Alzheimer disease (AD) is the most common neurodegenerative disease and is characterized by the accumulation of amyloid plaques, composed of amyloid beta (A?) peptides. Current consensus is that the AD pathological process begins decades before clinical symptoms occur. Emerging evidence suggests that sleep disruption may be an important factor in both the cognitive deterioration of AD and in the progression of molecular factors, such as the metabolism of A? peptides, that promote ultimate plaque deposition and neurodegeneration. Obstructive sleep apnea (OSA) is the most common sleep disorder in the US and is thought to exert its pathogenic effects through some combination of sleep fragmentation (SF) and intermittent hypoxia (IH). A better understanding of the mechanisms by which sleep disruption impacts memory and risk for AD can stem from evaluating the role of disruption of specific sleep stages and, when such disruption occurs through OSA, from evaluating the individual contributions of SF and IH. We have strong preliminary evidence showing that the presence of OSA lowers the age at which individuals experience cognitive decline to mild cognitive impairment by 10 years, and subjects with OSA show the greatest increases in cerebrospinal fluid (CSF) levels of A? peptides when followed longtidinally. Furthermore, we have preliminary evidence linking decreases specifically in slow wave sleep (SWS) to both decreased overnight consolidtion of spatial navigational memory and increases in CSF levels of A?42. We have developed a novel model of sleep stage-specific induction of OSA through continuous positive airway pressure (CPAP) withdrawal in subjects who have severe OSA and who are fully adherent to CPAP on a nightly basis. By limiting CPAP withdrawal to slow wave sleep (SWS) through real time EEG monitoring, we can recapitulate severe OSA in SWS only, with negligible OSA in other sleep stages. This model allows us to address a potential causal role for SWS disruption in the impairment of spatial navigational memory (Aim 1) and in increasing CSF concentrations of A? peptides (Aim 2). By providing supplemental oxygen during the CPAP withdrawal, we can create OSA in which sleep fragmentation continues to occur while IH is significantly minimized. This model will allow us to address a second major focus: to differentiate effects of SF and IH on spatial navigational memory (Aim 3) and regulation of CSF A? (Aim 4). To test these ideas, 85 adult subjects (age 25-70) will be recruited to perform brain imaging and ApoE genotyping and serial tests of spatial navigational memory, morning psychomotor vigilance, a lumbar puncture (LP) synchronized to their circadian rhythm (by actigraphy). Subjects will be tested in 3 conditions across different nights separated by at least 2 weeks: 1) CPAP held at the therapeutic value throughout 2) CPAP withdrawn exclusively in SWS and 3) CPAP withdrawn exclusively in SWS with simultaneous addition of supplemental oxygen.

Public Health Relevance

Alzheimer disease is the most common neurodegenerative disease and its current lack of effective treatment makes determining factors that may modify the disease course of paramount importance. Sleep disruption is one such factor, and obstructive sleep apnea represents the most common clinical form of sleep disruption, affecting up to 20% of the population. The current proposal addresses the role of stage-specific sleep disruption and mechanisms of obstructive sleep apnea's effect on memory and risk for Alzheimer disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Mackiewicz, Miroslaw
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Icahn School of Medicine at Mount Sinai
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Mokhlesi, Babak; Varga, Andrew W (2018) Obstructive Sleep Apnea and Cardiovascular Disease. REM Sleep Matters! Am J Respir Crit Care Med 197:554-556
Ahuja, Shilpi; Chen, Rebecca K; Kam, Korey et al. (2018) Role of normal sleep and sleep apnea in human memory processing. Nat Sci Sleep 10:255-269