Poor sleep and amyloid pathology have been linked, but how they influence each other over time remains a mystery. Now, researchers led by Prashanthi Vemuri at the Mayo Clinic in Rochester, Minnesota, report that older healthy people who are sleepier during the day also accumulate Aβ in their brains more quickly. Published in the March 12 JAMA Neurology, the study found that the Aβ appeared primarily in the cingulate and precuneus regions, which accumulate plaques early in the progression of Alzheimer’s disease.
Daytime sleepiness correlated with faster amyloid deposition in elderly people without dementia.
The cingulate and precuneus regions were most affected.
The correlation was strongest in people who tested positive for Aβ at baseline.
“This study is a nice addition to a growing body of research, both in animals and humans, that link amyloid and sleep,” noted Barbara Bendlin, University of Wisconsin, Madison, who recently correlated poor sleep with Aβ42 and other AD biomarkers in the cerebrospinal fluid of cognitively healthy adults (Sprecher et al., 2017). In a JAMA Neurology editorial, Joseph Winer, University of California, Berkeley, and Bryce Mander, UC Irvine, also welcomed the results. “This study is the first in humans to demonstrate a predictive association between a measure of sleep disturbance at baseline and change in an AD biomarker across multiple points,” they wrote.
Many studies have linked disturbed sleep to AD. A recent meta-analysis concluded that people with sleep problems run a 1.7-fold higher risk of developing cognitive impairment or AD, and that 15 percent of AD may be attributed to disturbed sleep (Bubu et al., 2016). While some studies have suggested Aβ fractures sleep patterns in mice and in people (Sep 2012 news; Jun 2015 news), others have proposed the reverse—that poor sleep drives amyloid accumulation (Oct 2013 news; Aug 2017 conference news).
So far, it has been difficult to unravel how exactly the two affect each other in people, in part because studies have been limited to single snapshots, or snapshots taken only a few hours apart. To broaden this view, first author Diego Carvalho searched for correlations between daytime sleepiness and changes in Aβ buildup over two years, on average. He analyzed data from 283 people enrolled in the Mayo Clinic Study of Aging, a longitudinal, population-based cohort in Olmsted County, Minnesota. Participants were at least 70 years old and had undergone two or more PET scans using the Aβ-detecting agent 11C-labeled Pittsburgh compound B (PiB). Most were cognitively normal, but 33 had been diagnosed with mild cognitive impairment.
Using the cerebellum as a reference, the researchers computed PiB-PET standardized uptake value ratios (SUVRs) for brain regions known to develop plaques early in AD, including the prefrontal, anterior cingulate, cingulate-precuneus, and parietal cortices. For a global PiB score, they averaged the values from all these regions, as well as the orbitofrontal and temporal areas. A global SUVR of 1.4 or more was considered PiB-positive.
The authors used the Epworth Sleepiness Scale as a measure of excessive daytime sleepiness (EDS). It relies on a questionnaire that asks people to rate their tendency to doze off in various situations, such as watching TV, sitting quietly after a lunch without alcohol, or while stopped for a few minutes in traffic. Twenty-two percent of participants cleared the authors’ threshold for EDS—10 or higher out of a total of 24 on the Epworth scale.
Brendan Lucey, Washington University in St. Louis, commended the breadth of data collected and analyzed. “It is an impressive number of individuals with PiB-PET scans, cognitive assessments, and sleep questionnaires,” he said.
The researchers searched for correlations between EDS and Aβ, adjusting for possible confounding factors, including age, gender, presence of the ApoE4 allele, midlife physical activity, cardiovascular problems, sleep respiratory symptoms, and depression. Initial studies were also adjusted for baseline global Aβ burden.
Aβ accumulated more rapidly in the anterior cingulate, cingulate-precuneus, and parietal regions of people with EDS (image above). The association was even stronger in people who tested positive for brain Aβ at baseline. According to Bendlin, Winer, and Mander, this hints at a vicious cycle in which disrupted sleep affects amyloid accumulation, and amyloid accumulation in turn affects sleep.
Still, scientists don’t know which comes first. “Our study was a step toward trying to answer that,” said Vemuri. Her group plans longer studies, including earlier time points. They might reveal which occurs first, EDS or amyloid.
Kristine Yaffe, UC San Francisco, who recently reported a link between sleep-disordered breathing and cognitive impairment (Leng et al., 2017), considered the study an important contribution, but noted it will be important to tease apart the factors driving sleepiness. While being easy to administer and inexpensive, the Epworth questionnaire does not distinguish between sleep disorders such as insomnia or sleep apnea. Commenters suggested using actigraphy to better measure sleep disruption, or the more comprehensive polysomnography, which records brain waves, blood oxygen levels, heart rate, and breathing, as well as eye and leg movements. Vemuri and colleagues want to add such objective measurements in future studies.
This study is a nice addition to a growing body of research, both animal and human, that links amyloid and sleep. Carvalho et al. found that self-reported excessive daytime sleepiness was associated with longitudinal amyloid accumulation measured with [C11]PiB PET.
Strengths of the study include the fact that participants were well-characterized and the analysis controlled for factors that may affect amyloid accumulation and/or risk for Alzheimer's dementia, including midlife physical activity, cardiovascular risk factors such as obesity and diabetes, as well as depression. Furthermore, the study was sizeable for a longitudinal PET study, including 283 participants.
An outstanding question is whether amyloid accumulation precedes sleep abnormalities, or sleep changes are the result of AD-associated brain changes, even at the preclinical stage of the disease. Data in animals suggest that the relationship is likely bidirectional, with disrupted sleep affecting amyloid accumulation, and amyloid accumulation in turn affecting sleep. In this study, restricting the analysis to participants who were amyloid-positive at baseline revealed an even stronger relationship between excessive daytime sleepiness and amyloid accumulation over time, hinting that perhaps a bidirectional process may already be at play. Additional studies are needed to determine whether treating sleep disorders early may mitigate amyloid accumulation, or could slow amyloid accumulation in people who are already amyloid-positive.
This is a very interesting study in JAMA Neurology by Vermuri and colleagues, showing a link between excessive daytime sleepiness (EDS) and longitudinal accumulation of Aβ. As stated by the authors, EDS is likely a consequence of disruption of night-time sleep patterns, and thus adds to the growing literature supporting the link between poor sleep and increased risk for Alzheimer’s disease—particularly the relationship between poor sleep and increased brain Aβ burden. This work, in a quality longitudinal cohort, adds further support to previous work from other highly characterised longitudinal studies of aging, such as the Australian Imaging, Biomarker, and Lifestyle (AIBL) study. Previous studies in AIBL have reported associations of suboptimal sleep characteristics (determined by PSQI) and increased brain Aβ burden (Brown et al., 2016). Together these studies add further weight to the exploration of potential mechanisms that mediate the relationship between suboptimal sleep and brain Aβ burden. One such suggested mechanism is the glymphatic system (Iliff et al., 2012), which functions during sleep and would likely be significantly affected by poor sleep. Supporting the potential importance of the glymphatic system in this relationship is our recently published study that shows moderation of the sleep-Aβ-burden relationship by genetic variation in the Aquaporin-4 (AQP4) gene (Rainey-Smith et al., 2018). AQP4 encodes a water-channel protein located in the astrocytic end feet and is believed to be a key component of the glymphatic system. Overall, the growing body of literature strongly indicates that potentially addressing suboptimal sleep, through intervention strategies, warrants further investigation. Further, the potential that there is genetic moderation of these relationships is also of significant interest as it could allow for more individualised interventions.
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I find this study to be very interesting and I'm looking forward to see what doors it can open for future research.
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