The duration and quality of a person’s sleep influence their risk of developing Alzheimer’s disease, according to two papers in the October 21 JAMA Neurology. In a longitudinal study led by David Bennett, Rush University Medical Center, Chicago, good, restful slumber dampened the harmful effects of the top AD risk gene, ApoE4. In a smaller, cross-sectional study, researchers led by Susan Resnick, National Institutes of Health (NIH), Baltimore, found that seniors who sleep less rack up more Aβ deposits, a key pathological hallmark of AD in the brain. The studies provide further evidence that the quality of a person’s sleep—which is distinct from a disorder such as sleep apnea—influences the risk of dementia. A paper in the October 18 Science offers a possible reason for the connection. From real-time analyses of protein trafficking in mice, researchers led by Maiken Nedergaard, University of Rochester Medical Center, New York, found that animals clear Aβ and other metabolites from the brain more effectively while they are in the land of nod. This paper implies that the physiological function of sleep is to essentially wash the brain free of the day’s debris.
Since the 1990s, researchers have known that AD patients have trouble sleeping (Foley et al., 1995). More recent work suggests that people sleep poorly in the preclinical phase of AD, even before cognitive symptoms show up (ARF news story). Interrupted sleep has been linked to poorer cognition and greater risk of dementia and mild cognitive impairment (Blackwell et al., 2006; Blackwell et al., 2011; ARF news story).
In July, Bennett and colleagues reported that cognition declined faster in older adults who slept in fits and starts, and that they were more likely to be subsequently diagnosed with AD than those who slept well (Lim et al., 2013). Studies in AD mouse models and cultured cells have shed light on possible mechanisms. They suggested that brain Aβ levels drop during sleep and rise with wakefulness (ARF news story), and that ApoE may stymie Aβ clearance (ARF news story).
The current paper extends these findings by addressing whether a good night’s sleep influences ApoE4’s effect on AD risk and disease pathology. First author Andrew Lim, University of Toronto, and colleagues fitted healthy older people in the Rush Memory and Aging Project (mean age 82)—the same cohort they studied for their July paper—with actimetry sensors that monitored their wrist movements. That served as a readout for how fragmented their sleep was over 10 days. During a 3–6 year follow-up in which participants underwent annual neuropsychological testing, 98 of the 698 participants developed AD. Among those who slept fitfully, four times as many ApoE4 carriers developed AD as non-carriers, consistent with the three- to fourfold increased risk normally conferred by these risk gene. However, among participants who slept well (90th percentile), E4 carriers were only twice as likely to develop the disease. In other words, a restful sleep halved the AD risk otherwise associated with the E4 allele, Lim told Alzforum. Since follow-up sleep measurements were unavailable for some participants, the researchers only analyzed baseline actigraphy when looking at E4 effects on incident AD and cognitive decline. For neuropathological analyses, they used the last available sleep data for those participants, which occurred on average 18 months prior to death, Lim noted.
The researchers also analyzed postmortem brain tissue from 201 participants who had died during the course of the study. Neurofibrillary tangles had ravaged the brains of E4 carriers more severely than the brains of non-carriers. However, the tangles were less dense in good sleepers than in poor sleepers. Curiously, Lim and colleagues found no relationship between sleep and Aβ deposition. Research, including human neuroimaging studies, suggests ApoE4 can contribute to brain function and AD via Aβ-independent mechanisms (ARF news story; Huang, 2010).
The other JAMA Neurology study did find a connection between sleep and amyloid, albeit using a different approach. First author Adam Spira of Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues wondered if disturbed sleep drives cognitive decline by promoting Aβ accumulation in the brain. The researchers analyzed brain scans of 70 older adults (mean age 76) who had undergone positron emission tomography (PET) with the amyloid tracer Pittsburgh Compound B (PiB) as part of the Baltimore Longitudinal Study of Aging. They stratified participants by duration and quality of sleep through questionnaires and interviews administered within two years of the scans. People who slept fewer hours or with more interruptions had more brain amyloid than those who slept longer or more soundly, Spira told Alzforum. The association held after accounting for four people who turned out to have had MCI or dementia at the time of their scan, suggesting that a connection between sleep and amyloid exists before people become cognitively impaired.
David Holtzman of Washington University School of Medicine, St. Louis, found it interesting that the authors could detect elevated Aβ deposition without direct measures of sleep such as actigraphy or electroencephalography (EEG). “It demonstrates the usefulness of questionnaires in sleep research,” he said, noting it will be important to validate the results with EEG-based measures.
It remains unclear if sleep troubles cause or result from brain Aβ accumulation, or both. It could be that sleep disruption helps kick off plaque formation, but once enough pathology accumulates, the Aβ causes further breakdown of circadian rhythms, suggested Bryce Mander of the University of California, Berkeley. He said further research is needed to clarify how sleep physiology relates to AD neuropathology, and how those relationships lead to cognitive decline. Another big question is whether a sleep deficit in midlife could make people more prone to dementia years later. “We are such a sleep-deprived society that we have to wonder whether that might have scary implications for AD prevalence,” Spira told Alzforum.
To Sleep, Perchance to Flush?
Aβ and other toxic molecules associated with neurodegenerative disease flow out of the brain more quickly when the mouse is asleep (left) than when it is awake (right). Image credit: Nedergaard Lab, University of Rochester Medical Center.
The Science paper offers some clues. It extends earlier work from the Nedergaard lab showing that mice flush Aβ out of their brain by way of a newly discovered glymphatic pathway detectable by magnetic resonance imaging (see ARF news story and ARF related news). This pathway mimics the lymph system that filters fluids everywhere in the body except the brain. In the current study, lead author Lulu Xie and colleagues infused fluorescent tracers into the cerebrospinal fluid (CSF) of wild-type mice and tracked their movement in and out of the brain’s interstitial space. They found that 60 percent more CSF flows through the interstitial space when animals are asleep, relative to when they are awake. To test if the increased flow clears harmful metabolites from the brain, the scientists monitored interstitial levels of I125-radiolabeled Aβ1-40 injected into the brains of awake, sleeping, or anesthetized mice. They found that sleeping or anesthetized animals cleared Aβ, as well as other solutes, twice as quickly as did the mice that were awake. “It is possible that sleep subserves the important function of clearing multiple potentially toxic central nervous system waste products,” the authors write.—Esther Landhuis
- Sleep Patterns, Circadian Clock Linked to Aβ Oxidative Stress
- Breathe Deep—Nighttime Oxygen Loss Linked to Dementia
- Sleep Deprivation Taxes Neurons, Racks Up Brain Aβ?
- ApoE Does Not Bind Aβ, Competes for Clearance
- Does ApoE4 Lower Brain Metabolism Independently of Aβ?
- Brain Drain—“Glymphatic” Pathway Clears Aβ, Requires Water Channel
- Spinal Fluid Flush: Visualizing the Brain Drain With MRI
- Foley DJ, Monjan AA, Brown SL, Simonsick EM, Wallace RB, Blazer DG. Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep. 1995 Jul;18(6):425-32. PubMed.
- Blackwell T, Yaffe K, Ancoli-Israel S, Schneider JL, Cauley JA, Hillier TA, Fink HA, Stone KL, . Poor sleep is associated with impaired cognitive function in older women: the study of osteoporotic fractures. J Gerontol A Biol Sci Med Sci. 2006 Apr;61(4):405-10. PubMed.
- Blackwell T, Yaffe K, Ancoli-Israel S, Redline S, Ensrud KE, Stefanick ML, Laffan A, Stone KL, . Association of sleep characteristics and cognition in older community-dwelling men: the MrOS sleep study. Sleep. 2011 Oct;34(10):1347-56. PubMed.
- Lim AS, Kowgier M, Yu L, Buchman AS, Bennett DA. Sleep Fragmentation and the Risk of Incident Alzheimer's Disease and Cognitive Decline in Older Persons. Sleep. 2013;36(7):1027-1032. PubMed.
- Huang Y. Abeta-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease. Trends Mol Med. 2010 Jun;16(6):287-94. PubMed.
- Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012 Aug 15;4(147):147ra111. PubMed.
- Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, Benveniste H. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest. 2013 Mar 1;123(3):1299-309. PubMed.
- Canessa N, Ferini-Strambi L. Sleep-disordered breathing and cognitive decline in older adults. JAMA. 2011 Aug 10;306(6):654-5. PubMed.
- Mander BA, Rao V, Lu B, Saletin JM, Lindquist JR, Ancoli-Israel S, Jagust W, Walker MP. Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging. Nat Neurosci. 2013 Mar;16(3):357-64. PubMed.
- Spira AP, Gamaldo AA, An Y, Wu MN, Simonsick EM, Bilgel M, Zhou Y, Wong DF, Ferrucci L, Resnick SM. Self-reported Sleep and β-Amyloid Deposition in Community-Dwelling Older Adults. JAMA Neurol. 2013 Oct 21; PubMed.
- Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18;342(6156):373-7. PubMed.
- Lim AS, Yu L, Kowgier M, Schneider JA, Buchman AS, Bennett DA. Modification of the Relationship of the Apolipoprotein E ε4 Allele to the Risk of Alzheimer Disease and Neurofibrillary Tangle Density by Sleep. JAMA Neurol. 2013 Oct 21; PubMed.