Dr Ricardo OsorioRicardo Osorio, MD
Even without the growing number of adults with dementia in the United States, the need to understanding factors responsible for cognitive impairment has reached a critical point.

Recent studies have suggested that the sleep-wake cycle may have a direct influence on the levels of cerebrospinal fluid (CSF) amyloid beta (Aβ) and tau concentrations—2 of the key biomarkers of Alzheimer disease pathology.

Specifically, research has shown that slow-wave sleep activity in non-REM stage 3 is associated with high levels of CSF Aß, and disruption of slow-wave sleep can increase Aß peptides in the CSF. However, the associations between slow-wave sleep and tau have not been observed, which may be suggestive that disruption in other sleep oscillations could potentially be linked to tau pathology, according to Ricardo Osorio, MD, an associate professor in the department of psychiatry at NYU Langone.

To find out more about the research Osorio and others have done, NeurologyLive sat down with Osorio to discuss the relationship between sleep disruption and Alzheimer disease.

NeurologyLive: What’s been learned recently about sleep’s association with Alzheimer disease?

Ricardo Osorio, MD: For years we've known that Alzheimer disease disrupts sleep, and in the last 5 to 7 years, we have new data that is showing that sleep disruption is not only a consequence of Alzheimer but also a risk factor. Meaning that sleep disruption early in late adulthood or early in the younger elderly could be a risk factor for Alzheimer. What our data are showing is that when there is a disruption in slow-wave sleep, one of the stages of non-REM sleep, there is an increase in Aß production, which is biomarker and one of the hallmarks of Alzheimer. We believe that disruption of slow-wave sleep could increase amyloid burden and, in the long-term, increase risk for Alzheimer.

What does this mean for the clinician community?

The interesting part about learning about this mechanism is that slow-wave sleep is a stage of sleep that we can enhance using drugs, but there are new therapies that do not involve pharmacological therapy. You can increase the slow-wave sleep using sounds or electrical stimulation, so this opens a new potential therapy of for prevention of Alzheimer and this is very exciting.

There's also a second finding that we reported, which is that we also see an association between tau and sleep spindles. We are seeing that the elderly that are cognitively normal that have increased levels of CSF P-tau and T-tau, which are markers of neurofibrillary tangles, have decreased sleep spindles. Sleep spindles are sleep oscillations that occur in non-REM Stage 2 that have been associated with memory and sleep memory consolidation. Our findings suggest that if you have increased neurofibrillary tangles, you have less you sleep spindles, and this could be one of the mechanisms by which tau disrupts memory.

We know that tau is associated with cognition much better than Aß, and when tau is increased in hippocampus, it's usually correlated with decrease memory. This association between tau and decreased sleep spindles could explain how this happens. We think that's also very relevant. Again, sleep spindles can also be increased using sounds or electrical stimulation, so we're talking about potential new therapies to prevent Alzheimer and to treat some of the symptoms of Alzheimer's before the dementia stage, and potentially new therapies for prevention.

Was there anything else your research has shown?

We also looked at one of the most common sleep disorders, which is sleep apnea, and research in my lab has also shown that sleep apnea in the normal elderly also changes Alzheimer biomarkers. We have shown that the normal elderly with sleep apnea show more change in amyloid biomarkers over time, and they have increased Aß over time, suggesting that sleep apnea increases Alzheimer disease risk and that the treatment of sleep apnea could also delay the onset of Alzheimer.

What still needs to be addressed in the relationship between sleep and Alzheimer?

We still need to know more about the mechanism. We are just seeing some of the pathways that could be in both—we don't know if inflammation caused by sleep apnea is involved and we don't know if there are differences in men and women. The biggest question would be if we start therapy with CPAP for sleep apnea or with this neurostimulation of slow-wave sleep. if we can actually have an effect and show that we are able to delay or prevent the onset of Alzheimer. We need to know a little bit more about mechanism, and we need to know more about clinical relevance of these findings. The most difficult question would be if we improve sleep, do we really have an effect on how Alzheimer presents, and actually if we can prevent the onset.
REFERENCES
Osorio RS, Varga AW. Sleep oscillations and the pathogenesis of
Alzhiemer’s disease. Presented at: Congress of the European Sleep Research Society meeting; Basel, Switzerland; September 25 to September 28, 2018. onlinelibrary.wiley.com/doi/epdf/10.1111/jsr.12751. Accessed January 14, 2019.