By Daniel A. Barone, MD, FAASM, FANA
Assistant Attending Neurologist, NewYork-Presbyterian Hospital, and Assistant Professor of Clinical Neurology, Weill Cornell Medical College
Summary Points
- In this study by Himali et al, the aim was to determine whether slow-wave sleep (SWS) loss with aging is associated with the risk of incident dementia. The authors also attempted to examine whether Alzheimer’s disease (AD) genetic risk or hippocampal volume reduction were associated with SWS loss.
- The study measured changes in SWS percentage across repeated overnight polysomnographies over a mean of 5.2 years apart. The main outcome was the risk of all-cause dementia ascertained over 17 years of follow-up from the second PSG. As a proxy for neurodegeneration, hippocampal volumes on brain magnetic resonance imaging (were ascertained as a percentage of intracranial volume. The incidence of dementia was monitored through uninterrupted surveillance of all participants. They were diagnosed via the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition).
- Ultimately, SWS percentage declined with aging and AD genetic risk, with greater reductions associated with the risk of dementia, suggesting that SWS loss may be a modifiable risk factor for dementia.
SYNOPSIS: In this long-term observational study of sleep efficiency in the Framingham Heart Study population, researchers found a strong correlation between a decline in duration of slow-wave sleep during aging and the risk of incident dementia from all causes. However, a direct cause-and-effect relationship cannot be determined from this observational study.
SOURCE: Himali JJ, Baril AA, Cavuoto MG, et al. Association between slow-wave sleep loss and incident dementia. JAMA Neurol 2023; Oct 30:e233889. doi: 10.1001/jamaneurol.2023.3889. [Online ahead of print].
Slow-wave sleep (SWS), sometimes referred to as deep sleep, is defined as stage 3 of non-rapid eye movement (REM) sleep. It usually lasts between 70 and 90 minutes and takes place during the first hours of the night. It consists of slow waves with a frequency range of 0.5 Hz to 4.5 Hz, with a relatively high amplitude. SWS is considered important for memory consolidation, and it is thought to support the aging brain in many ways, including in the glymphatic clearance of proteins that aggregate in Alzheimer’s disease (AD). Despite this association, the role of SWS in the development of dementia remains equivocal.
In this study by Himali et al, the aim was to determine whether SWS loss with aging is associated with the risk of incident dementia. The authors also attempted to examine whether AD genetic risk or hippocampal volume reduction were associated with SWS loss. This study was designed to include a prospective cohort of participants from the Framingham Heart Study who completed two overnight polysomnography (PSG) studies in the time periods 1995 to 1998 and 1998 to 2001. Inclusion criteria were an age of 60 years or older and no dementia at the time of the second overnight PSG.
The study measured changes in SWS percentage across repeated overnight PSGs over a mean of 5.2 years apart (range, 4.8 to 7.1 years). The main outcome was the risk of all-cause dementia ascertained over 17 years of follow-up from the second PSG. As a proxy for neurodegeneration, hippocampal volumes on brain magnetic resonance imaging (MRI) were ascertained as a percentage of intracranial volume. The incidence of dementia was monitored through uninterrupted surveillance of all participants. They were diagnosed as per the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition).
Out of 868 Framingham Heart Study participants who underwent a second PSG, 346 were included, with a mean age of 69 years (range, 60 to 87 years), with 179 (52%) being female. Aging was associated with reduced SWS loss across repeated PSGs. SWS loss with aging was not associated with hippocampal volumes measured proximal to the first PSG.
Over the 17 years of follow-up, there were 52 cases of incident dementia. In models adjusted for age, sex, cohort, positivity for at least one APOE-ε4 allele, smoking status, hypnotic use, antidepressant use, and anxiolytic use, each percentage decrease in SWS per year was associated with a 27% increase in the risk of dementia (hazard ratio, 1.27; 95% confidence interval, 1.06-1.54; P = 0.01).
Ultimately, SWS percentage declined with aging and AD genetic risk, with greater reductions associated with the risk of dementia, suggesting that SWS loss may be a modifiable risk factor for dementia.
Commentary
This was a well-done and important study; however, its observational nature precludes applicability in the determination of whether SWS loss causes dementia. As the authors pointed out, gold-standard AD biomarkers were not used, nor was SWS loss compared to accumulation of amyloid beta or tau. Regardless, there are several takeaways from this study. Prior studies have suggested that SWS loss potentially increases dementia risk via effects on glymphatic clearance, vascular risk factors, or both. Therefore, efforts are needed to establish whether SWS enhancement can limit cognitive decline and neurodegeneration in at-risk individuals.
If SWS enhancement is found to stave off cognitive decline and, possibly, dementia, the natural follow-up question would be how to accomplish this. Clearly, improved sleep habits and treatment of sleep disorders (such as obstructive sleep apnea) will be of utmost importance, but beyond these initial steps, there are some data to suggest that certain medications may promote SWS.
A 2021 meta-analysis examined 18 randomized controlled trials of anti-seizure medications regarding their effect on PSG parameters, including SWS.1 The five main groups included sodium channel blockers, calcium channel blockers, gamma-aminobutyric acid (GABA) enhancers, synaptic vesicle glycoprotein 2A ligands, and broad-spectrum medications. Compared with placebo, calcium channel blockers and GABA enhancers significantly increased SWS. GABA enhancers also decreased REM sleep percentage, whereas calcium channel blockers significantly increased sleep efficiency. These data are compelling but raise further questions: Is reduced REM sleep problematic if SWS is increased? Is increased sleep efficiency more meaningful than increased SWS?
Furthermore, some studies have suggested that hypnotic medication increases the risk of dementia, so these results will need to be tempered against such potential outcomes. These and other questions are important both clinically and for the field of cognitive science research. One hopes further studies will elucidate the fascinating intersection of sleep and cognition.
Reference
- Yeh WC, Lu SR, Wu MN, et al. The impact of antiseizure medications on polysomnographic parameters: A systematic review and meta-analysis. Sleep Med 2021;81:319-326.
In this long-term observational study of sleep efficiency in the Framingham Heart Study population, researchers found a strong correlation between a decline in duration of slow-wave sleep during aging and the risk of incident dementia from all causes. However, a direct cause-and-effect relationship cannot be determined from this observational study.
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