Small Trial Shows FDA-Approved Insomnia Treatment Decreases Alzheimer Proteins in Healthy Adults

In a small clinical trial, researchers found that patients taking suvorexant, an FDA-approved treatment for insomnia, had reduced levels of amyloid beta (amyloid-β) and tau phosphorylation proteins, which play a major role in neurodegeneration in Alzheimer disease. Still, further trials are needed to determine whether suvorexant has long-term efficacy in reducing neurodegeneration.

Additional Resource: Lucey BP, Liu H, Toedebusch CD, et al. Suvorexant acutely decreases tau phosphorylation and aβ in the human CNS. Ann Neurol. 2023;94(1):27-40. doi:10.1002/ana.26641

Want to learn more about this research? Read our research summary on the study, "Suvorexant acutely decreases tau phosphorylation and aβ in the human CNS" by Lucey et al.

For all of our research summaries, click here.

TRANSCRIPTION:

Consultant360: Can you provide some background on how your study came about?

Brenden P. Lucey, MD, MSCI: There's been a lot of work over the last 15 to 17 years looking at the relationship between sleep and Alzheimer's disease. There was a study published back in 2009 in David Holtzman's lab at Washington University, where, in mice, they were able to show that an important protein in the development of Alzheimer's disease, amyloid beta, fluctuates up and down with sleep-wake activity. It's higher during wakefulness/lower during sleep. This was later shown in humans to also be true, that this soluble level of amyloid beta went up and down with sleep-wake activity.

In that 2009 science paper, the Holtzman Lab had also manipulated sleep to see if they could alter the concentration. They used a drug called almorexant, which is a dual orexin receptor antagonist. They showed that when that drug was administered, sleep was increased. The amount of amyloid beta in the fluid dropped acutely. Over hours, that the level got lower. If they gave this drug for eight weeks, they actually reduced the amount of plaque that formed in the brain.

I was very interested in doing translational work in this area. We first did a paper looking at sleep deprivation, like could you sleep deprive individuals and increase the levels? We showed that could be done. Then, as a follow-up study, we used a drug called suvorexant, which is in the same class as almorexant. It blocks this wake-promoting protein in the brain called orexin. Suvorexant had just been approved by the Food and Drug Administration to treat insomnia, so very safe and had good efficacy data about its effect on sleep. We were interested in translating that finding of... Could you lower the amount of the amyloid beta protein in the fluid around the brain with this drug? We couldn't look at the amyloid deposition because they would've to be on drug for a very long period of time to see that.

The study was set up to look for individuals who are cognitively unimpaired. No problems with memory and thinking, but they had some evidence based on actigraphy, which is a watch device that measures movement and light. They had to have poor sleep efficiency on that. They didn't sleep very much relative to the amount of time they were in bed. Then, we brought them into our research unit. I placed lumbar catheters which are little tubes that go into the lower back where there's a fluid-filled space that connects with the brain. By sampling that fluid, you're sampling the fluid that's also around the brain. Then, those were placed at night: those catheters.

That first night, they got either placebo or the drug. Then, they were there for 36 hours. The second night, they also got the placebo and the drug. The study's really a proof of concept or a direct translational study to those mouse experiments because it's important to show that what we can see in mice, where we can seemingly cure everything, also translates to humans before going on and doing larger studies. That was the background of how we came to do the study and really what we were hoping to accomplish with it.

Consultant360: Can you provide an overview of the results of the study and did any of the results surprise you?

Dr Lucey: Yeah. What we found was that the highest dose of the drug... We tested two doses: suvorexant, 10 milligrams, and suvorexant, 20 milligrams, lowered amyloid beta levels. Since that 2009 paper and since the study was conceived, there's been additional work, some of which we've been involved in, showing that sleep can alter the levels of tau in the fluid around the brain, and that sleep actually affects the phosphorylation of the tau protein. If you have too much phosphorylation of tau, you can get a problem with microtubule formation. It leads to these tangles, these accumulations of hyperphosphorylated tau and neurons, which then leads to neuronal death and the symptoms of Alzheimer's disease.

The fact that sleep seemed to be affecting phosphorylated tau was potentially an important finding. We were able to get some additional funding from the NIH to look at different tau forms and phosphorylated forms in samples from the study. We showed that the most abundant phospho-tau form was actually lowered by the drug as well. That was unexpected and very exciting because it raises the possibility of more of a secondary prevention approach.

If the drug only affects amyloid beta, would it reverse the plaques or slow the plaque formation? Or maybe a primary prevention? Prevent them from forming. But if it also can target phosphorylated tau, that gets to this question of... Could you have amyloid accumulated in the brain? You take this drug. You lower the amount of phosphorylated tau/prevent that other step that's necessary to get Alzheimer's disease.

That was one thing that surprised us. We were very thankful to the NIH for providing those additional supplemental funds to do that part of the study. The other thing that I was surprised about was how long the effect persisted. The participants all got the drug about the same time, nine o'clock at night. I had thought that we would be seeing, after a few hours, a drop in amyloid beta. Then, an hour or two, maybe three hours after they woke up, you'd start to see it rise up.

We actually saw a very persistent effect for both the phosphorylated tau and amyloid beta into the middle of the afternoon, which was very surprising and suggests there may be a more persistent effect than just lowering it overnight, which was my initial hypothesis. Then, there was one other thing that surprised me with the study, is that we actually didn't see a significant effect of sleep between the groups. There was a trend for sleep efficiency in the highest group. But it wasn't technically significant. It was only seen for one night. I don't think that this is a problem with the drug. I think this is a significant problem of our study design.

We bring these people into a research unit. It's a new bed. They've got electrodes on their head to monitor sleep. They've got a catheter in their back. Someone's coming into the room literally every two hours to draw blood and CSF samples. It's not conducive to good sleep. We didn't get a great effect. Yet, we saw these fairly significant changes in amyloid beta and phospho-tau.

As we hypothesize in the paper, I wonder if it's a signaling effect because orexin... Its receptor is a G-protein coupled receptor, which has a lot of downstream pathway effects, including some that could affect amyloid beta production and tau phosphorylation. It's very speculative and much more hypothesis-driven. But it was surprising. It suggests... Could there be sleep and non-LEP effects of this drug?

Interestingly, there has never been, to my knowledge, a study testing in mice or humans or any other organism, two different sleep drugs with different mechanisms happen to head, which I think would help to address that question. You have a placebo group, a DORA group, like suvorexant, and then something like zolpidem, which is Ambien. It affects the GABA system. You see... Do you get different effects on these proteins?

Consultant360: What gaps in our knowledge still remain? What studies do you anticipate moving forward?

Dr Lucey: Yeah. I think there's a lot of gaps. There's definitely these mechanistic questions because I work in... Humans are not really things that I can easily work on. I think that these require almost cell lines or mice to really determine what pathways are involved. What I'm interested in and what we're pushing into is taking this class of drug and doing next-step studies, looking at, "How do they affect these biomarkers over longer periods of time, both the soluble and the imaging biomarkers for, say, amyloid as well as tau?"

I think there's important questions here that need to be answered. One, we showed these effect acutely over hours. But you could get a tachyphylaxis phenomenon, where, after three days, everything equilibrates. There's no effect of the drug. I mean, we would not have picked that up with this type of study. You would need to give the drug for longer periods of time.

I think also finding the right dose... This is a problem that has really plagued Alzheimer's disease research. I think the doses that were approved by the FDA were really driven by the effect for insomnia and the risk and benefit of treating the insomnia versus side effects. I do think the equation would change somewhat if this is something that could prevent or delay Alzheimer's disease in terms of what side effects might be tolerated by patients and regulatory agencies. Could you do a higher dose than these? Is it even needed to do a higher dose? I mean, I think that's an important question. If you use the FDA max dose of one of these medicines, if you double it, how much more benefit do you get? Maybe you don't get much more benefit, and you don't need to do that. But demonstrating that chronic treatment, you still get these effects. Then, determining what's the right dose to take forward into larger studies, I think are really key questions.

But one thing I'm incredibly excited about in this area is that these are drugs that are approved. There's actually three in this class now that are approved by the FDA. I mean, if you were my patient, I could prescribe suvorexant, lemborexant, and daridorexant. You go down to the pharmacy and get them. AD has been just really plagued by medications having bad side effects. Even these monoclonals that have recently been approved have leaky blood vessels in the brain and even hemorrhages that have occurred in patients. Suvorexant has been on the market since 2015, lemborexant since 2020, and daridorexant last summer, 2022. A lot of people have taken them and done very well. I think that that's a really exciting aspect, I think, for the future.

Consultant360: Looking ahead, would this approach be one part of a cocktail for somebody who has Alzheimer's disease?

Dr Lucey: No, it's a great question. I think it could depend on how things play out over time. I mean, if this class of drug had a significant effect in terms of preventing either tau phosphorylation... so even someone who has amyloid deposition. They're not going on and having the additional... Because amyloid deposition is not enough to give you Alzheimer's disease. If this drug is slowing or pausing or whatever the other processes that are important, you could imagine using it as a secondary prevention maybe even by itself, where somebody is amyloid positive and cognitive and normal. You start them on this drug.

I think, alternatively, you could have another model where you use these monoclonals, which are very effective at removing amyloid from the brain. Then, something like this drug is used for maintenance because it is so well tolerated and has so few side effects. I certainly think the monoclonals, as they're currently approved in the data we have... I don't think they're going to be the last word by any means or sufficient in and of themselves but potentially paired with other treatments. There's all different interesting... Could you use a lower dose of the monoclonals that maybe have fewer of these bleeding side effects and a drug like suvorexant in combination and see what effect that would be? I think there's a lot of interesting possibilities.

Consultant360: What are the main takeaways from your study?

Dr Lucey: Yeah. I definitely don't think the data in this study would justify any changes in practice. It certainly, though, gets to the potential for these drugs to be a future treatment to prevent or delay Alzheimer's disease symptoms down the road. What I usually tell audiences is that if someone has insomnia or untreated sleep apnea, those should be treated not purely just to prevent Alzheimer's disease but there's a whole host of poor health outcomes that are associated with sleep disturbances and different sleep disorders. Someone has insomnia. You think they need medication. I think that this class of drug... There's a lot of reasons why you might want to have someone on it. This may be evidence that a provider might weigh as well.

There's other reasons, actually, why this class of drug is one that you would consider in certain populations. Suvorexant has an additional indication for insomnia and mild to moderate Alzheimer's disease. It's the effect on sleep, not the effect on the Alzheimer's disease process that's the indication. But it gets to its safety in older adults and everything. I think it's more a promise of something that may come down the road to change practice. But I don't think it changes the way people would practice now. They may get folks who come to their clinic if they're a sleep doctor concerned about sleep and developing Alzheimer's disease based on this research.