Researchers have uncovered new evidence of a link between disturbed sleep and Alzheimer’s disease (AD) that involves neuronal damage and inflammation in addition to amyloid plaques.
Investigators at the University of Wisconsin-Madison found that self-report of inadequate sleep and greater daytime sleepiness in older, middle-aged, cognitively normal persons is associated with cerebrospinal fluid (CSF) biomarkers of amyloid deposition in combination with tau pathology, axonal degeneration, and neuroinflammation.
Previous research has also suggested a link between sleep and AD.
Dr Barbara B. Bendlin
“What’s new about our study is that participants were somewhat younger than in prior studies, none of them had dementia yet, and we also were able to look at these novel markers in CSF,” Barbara B. Bendlin, PhD, associate professor, medicine, University of Wisconsin-Madison and Wisconsin Alzheimer’s Disease Research Center, told.
“The results are, again, providing support that quality of sleep and brain changes may be linked. But the follow-up to that would be to see if modifying sleep could potentially protect the brain,” she added.
The study was published online July 5 in Neurology.
CSF Biomarkers
The study included 101 participants in the Wisconsin Registry for Alzheimer’s Prevention (WRAP), mean age 64 years, who had undergone lumbar punctures to provide CSF samples, were cognitively normal, and had completed sleep questionnaires.
One of these questionnaire was the Medical Outcomes Study (MOS) Sleep Scale, which provides scores in six sleep domains, derived from 12 questions. Another was the Epworth Sleepiness Scale (ESS), which rates the likelihood of dozing off in eight common situations, with higher scores indicating greater sleepiness.
Researchers also conducted secondary analyses of symptoms of sleep-disordered breathing, including snoring and being short of breath upon wakening.
CSF biomarker data included amyloid deposition and plaque formation (Aβ42), tau phosphorylation state and tau pathology (p-tau), axonal degeneration (t-tau), neurofilament light (NFL), neuroinflammation (MCP- 1), chitinase-3–like protein 1 (YKL-40), and synaptic dysfunction/degeneration (neurogranin).
Aβ42 was expressed in ratios to Aβ40, and the other biomarkers were expressed in ratios to Aβ42. CSF Aβ42 decreases as plaque burden increases, whereas the other CSF markers are elevated when pathology is greater. So lower Aβ42 and Aβ42/Aβ40 indicate greater pathology, while ratios of other markers to Aβ42 indicate greater pathology when elevated.
Investigators classified study participants into carriers or noncarriers of one or more APOE ε4 alleles.
The investigators found that lower Aβ42/Aβ40 levels were associated with worse sleep adequacy and that increased phosphorylated tau, total tau, NFL, MCP-1, and YKL-40, which reflect greater neuropathology, were associated with somnolence and/or sleep problems.
The researchers found essentially the same relationships in the approximately 30% of the study participants who had an APOE ε4 allele.
“So even though the group is enriched for genetic risk for sporadic AD, in this case we didn’t see different relationships between the carriers and noncarriers,” said Dr Bendlin.
“That may be not surprising because we know that people who are noncarriers, who don’t carry genetic risk, can develop dementia in future as well.”
No Link to Sleep Apnea?
Interestingly, CSF biomarkers of AD pathology were associated with daytime sleepiness according to the MOS but not the ESS. The difference could be due to the somnolence subscale assessing “resistible” sleepiness, wherein individuals feel drowsy and deliberately nap, whereas the ESS assesses “irresistible” sleepiness, which means falling asleep in inappropriate situations.
“They are probably capturing slightly different self-report qualities of sleep,” said Dr Bendlin.
The study did not show a relationship between CSF biomarkers and symptoms of obstructive sleep apnea (OSA), which the authors found surprising given the evidence that OSA is a risk factor for dementia.
It’s possible, they note, that OSA impedes the transfer of proteins into the CSF, altering the relationship between CSF concentrations and central nervous system pathology in patients with OSA.
It also might be that OSA severity in the sample was too low to detect a relationship with CSF, as on average participants rated their snoring frequency as low.
Dr Bendlin said the study relied on self-report measures and did not objectively measure sleep apnea. “It’s not uncommon for people who have sleep apnea not to know about it.”
The researchers previously showed that poor sleep was associated with greater brain amyloid burden, but the new research reveals further relationships between sleep and CSF biomarkers of cumulative AD pathology.
Modifiable Risk Factor
“These CSF biomarkers have not been validated for predicting future dementia,” so there’s no proven “abnormal level” of a CSF biomarker that shows someone will develop dementia, said Dr Bendlin.
CSF and brain imaging are both “good tools” for studying the development of AD, with each providing complementary information, she said.
“From one CSF sample, we can measure a lot of different proteins, but on the other hand, when we use brain imaging such as amyloid PET, we can actually see where in the brain the amyloid is accumulating.”
The authors noted that abnormalities may become apparent in CSF before PET and that CSF can be collected and assayed by using widely available methods. In contrast, PET remains more expensive and requires substantial infrastructure.
It’s important to identify modifiable risk for AD —including sleep — given that delaying the onset of AD by a mere 5 years would reduce AD cases by 5.7 million and save $367 billion in healthcare spending in the United States, the authors note.
“Many effective pharmaceuticals, devices and behavioral interventions are already available in the clinic for improving sleep quality,” they write.
A limitation of the study was its design. “There is evidence of bidirectional relationships between sleep and amyloid that cannot be disentangled by this cross-sectional study design,” the authors write.
Another limitation was that the study measured sleep through self-report.
“Objective sleep measures such as actigraphy and polysomnography would clarify the contribution of sleeping brain activity, breathing, and sleep-wake rhythmicity to AD pathogenesis” they note.
The researchers are planning a prospective study that will include objective measures of sleep, including OSA, said Dr Bendlin.
Extending the Evidence
In an accompanying editorial, Adam P. Spira, PhD, Johns Hopkins Bloomberg School of Public Health, and Yo-El S. Ju, MD, Washington University School of Medicine, St. Louis, Missouri, note that the study’s use of lesser-known and subjective measures of sleep, with some subscales comprising only two or three items, “is arguably its greatest limitation.”
The lack of objective assessment of sleep-disordered breathing (SDB), which has been associated with CSF measures of both amyloid and tau pathology and with increased risk for cognitive decline, was another limitation for the editorial writers. SDB, they write, is one of the most common and treatable causes of sleep disturbances in the older population.
The editorialists told the study’s most important contribution is that it extends previous research on the link between sleep disturbances and amyloid deposition.
“Prior studies have already shown an association between amyloid plaques — the first known step of Alzheimer’s disease — and sleep disturbance,” said Dr Ju.
“This study adds to that by showing an association between tau and other Alzheimer’s disease biomarkers, which occur later in the Alzheimer’s disease process and sleep disturbance.”
Dr Ju agreed that it’s too early for clinicians to rely on these biomarkers to detect early signs of dementia.
“Since there are no currently known treatments that reverse the AD process, there is no role for CSF biomarker testing for Alzheimer disease in cognitively normal individuals,” she said.
However, she added, treatments are being tested in the preclinical stage of AD through, for example, the Dominantly Inherited Alzheimer’s Network Treatment Unit (DIAN-TU) study and the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study.
“If any of these treatments are shown to be effective, then there would be a strong reason to screen for AD biomarkers — either through neuroimaging or CSF.”
The new findings suggest that while nocturnal sleep may be disturbed early in the process of amyloid deposition, daytime somnolence may be a sign of neurodegeneration and “a window of opportunity for intervention,” the editorialists write.
Dr Bendlin has disclosed no relevant financial relationships. Dr Spira is supported in part by grants from the National Institute on Aging and received funding from the William and Ella Owens Medical Research Foundation. He has agreed to serve as a consultant to Awarables Inc, in support of a National Institutes of Health(NIH) grant. Dr Ju received funding from NIH grants and an investigator-initiated research grant from Philips-Respironics, received honoraria and travel funding from the American Academy of Neurology and the American Academy of Sleep Medicine, and has immediate family members who received honoraria from the Muscular Dystrophy Association and Mercy Hospital St. Louis.
Neurology. Published online July 5, 2017.
