Lucey BP, McCullough A, Landsness EC, Toedebusch CD, McLeland JS, Zaza AM, Fagan AM, McCue L, Xiong C, Morris JC, Benzinger TL, Holtzman DM. Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer's disease. Sci Transl Med. 2019 Jan 9;11(474) PubMed.

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  1. The combined methods to assess sleep in this study provide a high-quality snapshot of sleep in this population of essentially cognitively normal or only mildly impaired people. By combining biomarker methods, an equally high-quality phenotyping of presence versus absence of presumed Alzheimer pathology has been combined with this information on sleep. Previous work on sleep and Alzheimer’s has been limited to amyloid. This group has had their suspicions that tau also comes into play in this relationship, and this study provides the first clear indications that indeed it does. Given the cross-sectional nature, I agree with the authors that no causal inferences can be made from this work, however, if you read between the lines, I think this study does shed some light on causality. For example, a quick and dirty interpretation is that sleep overall shows only relatively mild changes; in other words, there is no clear indication that this study population contains people who have had a prolonged exposure to poor sleep quality or substantially impaired slow-wave sleep in their lives. Nevertheless, they have developed amyloid accumulation, and in some cases already progressed to tau pathology and now show signs of altered sleep.

    I do not think this study provides sufficient evidence yet to start using sleep as a marker for Alzheimer’s pathology in settings other than etiological/pathophysiological research. It does, however, provide fuel to rethink hypotheses around sleep and Alzheimer’s:

    • (Subtly) reduced slow-wave sleep could be a factor that accelerates amyloid accumulation, as a co-factor explaining individual differences in disease progression, rather than a main causal factor.
    • Similarly, reduced slow-wave sleep may accelerate the development of tau pathology in AD.
    • Conversely, sleep changes may be a consequence, not cause, of AD, such that tau pathology, more than amyloid, causes sleep alterations already in asymptomatic or mildly symptomatic AD.

    For now, I don’t see assessments of slow-wave sleep as a valid or wise marker for tau pathology to identify AD in the absence of clear evidence on diagnostic markers (sensitivity, specificity, positive predictive value, etc.), and because it will not necessarily be much cheaper or better than tau PET.

    View all comments by Jurgen Claassen

  2. This is an excellent study from the WashU group and represents an important contribution to our understanding of the link between sleep and AD. New in this study is the combined use of objective sleep measures together with tau PET imaging in humans. We are encouraged to see a convergence between these findings and previous publications. Lucey et al. found that higher CSF t-tau/Aβ42 and p-tau/Aβ42 were associated with lower non-REM (NREM) slow-wave activity (SWA) and more daytime napping. SWA contributes to feeling refreshed after sleeping, therefore these results align with our findings, where we observed that less adequate sleep was associated with higher CSF tau levels, and that higher CSF t-tau/Aβ42 and higher p-tau/Aβ42 were both associated with self-reported inadequate sleep, greater daytime sleepiness, and more sleep problems (Sprecher et al., 2017).

    An important issue raised by the results of this study is that even when it appears that people are getting enough sleep, tau and amyloid may still impair the brain’s ability to engage in the restorative neural processes that underlie SWA. The longer we are awake, the more we need to sleep, and slow-wave activity is a marker of this homeostatic need for sleep: the longer one is awake, the greater the slow-wave activity will be near the beginning of the sleep period, with slow-wave activity progressively declining across a night of sleep. If the observed SWA deficits in this study were due to too little sleep (i.e., insufficient sleep time to obtain adequate SWA), one might expect that shorter sleep duration would be associated with greater tau. Yet, Lucey and colleagues found that greater tau was associated with longer sleep duration (albeit still less than the recommended 7 hours of sleep per night). This, combined with findings indicating that greater tau and amyloid are associated with complaints of unrefreshing sleep and more daytime sleepiness (Sprecher et al. 2017),  suggests that tau and amyloid pathology may be impairing the brain’s ability to generate slow waves. SWA arises from highly coordinated neural activity that is critical for brain maintenance and cognition. Rodent studies have demonstrated mechanisms through which tau and amyloid could disrupt SWA, and as the authors state, it will now be important to investigate causality in humans using longitudinal and experimental studies.

    While the authors note that the use of single-channel EEG recording has limitations, implementing at-home recording is also a major strength of the study. At-home sleep measures may have greater ecological validity than laboratory sleep measurements. Compared with polysomnography, this approach is lower cost for monitoring several nights of sleep, and lessens the burden on patients and caregivers. With regard to implications for preventing or treating AD, it’s worth noting that several sleep conditions already have readily available treatments, and the technology for manipulating slow-wave activity is an active field of development. This study gives new impetus to conduct the longitudinal and validation studies needed to establish causality between disrupted sleep and AD, as well as test whether interventions for disrupted sleep can impact AD.

    References:

    Sprecher KE, Koscik RL, Carlsson CM, Zetterberg H, Blennow K, Okonkwo OC, Sager MA, Asthana S, Johnson SC, Benca RM, Bendlin BB. Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adults. Neurology. 2017 Aug 1;89(5):445-453. Epub 2017 Jul 5 PubMed.

    View all comments by Kate Sprecher

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