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.

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  1. By definition, large studies like these are inherently limited to very simple measurements. In this study, something as physiologically complex as sleep is reduced to participants ticking a single box as part of a larger general questionnaire at two single time points several years apart. This is then further simplified by dichotomizing: If you sleep 8 hours and 59 minutes you are fine, but if you sleep 9 hours and one minute you are at risk of dementia. Added to this is a reduction of “completed high school education, yes-no” to a measure of education, ignoring the related differences in socio-economic status and all associated confounders.

    As we progress in this field of the relationship between sleep and dementia, we need to become more cautious interpreting data. We need polysomnography to provide objective measures of sleep time, sleep stages, sleep efficiency, arousals, apnea, restless legs, etc. A second best is actigraphy to separate time asleep from time lying in bed awake.

    In essence, the present study is not so much about sleep as about what people have indicated as their estimated sleep time at the time of the questionnaire. We don’t know if this reflects their actual sleeping patterns, or whether it is more a reflection of sedentary behavior (people who are so inactive they stay in bed until late in the morning may report this as sleeping time). The strong relationship in people without high school education suggests to me that we may actually be looking at something that has nothing to do with sleep. People with poor education are more likely to be unemployed. Employment forces regular sleep/wake patterns, whereas unemployment does not. So we may be looking at relationships between poor socio-economic status and all associated health issues (unhealthy lifestyle, lack of insurance, poor health care, unhealthy eating habits, substance abuse) and it is impossible in this study to truly correct for this.

    So, while the authors acknowledge the study’s limitations, I think there is a risk of over-interpreting the data. Nonetheless, there are some positive things to note. The study clearly demonstrates the complexity of dementia. This is highly relevant in the light of the discussion on the amyloid hypothesis and the failing anti-amyloid trials. In this discussion, AD is often presented as a simple, linear disease: There is amyloid accumulation and this leads to dementia; removing amyloid will reduce dementia. The present study identifies several factors (reported sleep time, socio-economic class) that strongly influence the risk of developing AD dementia that have not been taken into account in the design of anti-amyloid trials. This again to me indicates that late onset AD is a multifactorial disease and explains why the simplified single factor approach has failed repeatedly.

    View all comments by Jurgen Claassen

  2. Linking Sleep Duration with Pathological Brain Aging: A Novel Risk or Warning Prodrome?

    Scientific evidence connecting sleep disturbance and impaired cognitive function date back more than 120 years when the first experimental sleep deprivation study on humans was reported (Patrick and Gilbert, 1896). The focus of previous clinical studies has been on short-term sleep deprivation. Although the epidemiologic data linking sleep with dementia risk remain limited, a small number of longitudinal studies have begun to examine whether habitual short or long sleep duration may impose long-term consequences for the aging brain by increasing the risk for dementia. Recently, we demonstrated a V-shaped association between sleep duration and dementia risk in older women (Chen et al., 2015). Two other previous studies also suggested a similar pattern, but did not reach statistical significance (Benito-León et al., 2009; Yaffe et al., 2011). The epidemiologic link between short sleep and increased dementia risk has received strong support for its neurobiological plausibility, and some neuroscientists even advocate the inclusion of sleep deprivation in developing translational models (Babiloni et al., 2013) for drug discovery in Alzheimer’s disease (AD). However, the reported associations (Chen et al., 2015; Hahn et al., 2014) between prolonged sleep and increased risk for dementia, including AD, raise two possible and somewhat competing hypotheses: Whether one supports long sleep duration as a novel risk factor or considers it simply a neurobehavioral manifestation in the prodromal phase of dementia, we need strong data from high-quality studies testing both hypotheses, as each has obviously different clinical implications.

    This new report by Westwood et al. represents one important step toward better understanding the link between long sleep duration and increased dementia risk. The powerful approach with longitudinal design was clearly illustrated in this study with repeated assessments of self-reported sleep duration on two occasions, separated by more than 10 years, but both before the clinical follow-up for dementia ascertainment. Given the extensive neurocognitive outcome and brain MRI data already collected in their study cohort, this powerful design allowed the investigators to look at the change in sleep duration, how it relates to brain structure and cognitive status at base, and how it affects the subsequent risk for dementia, including AD. In the presented multivariable analyses, prolonged sleep duration (>9h vs. 6-9h) was associated with an increased risk of incident dementia (hazard ratio [HR] 2.01; 95 percent confidence interval [CI] 1.24-3.26). Change from ≤9 to >9 h of sleep was associated with an increased risk of all-cause dementia (HR 2.43; 1.44-4.11) and clinical AD (HR 2.20; 1.17-4.13). In their “sensitivity analyses,” the authors showed that the observed increase in dementia risk associated with baseline sleep >9h (vs. ≤9h) was primarily driven among those with mild cognitive impairment (MCI) at baseline. These led to the authors’ argument that long sleep duration would more likely be an early marker of neurodegeneration. Another important finding from their sensitivity analyses was that long sleep elevated dementia risk sixfold among study participants with less than high school education. This was an interesting observation, because many sleep researchers found that self-reported long sleep was more common in racial/ethnic minorities and those of low socioeconomic status. If long-duration sleep is a prodromal manifestation of early dementia, then what kind of early neurodegenerative pathologies could affect the subpopulations with presumed social adversities?  Future studies designed to answer this question may help us better understand if, and how, sleep behavior shapes the social disparities in AD and related dementias. 

    Although Westwood et al.’s is the first study designed to look into the competing hypothesis (a novel risk factor versus a warning prodrome), debates are likely to continue before we better understand the connection between long sleep and dementia risk. In large population surveys, poor performance in cognitive tests was also found in individuals who were largely cognitively intact but self-reported with long sleep duration. Unless everyone subscribes to the belief of two different neuropathological processes (linking long sleep with cognitive aging versus pathological brain aging), extant evidence from longitudinal cohorts has not completely ruled out the possibility that long sleep duration imparts novel risk. For instance, as reported by Westwood et al., even among those without MCI at baseline, the relative risk for dementia associated with sleep >9h (vs. ≤9h) was still elevated (HR=1.66; 0.89-3.08]; Table 3), and transitioning to sleep >9h was associated with an increased risk for all-cause dementia (HR=2.43; 1.31-4.54) and clinical AD (HR= 2.52; 1.26-5.04). It is important for future studies to also examine whether long-sleep duration increases the subsequent risk for MCI or even preclinical AD. If that is the case, then the evidence will favor long sleep duration as a risk factor, although it is not clear whether it is possible for Westwood et al. to pursue the analyses in this reported study population. In their post hoc analysis, the authors did adjust for prevalent conditions (cardiovascular disease, diabetes, atrial fibrillation, depression) and the observed pattern of associations remained. These adjusted results reduce the legitimate concern that statistical associations were confounded by these prior medical co-morbidities, which often influence an individual’s sleep duration and increase the risk for dementia. Considering these clinical comorbidities is important because of the extant epidemiologic evidence linking long sleep duration with increased risks for these conditions (especially stroke; see Leng et al., 2015). If long sleep duration predisposes individuals to the new occurrence of conditions that contribute to neurodegeneration, then it will become another line of supportive evidence for long sleep duration as a novel risk factor for dementia.

    Researchers in the AD research community should not be intimidated by these complexities or feel alone, since stroke research communities are searching for similar answers (Ramos and Gangwisch, 2015). Putting it all together, one may start wondering what brain regions or neural networks are most vulnerable to occult cerebrovascular damage and early neurodegeneration that might lead to long sleep duration. Understanding this intriguing neurobiological basis of long sleep may provide important insights into how cerebrovascular dysfunction and neurodegenerative pathology interact in the preclinical pathogenesis of AD. For those in favor of novel risk hypothesis, it is perhaps a good idea to work with sleep-health scientists and chronobiologists to devise an experimental paradigm that simulates the behavioral phenotype of long sleep or mimics its neurophysiological underpinning and that could help design neurobiologically-based epidemiological investigations on long sleep and pathological brain aging. 

    References:

    Patrick G, Gilbert JO. On the effect of loss of sleep. Psychol Rev 3, 469-486 (1896).

    Chen JC, Espeland MA, Brunner RL, Lovato LC, Wallace RB, Leng X, Phillips LS, Robinson JG, Kotchen JM, Johnson KC, Manson JE, Stefanick ML, Sarto GE, Mysiw WJ. Sleep duration, cognitive decline, and dementia risk in older women. Alzheimers Dement. 2015 Jun 15; PubMed.

    Benito-León J, Bermejo-Pareja F, Vega S, Louis ED. Total daily sleep duration and the risk of dementia: a prospective population-based study. Eur J Neurol. 2009 Sep;16(9):990-7. Epub 2009 Mar 31 PubMed.

    Yaffe K, Laffan AM, Harrison SL, Redline S, Spira AP, Ensrud KE, Ancoli-Israel S, Stone KL. Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA. 2011 Aug 10;306(6):613-9. PubMed.

    Babiloni C, Infarinato F, Aujard F, Bastlund JF, Bentivoglio M, Bertini G, Del Percio C, Fabene PF, Forloni G, Herrero Ezquerro MT, Noè FM, Pifferi F, Ros-Bernal F, Christensen DZ, Dix S, Richardson JC, Lamberty Y, Drinkenburg W, Rossini PM. Effects of pharmacological agents, sleep deprivation, hypoxia and transcranial magnetic stimulation on electroencephalographic rhythms in rodents: towards translational challenge models for drug discovery in Alzheimer's disease. Clin Neurophysiol. 2013 Mar;124(3):437-51. Epub 2012 Oct 4 PubMed.

    Hahn EA, Wang HX, Andel R, Fratiglioni L. A Change in Sleep Pattern May Predict Alzheimer Disease. Am J Geriatr Psychiatry. 2013 Aug 13; PubMed.

    Leng Y, Cappuccio FP, Wainwright NW, Surtees PG, Luben R, Brayne C, Khaw KT. Sleep duration and risk of fatal and nonfatal stroke: a prospective study and meta-analysis. Neurology. 2015 Mar 17;84(11):1072-9. Epub 2015 Feb 25 PubMed.

    Ramos AR, Gangwisch JE. Is sleep duration a risk factor for stroke?. Neurology. 2015 Mar 17;84(11):1066-7. Epub 2015 Feb 25 PubMed.

    View all comments by Jiu-Chiuan (J.C.) Chen

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