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Less deep sleep tied to tau pathology in early Alzheimer’s disease
Researchers observed an inverse relationship between decreased slow-wave sleep and more tau protein in older adults who were either cognitively normal or very mildly impaired.
These findings, published in Science Translational Medicine, indicate that poor-quality sleep may be a red flag before or in the earliest stages of symptomatic Alzheimer’s disease, according to researchers.
“Sleep and Alzheimer’s disease are currently thought to have a two-way or bidirectional relationship: There is evidence to suggest that sleep disturbances increase the risk of developing Alzheimer’s disease. Alternatively, changes in sleep-wake activity may be due to changes in the brain from Alzheimer’s disease,” Brendan P. Lucey, MD, assistant professor of neurology department and director of the sleep medicine section at Washington University School of Medicine, told Healio Psychiatry. “Our paper investigated this second question: sleep as a marker for Alzheimer’s disease changes in the brain.”
Lucey and colleagues examined the connection between sleep and Alzheimer's disease in 119 adults aged 60 years and older enrolled in longitudinal studies of aging.
They analyzed participants’ cognitive performance, brain imaging and Alzheimer’s disease biomarkers in cerebrospinal fluid (CSF). They assessed participants’ sleep-wake activity over 6 nights using portable EEG worn on the forehead, wrist-worn actigraphy and participant-reported sleep logs that recorded both nighttime sleep sessions and daytime napping.
The results showed that non-REM slow-wave activity was inversely related to Alzheimer’s disease pathology, measured by PET imaging and CSF biomarkers, after adjusting for covariates. Specifically, Lucey and colleagues found that decreased slow-wave sleep was linked to higher levels of tau in the brain as well as a higher tau-to-amyloid ratio in CSF, according to the press release.
“A major implication of our study is that measuring non-REM slow-wave activity may be a way to non-invasively and inexpensively screen for risk for cognitive decline due to Alzheimer’s disease,” Lucey said. “This would be very helpful in future clinical trials and possibly screening in the clinic. There are a number of experimental therapies targeting tau that are in clinical trials. If any of these agents prove to be successful, the early detection of non-REM slow-wave abnormalities may prove to be a useful way to monitor the success of such treatments.”
The investigators also found that higher CSF tau/amyloid-beta 42 ratio, another marker of Alzheimer’s disease pathology, was inversely linked to non-REM slow-wave activity. Furthermore, analyses showed that decreases in non-REM slow-wave activity were most distinct with amyloid-beta deposition in areas of the frontal, temporal and parietal lobes.
“Regarding recommendations for patients and clinicians today, I recommend that patients with a sleep concern or evidence of a sleep disorder should be referred to a sleep specialist for evaluation and treatment if needed,” Lucey told Healio Psychiatry. – by Savannah Demko
Disclosure: Lucey reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Caring for patients with dementia is often extremely complicated, just as the course of dementia is for patients. Sadly, the care of patients with dementia is made more difficult by the inability of clinicians to accurately predict who will develop the disease, diagnose it early and modify its course. While research has not yet advanced to the point of answering these important questions, it has provided a pathological basis for the development of the most common type of dementia, Alzheimer’s disease (AD).
Before the clinical symptoms of AD develop, the brain begins to accumulate amyloid-beta (AB) which is followed later by the aggregation of tau proteins. This forms the basis of the pathology of AD as plaques and tangles form in the brain, leading to neuron death, brain atrophy and eventually cognitive impairment. Typically, this process takes many years to occur, by which time it is too late to intervene in changing the course of the disease. This inability to predict persons most at risk for developing AD and those already experiencing early pathological changes renders clinicians helpless to intervene.
In designing this study, Lucey et al. set out to push the discussion of previously well-established links between poor sleep and AD toward a focus on non-rapid eye movement sleep (NREM). A lack of total sleep hours, poor quality sleep with frequent awakenings and decreased rapid eye movement (REM) sleep have all been linked with the incidence of AD. These disturbances impair the clearance of extracellular AB which occurs during sleep and is key to the pathological development of AD.
While earlier research has focused on this link between REM and AD risk, slow wave non-rapid eye movement (NREM) sleep has also been investigated as a possible detector for AD risk. Lucey et al postulated that NREM may be associated with the increased deposition of AB and especially tau aggregation that precedes AD onset. By correlating CSF biomarkers for AD (AB-42, tau and phosphorylated tau) as well as AB and tau PET imaging with EEG tracings and sleep logs they were able to show an inverse relationship between slow wave NREM sleep and the accumulation of AD biomarkers. Regression analysis was used to remove important confounders such as age, cognitive impairment and biological sex. This adds credence to the findings given the close association of age with AD.
While more research is needed to substantiate these findings, they are nonetheless exciting. Decreased NREM slow wave sleep may be a positive predictor for the development of AD. If these sleep cycle changes can be clearly correlated with AD biomarkers and thereby pathology, clinicians move one step closer to having the means to predict and detect AD before it causes irreversible neuronal loss. It also makes it possible to utilize a disease modifying treatment, once available, to change the pathological development of AD. And that would be an absolute game changer.