August 25, 2017
Less time spent in the rapid eye movement (REM) stage of sleep appears to significantly increase dementia risk, new research shows. The association between REM sleep and dementia may be partially explained by sleep-disordered breathing, the study suggests.
"If you look at our paper in the context of other papers that are coming out, it appears that there's a role for sleep-disordered breathing in possibly increasing the risk of dementia, so it's important to screen and manage this as appropriate," Matthew P. Pase, PhD, senior research fellow, Swinburne University of Technology, Australia, and investigator with the Framingham Heart Study, told Medscape Medical News.
Framingham Heart Study.
The analysis included 321 participants in the Framingham Heart Study (FHS) Offspring cohort. The current study included participants aged 60 years and older (mean age, 67 years) for whom data on incident dementia were available.
At one examination cycle of the study (1995 to 1998), the cohort completed overnight polysomnography. Researchers investigated the percentage of time in stage 1, stage 2, slow-wave sleep (SWS; stage 3 and 4 combined, also referred to as "deep sleep"), and REM sleep. During this dream REM sleep stage, the eyes move rapidly and brain activity increases, accompanied by higher body temperature, quicker pulse, and more rapid breathing.
Sleepers typically pass through the five sleep stages in a cyclical pattern — from stage 1 to REM — and then begin again with stage 1. As the night progresses, time spent in REM sleep increases, so individuals typically spend about 20% of total sleep time in the REM stage, said Dr Pase.
Researchers also examined total sleep time, sleep onset latency, REM sleep latency sleep efficiency, wake after sleep onset, and the apnea-hypopnea index. In the FHS, cognitive screening is performed at each examination cycle using the Mini-Mental State Examination. Extensive neuropsychological testing is performed at selected examination cycles.
Over a mean follow-up of 12 years, there were 32 cases of incident dementia, 24 of which were due to Alzheimer's disease (AD). After adjustment for age and sex, a smaller percentage of REM sleep was associated with an increased risk for all-cause dementia (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.86 - 0.97); P = .004) and for AD dementia (HR, 0.92; 95% CI, 0.86 - 0.99; P = .02).
The results remained significant after additional adjustment for factors that may affect dementia risk or sleep, including body mass index; education; APOE ε4 status; smoking; systolic blood pressure; diabetes; heart disease; depression; and use of sleeping agents, antidepressants, anxiolytics, and antihypertensive medication.The authors found that each percentage decrease in REM sleep was associated with about a 9% increase in the risk for incident dementia.
Excluding cases of mild cognitive impairment and participants who developed dementia within 3 years of follow-up did not significantly change the association. Having an early or late chronotype, a circadian rhythm outside the norm, also failed to explain the association between REM sleep and dementia. However, the authors did not have information on shift work, which might have shed more light on the effect of varying circadian rhythms.
REM sleep latency was also linked to dementia. Compared with the highest tertile of REM sleep latency, the lowest tertile was associated with a lower risk for all-cause dementia after adjustment for age and sex (hazard ratio [HR], 0.37; 95% CI, 0.14 - 0.97) and after additional adjustments for vascular risk factors, depressive symptoms, and medication use (HR, 0.26; 95% CI, 0.08 - 0.85).
"We found that those who took longer to get into REM sleep had an increased risk of dementia, which complements, or goes hand in hand with, our other finding," of a link between percentage of REM sleep and dementia, said Dr Pase.
Greater wake after sleep onset, which is a measure of difficulty maintaining sleep, was also associated with an increased risk for dementia in the fully adjusted statistical model. On the other hand, stages of non-REM sleep were not associated with dementia. "We expected to see a relationship between time in deep sleep and risk for dementia, but that's not what we found. The results suggest that perhaps there's something that we are not quite understanding about REM sleep that is important," said Dr Pase.
REM sleep may be disrupted by an untreated sleep disorder. The authors found that the association between REM sleep and dementia was partially explained by hypopneas. After exclusion of participants with a high number of arousals from REM sleep due to hypopnea, the association between low REM sleep and dementia was reduced (HR, 0.94) but was insignificant (P = .17). "So there might be some role in the association of sleep-disordered breathing, but it doesn't seem to explain the whole picture," said Dr Pase. He stressed the difficulty of examining sleep disorders "in great detail" without very large sample sizes.
Anxiety, Stress May Play a Role
Although the mechanisms linking REM sleep with dementia are not fully understood, loss of cholinergic function may be involved, said the authors. Cholinergic neurons are important determinants of REM sleep, with cholinergic activity low during slow-wave sleep and high during REM sleep. In addition, AD is associated with the loss of cholinergic function. REM sleep may help maintain circuitry within the brain that is disrupted with dementia, said Dr Pase.
The authors originally thought that low REM sleep might be a marker for brain changes that occur in early stages of dementia, said Dr Pase. "But we found that lower REM sleep was predicting risk of dementia well into the future, so this doesn't seem a likely explanation for our findings." The fact that the association between low REM sleep and dementia was not driven by those with mild cognitive impairment does not support the idea that lack of REM is a marker for dementia. Anxiety and stress may play a role in increasing the risk for dementia or curtailing REM sleep. Dr Pase suggested a possible cyclical relationship.
"You might have this effect of, say, high stress levels interrupting sleep and contributing to dementia, and then compromised sleep might further increase the risk for dementia. So there might be a cyclical relationship between stress and poor sleep, and poor sleep and more stress, et cetera."While the findings are interesting from a biological perspective, there are no immediate clinical implications, except for the obvious advice to somehow optimize REM sleep, said Dr Pase.
"It's more in the hands of researchers to understand why we see this association, and to unpack it a bit further; that might then lead to more clinical recommendations for doctors." In the meantime, though, if stress or sleep-disordered breathing plays a role, "managing sleep disorders and controlling stress and anxiety could help" reduce dementia risk, said Dr Pase.
The research team is keen to combine their study group with other similar cohorts to create a larger data pool that would allow more powerful analyses of, for example, the role of sleep-disordered breathing.
Modifiable Risk Factor.
Commenting on the findings for Medscape Medical News, Heather Snyder, PhD, Alzheimer's Association senior director of medical and scientific relations, said the study authors were fortunate to be able to tap into data from the FHS.
"One of the strengths of the study was that the researchers have this really strong group of individuals who have been followed for a long period of time and about whom there is a lot of information." The new study "adds to a body of evidence that we continue to see emerge in the field," said Dr Snyder. The first evidence of a link between sleep and later dementia started to emerge perhaps 5 or 6 years ago, said Dr Snyder.
"Over the years, we have continued to see refinements of those studies, and we are able to get more in-depth information about what it is about sleep" that may affect dementia. Dr Snyder noted research presented at this year's Alzheimer's Association International Conference that linked disrupted sleep to a build up of amyloid and tau, two hallmarks of AD. However, she stressed that the link is still an association and that "we don't know if there's a cause and effect."
Nevertheless, the current interest in understanding the role of sleep in dementia may be kindled by the fact that sleep problems are treatable.
"If you're talking about sleep-disordered breathing, or obstructive sleep apnea, there are potential treatments," said Dr Snyder. "If you can actually treat the sleep disturbance, you may be able to augment your later life risk, if there is that causal relationship there."
Updated 25th August 2017
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