Does Amyloid Disturb the Slow Waves of Slumber—and Memory?
While you were sleeping ... In the June 1 Nature Neuroscience, researchers led by Matthew Walker, University of California, Berkeley, propose that amyloid deposition in the medial prefrontal cortex deprives people of the slow-wave, deep slumber needed to convert short-term memories to long-term ones. The data hint that amyloid pathology disrupts sleep, and that treating sleep deficits might curb Aβ-related cognitive decline.
“Lots of studies have looked at the association between sleep disturbances and cognitive outcomes in older people, but the mechanisms haven’t been clear,” said Adam Spira, Johns Hopkins University, Baltimore, who was not involved in the study. “This is the first evidence that amyloid deposition in a particular region of the brain may lead to reduced slow-wave activity during sleep, undermining overnight memory consolidation.”
Aβ Steals Shuteye: People with low amyloid (left) generate slow oscillations (red) from the medial prefrontal cortex more robustly than people with intermediate (middle) and high (right) amyloid loads. [Image courtesy of Mander et al., Nature Neuroscience.]
It has long been known that people who already have AD or mild cognitive impairment have trouble sleeping (Prinz et al., 1982; Hita-Yañez et al., 2013). In mouse models, too, sleep patterns deteriorate as the animals age and deposit more amyloid in the brain (Roh et al., 2012). Sleep disturbance, in turn, may cause amyloid to accumulate even more, because the brain clears the peptide during slow-wave sleep (Roh et al., 2014; Oct 2013 news on Xie et al., 2013).
How do sleep and amyloid pathology relate to memory? The authors had a hunch that Aβ deposition might disrupt the memory consolidation that happens during sleep. They suspected this because the peptide accumulates in the medial prefrontal cortex, a region that helps generate the slow neuronal rhythms characteristic of deep, non-REM sleep (Murphy et al., 2009). These slow waves are thought to coordinate activity between different areas of the brain and transform short-term memories stored in the hippocampus into long-term ones in the cortex. “It turns out that Aβ targets those specific waves, making them less frequent,” first author Bryce Mander told Alzforum.
Mander and colleagues recruited 26 cognitively healthy volunteers aged 65 to 81, all of whom underwent PiB-PET imaging to assess how much Aβ had built up in their brains. Within a year, they returned to the sleep lab at Berkeley for an overnight memory study. Just before bed, each was trained to pair 120 real words with nonsense ones. They then had eight hours to sleep while researchers recorded their brain-wave activity. In the morning, the subjects recalled as many word pairs as they could, while undergoing fMRI to determine how heavily their recollection relied on the hippocampus. If the memories were consolidated successfully , they should have called on the hippocampus less.
The researchers found that volunteers with the most amyloid deposition in the medial prefrontal cortex generated the fewest slow waves while they were sleeping (see image above). Reduced slow-wave activity in turn correlated with dependence on the hippocampus in the recall task, and with worse overnight retention of the word pairs. To see how these factors interacted, the researchers fit the data to three different mathematical models of association. The model that best fit the data predicted that Aβ impairs memory by first disturbing deep sleep. That then limits memory consolidation, creating a reliance on the hippocampus for recall the next day, which results in weaker memories.
“It’s never been shown in animals or humans that the disruption in sleep that is caused by Alzheimer’s results in memory impairment,” said Mander. “We showed that some of the memory loss resulted from amyloid disrupting specific brain waves associated with deep sleep.”
Mander is not sure which comes first, amyloid buildup or sleep disturbance. However, improving sleep might prevent the memory impairment caused by Aβ deposition, he said. Enhancing slow-wave sleep in young adults improves memory (Marshall et al., 2006). Exercise, electrical or acoustic stimulation, or drugs can all improve sleep patterns. Treatment would likely have the highest impact early in the disease process, said Mander, as it would precede significant neuron loss. However, it’s possible that even treatment later in disease would be somewhat effective, he said.
How does Aβ disrupt those sleep waves? The researchers suspect that the peptide reduces NMDA receptors, which are important for generating slow-wave oscillations and long-term potentiation (Jul 2005 news). Amyloid pathology could increase the amount of tau pathology in the hippocampus, which could degrade communication with the cortex for memory consolidation, or the peptide could kill the neurons that generate slow waves, Mander said. The mechanism remains to be determined.
That the authors have tied together two independent lines of research linking Aβ to memory impairment and sleep is compelling, said Brendan Lucey, Washington University School of Medicine in St. Louis. “If this is replicated, it would support the idea that changes in sleep are involved in the memory impairment of AD.” However, he cautioned that sleep disruption may not be a direct pathological consequence, but rather a biomarker that predicts progression to MCI or AD. He and Spira both agree with the authors that a cross-sectional study cannot prove causation. “To truly establish the sequence of changes that occur in sleep and memory with amyloid deposition, you’d need to do a longitudinal study,” Lucey said.—Gwyneth Dickey Zakaib
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- Prinz PN, Vitaliano PP, Vitiello MV, Bokan J, Raskind M, Peskind E, Gerber C. Sleep, EEG and mental function changes in senile dementia of the Alzheimer's type. Neurobiol Aging. 1982;3(4):361-70. PubMed.
- Hita-Yañez E, Atienza M, Cantero JL. Polysomnographic and subjective sleep markers of mild cognitive impairment. Sleep. 2013 Sep;36(9):1327-34. PubMed.
- Roh JH, Huang Y, Bero AW, Kasten T, Stewart FR, Bateman RJ, Holtzman DM. Disruption of the sleep-wake cycle and diurnal fluctuation of β-amyloid in mice with Alzheimer's disease pathology. Sci Transl Med. 2012 Sep 5;4(150):150ra122. PubMed.
- Roh JH, Jiang H, Finn MB, Stewart FR, Mahan TE, Cirrito JR, Heda A, Snider BJ, Li M, Yanagisawa M, de Lecea L, Holtzman DM. Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer's disease. J Exp Med. 2014 Dec 15;211(13):2487-96. Epub 2014 Nov 24 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.
- Murphy M, Riedner BA, Huber R, Massimini M, Ferrarelli F, Tononi G. Source modeling sleep slow waves. Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1608-13. Epub 2009 Jan 22 PubMed.
- Marshall L, Helgadóttir H, Mölle M, Born J. Boosting slow oscillations during sleep potentiates memory. Nature. 2006 Nov 30;444(7119):610-3. PubMed.
- Peter-Derex L, Yammine P, Bastuji H, Croisile B. Sleep and Alzheimer's disease. Sleep Med Rev. 2014 Apr 3; 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.
- Wang P, Wing YK, Xing J, Liu Y, Zhou B, Zhang Z, Yao H, Guo Y, Shang Y, Zhang X. Rapid eye movement sleep behavior disorder in patients with probable Alzheimer's disease. Aging Clin Exp Res. 2015 May 29; PubMed.
- Osorio RS, Gumb T, Pirraglia E, Varga AW, Lu SE, Lim J, Wohlleber ME, Ducca EL, Koushyk V, Glodzik L, Mosconi L, Ayappa I, Rapoport DM, de Leon MJ, Alzheimer's Disease Neuroimaging Initiative. Sleep-disordered breathing advances cognitive decline in the elderly. Neurology. 2015 May 12;84(19):1964-71. Epub 2015 Apr 15 PubMed.
- Villa C, Ferini-Strambi L, Combi R. The Synergistic Relationship between Alzheimer's Disease and Sleep Disorders: An Update. J Alzheimers Dis. 2015 Jun 25;46(3):571-80. PubMed.
- Musiek ES, Xiong DD, Holtzman DM. Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease. Exp Mol Med. 2015 Mar 13;47:e148. PubMed.
- Lucey BP, Holtzman DM. How amyloid, sleep and memory connect. Nat Neurosci. 2015 Jul;18(7):933-4. PubMed.
- Mander BA, Marks SM, Vogel JW, Rao V, Lu B, Saletin JM, Ancoli-Israel S, Jagust WJ, Walker MP. β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nat Neurosci. 2015 Jul;18(7):1051-7. Epub 2015 Jun 1 PubMed.
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