a well- characterized clinical sample of severe middle age obstructive SDB patients. This proposal may identify: 1) evidence of age-related SWS loss effects on CSF A42 dynamics; 2) a mechanism by which a highly prevalent sleep disorder may contribute to AD pathology; and, 3) SWS as new therapeutic target for AD prevention.

Public Health Relevance

We aim to test the hypothesis that soluble amyloid beta (A) levels in the brain are influenced by the sleep- wake cycle, with increases in the production of A during wakefulness and decreases during slow wave sleep (SWS). Our goal is to: a) evaluate the relationship between SWS and cerebrospinal fluid (CSF) A42/A40 ratio in 20 cognitively normal elderly in the abscense of Sleep Disordered Breathing (SDB) or brain amyloid burden; and, b) to evaluate the effect of disrupting sleep by acute CPAP withdrawal on CSF A42 levels in 22 middle age subjects with severe SDB and good CPAP compliance.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Mackiewicz, Miroslaw
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New York University
Schools of Medicine
New York
United States
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