October 18, 2017

Sleep Loss May Increase Risk of Alzheimer’s Disease

By Brian Hoyle

SAN DIEGO, California -- October 18, 2017 -- Sleep deprivation could increase the risk of Alzheimer’s disease (AD), according to results of a study presented at the 142nd Annual Meeting of the American Neurological Association (ANA).

Participants experiencing sleep loss had levels of amyloid-beta (Aβ) in their cerebrospinal fluid (CSF) that exceeded daytime baseline levels by approximately 30%. Elevations of 25% to 40% in Aβ concentration have been associated with a greater risk of developing AD, explained lead author Brendan Lucey, MD, Washington University School of Medicine, St. Louis, Missouri, speaking here at a poster session on October 15.

The purpose of this pilot study, Dr. Lucey and colleagues noted, was “to investigate how different sleep interventions altered the production and clearance mechanisms that underlie fluctuating Aβ concentrations in CSF.”

Twenty cognitively normal participants aged 18 to 60 years had their CSF collected every 2 hours for 36 hours during normal sleep (n = 7), sleep deprivation (n = 7), or slow-wave sleep induced using sodium oxybate (n = 6). Four of the participants completed the study a second time in a different intervention group, and 4 participants took part in all 3 intervention groups.

The researchers infused all participants with 13C6-leucine to isotopically label Aβ. The labeled and unlabeled forms were detected and quantified using mass spectrometry. The idea was that the removal of the labeled form could be followed by the changing ratio of the labeled and unlabeled forms of Aβ. The team monitored sleep-wake activity using polysomnography.

The control, sleep-deprived, and sleep-induced groups were similar in terms of age, sex, cognition (as measured using the mini-mental state examination score), and the initial ratio of labeled and unlabeled Aβ. As expected, participants in the sleep-deprived group displayed markedly reduced total sleep time and sleep efficiency, and did not experience slow-wave sleep.

Compared with the sleep-induced and control participants, those who were sleep-deprived had 25% to 40% greater levels of Aβ relative to the waking baseline value (P < .05). The quantity of labeled Aβ was similar between the groups that had a good sleep. The turnover of Aβ was similar in all 3 groups. The amount of labeled Aβ relative to the total amount of Aβ, however, was greater in the sleep-deprived groups.

The researchers interpreted the findings as indicating that sleep loss drives increased production of Aβ. “During sleep, lymphatic clearance alone would be ineffective at lowering central nervous system Aβ concentration without decreased Aβ production rate,” they explained.

The take-home message is that disrupted sleep results in the continued accumulation of Aβ. So, “sleep has potential as an AD preventative therapy.” Future studies will explore this idea by assessing whether Aβ concentrations increase in people with more clinically relevant aspects of abnormal sleep, such as poor sleep quality. Whether the increased Aβ levels can be normalised by drug-aided sleep also will be tested.

Aβ is a linchpin in the pathogenesis of AD when it accumulates in the brain. The level of the protein fluctuates normally during the sleep-wake cycle. Ordinarily, the protein that accumulates during wakefulness is removed by interstitial flow during sleep.

Funding for this study was provided by the National Institutes of Health, Bethesda, Maryland and the McDonnell Center for Systems Neuroscience at Washington University School of Medicine, St. Louis, Missouri, as well as the Florence Gould Endowment for Discovery in Stroke.

[Presentation title: Sleep Loss Increases Risk of Alzheimer’s Disease by Increasing CNS Ab Production. Abstract S176]
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