People with moderate to severe Alzheimer’s disease (AD) may be kept awake by a neurotransmitter that goes bump in the night. According to a study published October 13 in JAMA Neurology, cerebrospinal fluid levels of orexin, a peptide neurotransmitter that staves off shut-eye, are elevated in patients with moderate to severe AD. This correlated with bouts of wakefulness in the wee hours, and also with CSF tau, a marker of neurodegeneration. Led by Fabio Placidi at the University of Rome Tor Vergata, Italy, the study suggests that an abundance of orexin may play a part in AD-associated sleep disturbances, which some researchers believe may further promote progression of the disease.
“This study significantly adds to our understanding about the relationships among sleep, orexin, and AD,” wrote Brendan Lucey of Washington University in St. Louis in an email to Alzforum. “It provides additional evidence that sleep is disturbed in moderate to severe AD and that the orexinergic system is involved.”
Sleep disturbances often precede and accompany AD, and may even hasten its onset, though it is not clear how. Lucey’s colleagues at WashU, including Randall Bateman and David Holtzman, have reported that Aβ levels in the CSF drop during a normal night's slumber, whereas in people deprived of sleep it holds steady (Bateman et al., 2007, and Jun 2014 news story on Ooms et al., 2014). In mice, lack of sleep accelerates Aβ deposition, and orexin reportedly boosts Aβ levels as well (see Sep 2009 news story on Kang et al., 2009).
Lucey and colleagues have proposed that this potentially toxic relationship between Aβ deposition and sleep deprivation may accelerate AD pathology in humans as well, and that the neurodegeneration that ensues may further damage parts of the brain essential for a good night’s sleep (see Lucey and Bateman, 2014, and Ju et al., 2014). Overly active orexinergic neurons in the hypothalamus could be one way in which neurodegeneration keeps people awake. Through their far-reaching axon projections, this small population of neurons delivers this neuropeptide (also known as hypocretin) to multiple brain regions, where it promotes wakefulness. Narcoleptics have abnormally low orexin levels, though this does not protect from AD, according to one small study (see Scammell et al., 2012).
Other studies found no differences in CSF orexin levels between people with AD and healthy controls, whereas one study found that people with mild cognitive impairment or AD had elevated orexin levels compared to people with other forms of dementia, such as frontotemporal lobar degeneration and dementia with Lewy bodies (see Dauvilliers et al., 2014).
To help clarify orexin’s role in AD, first author Claudio Liguori and colleagues measured CSF levels of the neuropeptide in people in varying stages of the disease, and also factored in measurements of sleep quality and cognition. The study included 21 people with mild AD, 27 with moderate to severe AD, and 29 healthy controls. The researchers asked volunteers and their caregivers to record their nightly sleep experiences in a diary for one week, and then over two nights placed polysomnography electrodes on them to measure how much and how well they slept. After the second night, the researchers collected CSF samples via lumbar puncture. As expected, people with AD had higher levels of tau and p-tau, and lower levels of Aβ42, than did controls. People with AD also slept poorly—they took longer to enter REM sleep and woke up more often after falling asleep than did controls. Those with moderate to severe disease slept worst of all, according to both polysomnography and sleep diaries. CSF orexin levels did not differ from controls when considering the AD group as a whole. However, people with moderate to severe AD had higher orexin, suggesting that it ramps up as the disease progresses.
The researchers next looked for correlations between AD biomarkers, orexin, sleep quality, and cognition. Levels of CSF total tau rose with orexin levels in both AD groups, as did p-tau in the moderate to severe AD group. No link was found between Aβ42 and orexin in any group; however, waning CSF Aβ42 levels and higher orexin levels each correlated with reduced sleep quality. Scores on the mini mental state exam (MMSE) did not track with orexin or any AD biomarker, but in both AD groups those with the worst sleep patterns had the poorest cognitive scores.
How do these findings mesh with those of previous studies? Three prior studies found no relationship between CSF orexin and AD, but they did not stratify groups by disease severity and had fewer participants (see Wennstrom et al., 2012; Slats et al., 2012; and Schmidt et al., 2013). They may have missed the emergence of high orexin levels later in the disease, Ligouri said. Indeed, when he re-analyzed results from one of the studies (Schmidt et al., 2013), he found a trend toward higher orexin levels in patients with moderate to severe cognitive impairment. A fourth study reported lower levels of orexin and orexinergic neurons in postmortem brains from AD patients. Liguori and colleagues speculated that those patients had more advanced stages of the disease (Fronczek et al., 2013).
While Liguori and colleagues observed a link between CSF tau and orexin levels, they did not see a connection between CSF Aβ and orexin. This conflicts with Slats’ 2012 study on a small number of AD patients. Liguori concluded that in his cohort, CSF Aβ levels had already bottomed out; indeed, he found no difference in Aβ levels among patients with mild and moderate to severe AD.
“The results clearly demonstrate and support a role for dysregulation of the orexinergic system in AD,” wrote Henrietta Nielsen of the Mayo Clinic in Jacksonville, Florida, in an email to Alzforum. Nielsen, who led one of the studies that found no connection between orexin levels and AD, wrote that to understand the underlying molecular pathways, studies will have to combine antemortem CSF and postmortem brain tissue analysis of patients who progressed from mild cognitive impairment to AD.
Are rising orexin levels a consequence of AD, or an early part? Liguori believes that orexin’s rise may help drive the disease. “The increased orexinergic tone seems to cause poor sleep quality, and it is well known that sleep dysregulation alters cognition,” he wrote in an email to Alzforum, concluding, “In AD patients, impaired sleep may accelerate cognitive decline.” The authors hypothesized that a breakdown in cholinergic signaling, which normally dials down orexin output, may open the floodgates of orexin release in the context of AD.
In contrast, Lucey believes that abnormal orexin levels are likely a consequence of AD. “Given the lack of correlation between CSF orexin concentration and mild AD, I think the study suggests sleep disturbance is more likely to be a result of AD rather a key part of AD pathogenesis,” he wrote. He added, however, that a larger group size could have teased out the beginnings of orexin’s rise in mild cases.
Either way, Liguori and colleagues propose that blocking the neurotransmitter with receptor antagonists could at least help AD patients sleep better at night. In an accompanying editorial, Luigi Ferini-Strambi of the Vita-Salute San Raffaele University in Milan proposed to go even further. “It could be hypothesized that the use of orexin receptor antagonists as potential drugs targets the downregulation of the orexinergic system not only for the management of sleep disturbances in AD, but also for a slower progression of the neurodegenerative process,” Ferini-Strambi wrote. In August, Merck’s Belsomra became the first orexin receptor antagonist approved by the FDA for the treatment of insomnia.—Jessica Shugart
- While You Were Sleeping—Synapses Forged, Amyloid Purged
- Sleep Deprivation Taxes Neurons, Racks Up Brain Aβ?
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No Available Further Reading
- Liguori C, Romigi A, Nuccetelli M, Zannino S, Sancesario G, Martorana A, Albanese M, Mercuri NB, Izzi F, Bernardini S, Nitti A, Sancesario GM, Sica F, Marciani MG, Placidi F. Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. JAMA Neurol. 2014 Dec;71(12):1498-505. PubMed.