Wake up, sleepyhead—your risk of dementia may have just doubled. According to a study published February 22 in Neurology, people who slumber for more than nine hours per night have twice the risk of dementia as people who sleep for just six to nine hours. And for people without a high school diploma, the risk was three times higher again. Drawing on multigenerational data from the Framingham Heart Study, researchers led by Matthew Pase and Sudha Seshadri of Boston University in Massachusetts also reported that a gradual transition from normal to prolonged sleep may be a harbinger of incipient dementia. However, setting the alarm an hour earlier is unlikely to do much good, as the researchers proposed that prolonged sleep is a marker of ongoing neurodegenerative processes, rather than their cause.
Sleep is essential for brain health—that much is clear. During each rejuvenating bout, synapses are neatly pruned, the day’s highlights enshrined into memory, and the glymphatic system flushes unwanted detritus, including Aβ, out of the brain. Acute sleep deprivation taxes cognitive function, as everyone knows. However, the relationship between long-term sleep patterns and chronic processes such as neurodegeneration is hazy. Some studies have reported that both shortened and/or prolonged sleep predict dementia, but findings were limited by short follow-up periods, making it difficult to determine whether early symptoms of dementia could be the cause of sleep disturbances or vice versa (see Benito-León et al., 2014; Potvin et al., 2012; Chen et al., 2016). Other findings using polysomnography to assess sleep quality and duration found a link between sleep apnea, but not sleep duration, and dementia (see Aug 2011 news). Nearly in line with the current study, questionnaires and telephone interviews of 15,000 nurses identified a link between shortened or prolonged sleep duration in mid- or late life with poor cognitive performance later in life (see Aug 2012 conference news; Devore et al., 2014).
Against this complex backdrop, Pace, Seshadri, and colleagues turned to the Framingham Heart Study, an ongoing longitudinal health study initiated in 1948. Drawing on data from its more than 2,000 participants, the researchers asked whether how long a participant slept at baseline related to his or her risk of dementia within the following decade. They found that compared to people who slept between six and nine hours per night, those who reported sleeping more than nine hours at baseline had about double the incidence of dementia within the next 10 years. In a subsequent analysis, the researchers found that this association was primarily driven by people who had mild cognitive impairment at baseline. Furthermore, long sleepers who never graduated from high school had about a sixfold increase in dementia risk. Short sleepers (less than six hours) did not have an elevated dementia risk.
The researchers next asked whether a transition from short to longer sleep affected dementia risk. Referencing data from questionnaires given about 13 years before baseline, the researchers also found that people who transitioned from sleeping less than nine hours to more had nearly 2.5 times the risk of developing dementia or AD as those who remained below nine hours at both time points. This association held regardless of MCI status at baseline. Interestingly, for people who reported sleeping long hours at both time points, dementia risk was only slightly elevated. This suggested that a change in sleep status, rather than simply sleeping long hours, was the most important predictor of cognitive downslide in cognitively normal adults.
The participants also underwent cognitive testing and magnetic resonance imaging at baseline. Both short and long sleepers suffered from deficits in visual attention and executive function as measured by the Trail Making Test. Strikingly, long sleepers also tended to have smaller brains than those who slept normal hours, while short sleepers had larger brains. While ongoing neurodegeneration could explain the smaller brains of prolonged sleepers, the researchers were unsure what to make of the larger brain volumes in short sleepers.
Given the known importance of sleep for brain health, Seshadri told Alzforum she was initially surprised to find that prolonged sleep predicted dementia. She proposed that a shift to sleeping longer hours could be an early disease marker, perhaps triggered by the brain’s need to compensate for emerging neurodegeneration.
Jeffrey Iliff of Oregon Health Sciences University in Portland agreed. He commented that the most striking finding of the study was not that prolonged sleep at baseline predicted dementia in people with MCI, but rather that a conversion from normal sleep to longer sleep predicted it across the whole sample. “It’s the change in status that is most important,” he said.
While working at Maiken Nedergaard’s lab at the University of Rochester Medical Center, New York, Iliff helped reveal the existence of the glymphatic system, which clears solutes, including Aβ, from the mouse brain during sleep (see Oct 2013 news). Others have reported that sleep deprivation in humans promotes Aβ build-up, and that Aβ clears from the human brain in a diurnal rhythm (see Alzforum Timeline 2009; Jun 2014 news). Iliff proposed that sluggish brain clearance may lead to an accumulation of Aβ or other solutes that hasten neurodegeneration, which subsequently leads to changes in sleep patterns observed in the current paper.
How might early neurodegenerative processes lead to longer sleep? Iliff commented that neurodegeneration could alter the neurocircuitry that governs sleep homeostasis, a process already known to falter with age. The authors proposed a similar hypothesis, noting that levels of the wake-promoting neuropeptide hypocretin drop in AD patients. Indirect factors such as depression and anxiety could also influence sleep, they proposed.
Ricardo Osorio of New York University School of Medicine pointed out that in addition to the circadian rhythms that sync sleep with sunlight, there is also a force called sleep pressure. It gradually builds throughout the day as more sleep-promoting molecules, such as adenosine, accumulate in the brain. Therefore, if malfunctions in brain clearance mechanisms coincide with neurodegeneration, perhaps they increase solutes that promote sleep pressure. He added that neuroinflammation could also beckon sleep, as pro-inflammatory cytokines promote drowsiness.
Osorio, the authors, and other commentators all agreed on limitations of the study. The researchers relied on participants’ self-report of how long they slept, and Osorio said people are notoriously bad at assessing how long they sleep. Furthermore, the strong influence of low education could be confounded by many variables, including socioeconomic status and lifestyle.
As studies seek to tease out the relationship between sleep and dementia, researchers need to interpret findings cautiously, commented Jurgen Claassen of Radboud University Nijmegen Medical Centre in the Netherlands. “We need polysomnography to provide objective measures of sleep time, sleep stages, sleep efficiency, arousals, apnea, restless legs, etc.,” he said.
Seshadri agreed, and told Alzforum that she is currently using available polysomnography data from about 3,000 participants in the Framingham Heart Study to link sleep quality and duration to dementia risk.—Jessica Shugart
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No Available Further Reading
- Westwood AJ, Beiser A, Jain N, Himali JJ, DeCarli C, Auerbach SH, Pase MP, Seshadri S. Prolonged sleep duration as a marker of early neurodegeneration predicting incident dementia. Neurology. 2017 Mar 21;88(12):1172-1179. Epub 2017 Feb 22 PubMed.