Poor Quality Sleep Tied to Early Signs of Alzheimer's

Damian McNamara

January 14, 2019

Poor quality sleep in later life is associated with early signs of Alzheimer disease (AD), results of a longitudinal observational study show.

Investigators found higher levels of β-amyloid deposition and tau accumulation in the brain — both of which are hallmarks of AD — in older adults who spent less time in non-rapid eye movement (NREM) slow wave sleep.

"What's interesting is that we saw this inverse relationship between decreased slow-wave sleep and more tau protein in people who were either cognitively normal or very mildly impaired, meaning that reduced slow-wave activity may be a marker for the transition between normal and impaired," principal investigator Brendan P. Lucey, MD, director of the Sleep Medicine Section and assistant professor of neurology at Washington University School of Medicine, St. Louis, Missouri, said in a statement.

"Alzheimer’s disease and sleep are currently thought to have a two-way or bidirectional relationship," Lucey told Medscape Medical News.

"First, sleep disturbances may increase the risk of developing AD. Second, changes in sleep-wake activity may be due to AD pathology — and our paper primarily focused on this aspect of the relationship." 

"If sleep changes were a marker for AD changes in the brain, then this would be very helpful in future clinical trials and possibly screening in the clinic," he added.

The study was published online January 9 in Science Translational Medicine.

Sleep Disruption

The local accumulation of tau in the medial temporal lobe during normal aging is likely independent of β-amyloid, the researchers note.

"However, in AD, its spread to the neocortex appears to be downstream from β-amyloid peptide buildup and correlates strongly with neuronal cell loss, synaptic loss, brain atrophy, and cognitive impairment," they write.

In general, β-amyloid aggregation reaches close to peak levels by the time clinicians are able to detect the earliest clinical signs of AD.  At this point, some neocortical tau pathology is present in the majority of patients.

The investigators previously demonstrated overnight cerebrospinal fluid (CSF) β-amyloid concentrations increased by 10% to 30% in targeted, slow wave sleep disruption and sleep deprivation. The rise, they propose, is associated with increased β-amyloid production and/or release.

The current study included 119 individuals older than 60 years of age who underwent single-channel EEG monitoring. The investigators gathered additional information through actigraphy, sleep logs, and a home sleep test to detect sleep-disordered breathing or periodic leg movements.

The investigators evaluated cognitive performance using the Clinical Dementia Rating (CDR) scale.  Participants had AV-45 amyloid and AV-1451 tau PET imaging and/or a lumbar puncture to measure CSF β-amyloid 42, tau, and p-tau concentrations.

"Because tau pathology, but not β-amyloid pathology, is best associated with cognitive decline in AD, we hypothesized that decreased non-REM slow wave activity would be associated with increased tau pathology," the researchers write.

Robust Relationship

The associations between the non-REM findings and increased tau pathology were strongest in the entorhinal, parahippocampal, inferior parietal, insula, isthmus cingulate, lingual, supramarginal, and orbitofrontal regions of the brain. These regional results emerged on AV-1451 tau positron emission tomography (PET) composite imaging.

"I was surprised by the robustness of the relationship between non-REM slow wave activity and tau," Lucey said.

At the same time, decreased non-REM slow wave activity (SWA) was associated with increased β-amyloid deposition in the frontal, temporal, inferior parietal, supramarginal, and isthmus cingulate regions. The 1 Hz to 4.5 Hz and 1 Hz to 2 Hz EEG frequency ranges were particularly relevant.

Overall, the 1 Hz to 2 Hz range revealed the most information regarding the relationship between non-REM sleep and tau aggregation. This frequency range revealed tau spatial patterns similar to findings reported by other researchers, such as cortical thickness changes associated with AD.

"Because the study participants were predominantly cognitively normal with the remaining showing only very mild impairment, this suggests that decreased NREM SWA, especially at the lowest 1- to 2-Hz frequencies, might be associated with tau pathology either before or at the earliest stages of cognitive decline," the researchers note.

After correcting for multiple comparisons, several regions on AV-1451 tau PET remained significant in the 1- to 4.5-Hz non-REM slow wave activity frequency range, including the entorhinal, parahippocampal, orbital frontal, precuneus, inferior parietal, and inferior temporal regions (all P < .05).

"We also showed that increased CSF tau/β-amyloid peptide 42 ratio, another marker of AD pathology, was inversely associated with non-REM slow wave activity," the investigators write.

"We observed these associations after adjustment for multiple potential confounders, particularly age, sex and Clinical Dementia Rating, supporting a strong relationship independent of these factors," they add.

The CDR scores ranged from 0 for no impairment to 3, indicating maximal impairment. Of the 38 participants who completed PET imaging, 76% had a score of 0 and 24% had a score of 0.5.

These percentages aligned with findings among the 104 participants who underwent lumbar puncture for CSF collection; 80% of this group had a 0 and 20% scored a 0.5.

Ask About Napping

In terms of sleep characteristics measured on EEG, REM latency (F 1,30 = 12.5, P = .001) and sleep latency (F 1,29 = 4.4, P = .045) were significantly and inversely associated with β-amyloid deposition. This suggests that as β-amyloid levels increased, the time to fall asleep and enter REM sleep decreased, the researchers note.

"Not surprising" to investigators was the finding that male sex and older age were also associated with decreases in non-REM slow wave activity. No sleep parameters measured by sleep log or actigraphy were associated with AV-45 amyloid PET findings.

In contrast, increased total sleep time measured by single-channel EEG and sleep log were associated with increasing tau pathology on PET, as was self-reported increased time spent napping.

"These results, coupled with the non-REM slow wave activity findings, suggest that the quality of sleep decreases with increasing tau despite increased sleep time. Furthermore, self-reported napping time per day may be an important question to screen individuals for tauopathy," the researchers write.

With the rising incidence of AD in an aging population, the investigators note that the findings have "potential application in both clinical trials and patient screening for AD to noninvasively monitor for progression of AD pathology. For instance, periodically measuring non-REM slow wave activity, in conjunction with other biomarkers, may have utility [in] monitoring AD risk or response to an AD treatment."

"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 said.

Before the findings are ready for prime time in a clinical setting, "there needs to be further studies replicating and extending these results before we can use sleep to screen for AD risk or response to an anti-AD therapy," he noted.

Use of multiple measures is a strength of the study. An inability to establish whether sleep disturbances predated or came after development of AD pathology is a potential limitation.

"A critical piece of information missing from this study is the timing of sleep changes to when amyloid and tau pathology starts in the brain," Lucey said.  "Although we suspect, based on our results, that the sleep changes we observed occur either immediately before or immediately after memory problems begin, we need longitudinal studies to determine this timing."

A Clear Link

Commenting on the findings for Medscape Medical News, Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer’s Association, said there is a clear link between sleep and brain health.

"This study fits well into the growing body of research that shows a relationship between sleep and brain health. Though the exact nature of the relationship is not yet known, with continued investment in Alzheimer’s and dementia research we’re learning more all the time," he said.

"There are some key limitations that reduce our ability to interpret these results, or generalize about their meaning for clinicians and the public. Because of the way this study was conducted, it cannot demonstrate whether sleep irregularities preceded the Alzheimer's disease pathology, or vice versa, or whether they developed together. The study cohort was very small, with only 38 participants receiving PET imaging," Fargo added.

There have been studies that link conditions such as sleep apnea, insomnia memory, thinking memory, and thinking problems, said Fargo. He noted that the Alzheimer's Association's 10 Ways To Love Your Brain lists getting enough sleep as one healthy lifestyle habit to maximize overall brain and body health.

The study was supported by multiple NIH grants, The Ellison Medical Foundation, the Willman Scholar Fund, the Foundation for Barnes-Jewish Hospital, and a Physician Scientist Training Award from the American Sleep Medicine Foundation. Lucey and Fargo have disclosed no relevant financial relationships.

Sci Transl Med. Published online January 9, 2019. Abstract

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