Winer JR, Deters KD, Kennedy G, Jin M, Goldstein-Piekarski A, Poston KL, Mormino EC. Association of Short and Long Sleep Duration With Amyloid-β Burden and Cognition in Aging. JAMA Neurol. 2021 Oct 1;78(10):1187-1196. PubMed.

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  1. This large cross-sectional study does a nice job of extending our understanding of sleep duration and Alzheimer's risk. The data suggest that the steeper cognitive decline associated with long sleep may be an Aβ-independent process, as long sleep in this study did not predict Aβ burden.

    It would be tempting to conclude that short sleep contributes to the observed associated increased amyloid burden, but it is important to understand that short and long sleep are not two distinct conditions or behaviors, but rather are symptoms of diverse sleep behaviors and disorders. For example, both short sleep and long sleep frequently occur in untreated obstructive sleep apnea. The former occurs when sympathetic activity is high and the latter when sleep is disrupted without significant surges in catecholamines. The higher body mass indices and depression scores and the presence of daytime napping for both short and long sleepers are consistent with obstructive sleep apnea risk for both short and long sleepers. Similarly, sleep duration, as confirmed here, is increased in women and with higher education. 

    This being a cross-sectional study, it is also possible that the increased Aβ is increasing brain excitation and thereby disturbing sleep.

    It is critical now to further develop the sleep/wake phenotypes of short and long sleepers, to identify underlying causes, and then to analyze identified causes for amyloid burden risk and cognitive decline rather than the symptom of sleep duration.

    View all comments by Sigrid Veasey

  2. This nice study is consistent with several smaller previous studies linking self-reported sleep issues (in this case, short sleep duration) with brain amyloid level as assessed by amyloid PET. This study has a very large number of people with amyloid PET imaging, and also accounts for other lifestyle factors, which are its major strengths.

    Several previous studies have suggested that reported short sleep duration is associated with increased risk of future dementia, and some have shown that long sleep durations also have increased risk. This paper does a nice job of noting that short and long sleep are associated with other health and lifestyle factors that might also influence amyloid deposition and AD risk (such as increased BMI, alcohol use, etc.).

    It is very difficult to disentangle these factors. Self-report of sleep duration can only go so far, as objective measures such as actigraphy (better) or EEG (best) are really needed to get the detailed sleep quality data needed to fully understand the relationship between sleep and AD.

    The question of which comes first, sleep problems or amyloidosis, remains unanswered by this study, as it is cross-sectional. There is no marker of tau in this study, though brain tau deposition is associated with amyloid. Thus, we don’t know if it is amyloid or tau (or another amyloid-related neuropathology) that drives sleep changes, or vice versa.

    However, this study provides more strong evidence that brain amyloid is associated with short sleep in cognitively normal individuals, even though directionality cannot be proven. The integration of objective sleep measurements with multimodal AD biomarkers in longitudinal studies of preclinical AD is the ultimate goal, and this study is an important step toward that goal.

    View all comments by Erik Musiek

  3. Of the many potentially modifiable factors that putatively impact dementia risk, sleep is one of the more biologically plausible ones to be linked with AD pathology specifically. Rodent studies indicate that Aβ levels rise during wakefulness, and Aβ appears to be cleared during NREM sleep. Several human studies have also linked sleep characteristics, and disrupted sleep, with biomarkers of amyloid and tau.

    Our research group previously found that self-reported sleep quality among cognitively unimpaired individuals is associated with amyloid pathology, but these studies, using CSF and amyloid PET, were rather small. The size of the dataset included here is impressive, and a major strength of the current analysis.

    The caveat of course, is that we can't infer from this analysis whether shorter sleep duration is exacerbating amyloid accumulation, or whether individuals who harbor preclinical amyloid are sleeping less due to their accumulating AD pathology. Animal studies suggest that the sleep/amyloid relationship is bidirectional.

    It's also important to consider that there are other pathologies that co-occur with amyloid that could be playing a role. Longitudinal human studies where sleep is well-characterized, and which incorporate comprehensive AD biomarkers, could shed further light on the mechanisms at play.

    Sleep intervention studies will also tell us whether sleep can be modified to reduce dementia risk.

    View all comments by Barbara Bendlin

  4. This study is a very important contribution to the literature and builds on previous research showing a non-linear, or U-shaped, relationship between sleep and cognitive performance.

    Although short or long sleep duration likely represent poor sleep quality, multiple factors may lead to disturbed sleep in older adults, and this cross-sectional study is unable to sort out the potential cause(s) of sleep disturbance. Several of the factors identified in this study, such as depressive symptoms as well as sleep, are potential targets for intervention trials. However, longitudinal studies and more objective sleep measures in well-characterized cohorts are first needed to sort out these complex relationships.

    View all comments by Brendan Lucey

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  1. Getting Too Little Sleep? You May Be Accumulating Amyloid.