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Could Viruses, Olfactory ‘Railroad Track’ Unlock Alzheimer’s Puzzle?

Researchers collaborate on possible triggers and accelerants of early onset Alzheimer’s, seek potential therapies

minute read

Written by Chris Casey on March 11, 2022
What You Need To Know

The CU Anschutz 360 podcast features the inspiring teamwork of Diego Restrepo, PhD, and Maria Nagel, MD. Their random meeting in 2018 led to focused study and insights into the triggers, or accelerants, of Alzheimer’s as well as potential therapies for this devastating disease.

More than one in nine Americans 65 and older are now battling Alzheimer’s disease, and the numbers are expected to greatly increase in the coming decades as our population ages.

This episode of the CU Anschutz 360 podcast focuses on two University of Colorado Anschutz Medical Campus researchers who are collaborating on Alzheimer’s research. Maria Nagel, MD, is a neurology clinician and neurovirology researcher at the CU School of Medicine’s (SOM) Department of Neurology. Diego Restrepo, PhD, is a systems neuroscientist at the SOM’s Department of Cell and Developmental Biology. Thomas Flaig, MD, vice chancellor for research, also joins the discussion.


Thomas Flaig, MD, vice chancellor

for research

Restrepo’s lab focuses on the olfactory system – the “railroad track” to the central nervous system – and how smell loss is an early symptom associated with multiple diseases, including Parkinson’s and Alzheimer’s.

Nagel’s lab concentrates on the varicella-zoster virus, or the chickenpox virus (VZV), which lies latent in more than 90% of the world’s population. She focuses on this virus’s role in strokes, studying how it travels to the brain, infects arteries and ultimately produces a stroke. Her lab discovered proteins that the virus triggered that were involved in Alzheimer’s disease.

Nagel and Restrepo’s areas of research intersected in 2018, when the scientists attended the same conference in Fort Collins. They discussed how Nagel’s area of expertise – VZV and HSV-1, which causes cold sores – overlaps with Restrepo’s exploration of smell loss in that the dormant viruses travel into the olfactory system where they can then move into the brain.

“If our hypothesis – that viruses can contribute to smell loss, thereby accelerating Alzheimer’s – holds true, then maybe we could treat patients with early cognitive problems with an antiviral to prevent them from actually becoming demented,” Nagel said.

The podcast explores this inspiring teamwork, where a random meeting led to focused study and insights into the triggers, or accelerants, of Alzheimer’s as well as potential therapies for this devastating disease.

Listen here

Podcast transcript:

Disclaimer: Transcripts are generated using a combination of speech recognition software and human transcribers. It may contain minor differences from the audio, including some edits for clarity in print. Please check the recording and with the Communications team before quoting. 

Chris Casey: Today's installment of CU Anschutz 360 focuses on a collaboration that is yielding significant insights into potential triggers of early onset dementia. 

My name is Chris Casey, and I'm the director of digital storytelling in the Office of Communications. I'm pleased to be joined by Dr. Thomas Flaig, CU Anschutz vice chancellor for research, who will co-host our discussion on this important research. 

We talk with two researchers at CU Anschutz, Diego Restrepo and Maria Nagel, who come from somewhat different worlds. Dr. Restrepo is a systems neuroscientist in the School of Medicine's Department of Cell and Developmental Biology. Dr. Nagel, meanwhile, is a neurology clinician and neurovirology researcher in the Department of Neurology. Their labs are teaming on Alzheimer's research, hoping their discoveries can lead to insights into the triggers or accelerants of Alzheimer's as well as potential therapies for this devastating disease. 

First of all, could you just explain –  both of you – what your different labs do?

Diego Restrepo: Yeah, I study smell. I literally started, I went into a brain through the nose. I was interested in how the neurons in the nose respond to the odors and very quickly it became interesting because it's a very complex system. I started studying decision making and learning and memory. 

And at the time I was doing work, in fact, I started with catfish and then I started work with mice and very quickly it became clear that it was important to the work in humans because losses in the sense of smell happen very early on in Alzheimer's, in Parkinson's and different diseases. And that's how I became interested in Alzheimer's.

Maria Nagel: Yeah. I focus on varicella-zoster virus or VZV, and it causes chickenpox when you first get infected and then it actually becomes dormant in your body. More than 90% of the world population has this virus dormant. We think of it as flaring up when we're older and causing shingles or herpes zoster. We think of it as a pretty benign disease. ‘Oh, we just get a rash.’ 

My lab focuses on this virus also causing strokes. That was the predominant research that my lab did, is how does this virus get to the brain? How does it infect arteries and produce a stroke? Through our investigations, we just stumbled upon some proteins that this virus triggered, that were involved in Alzheimer's disease.

Thomas Flaig: You know, before we dive into this really interesting conversation, and I'm really looking forward to this today, maybe you could make just a few comments about viruses in the central nervous system (CNS). I think a lot of people that are listening to this think of a virus, they got upper respiratory tract infection, maybe about hepatitis or something more serious, but they may not think of viruses in the CNS sort of as their first thought. What do you want to share about that and the interaction of viruses with the central nervous system?

Diego Restrepo: Yeah. Something that's really interesting about olfaction, smell, is that the cells that detect the odors are neurons and they are the one central nervous system neuron that's exposed to the mucus. So it's exposed to viruses and that is a direct route to the brain, which could be a big problem because of encephalitis. There's been a lot of interest in smell on viral infection as well, because of loss of smell, which is now it's totally evident with SARS-CoV-2. But in the past it happened with influenza virus and other viruses.

Thomas Flaig: For the general population in terms of clinical neurology, you mention shingles and VZV, but what other places might viruses be important in neurology?

Maria Nagel: Yeah, so specifically for the neurotropic viruses. I study varicella-zoster virus and its sister virus, herpes simplex virus type one, which produces cold sores, but these viruses actually reside in neurons throughout your body. What's fascinating is that every single organ system has nerve fibers connected to it. 

These two viruses can actually flare up and hit every single organ system. So aside from entering the brain and causing stroke or causing seizures, these viruses can also affect the esophagus and cause difficulty swallowing or they can affect the stomach, cause inflammation and cause chronic stomach pain. These latent viruses have these really interesting effects. 

Then as you know, there are other viruses that are not latent in our body that we can be exposed to like West Nile virus and Zika virus. And some of these viruses also have some rare complications of being able to affect the brain or even the spinal cord causing weakness.

Chris Casey: How did your disparate areas first intersect and what prompted this collaboration initially?

Diego Restrepo: It was a random meeting in this neuroscience meeting in Fort Collins. Maria and Andrew Bubak (PhD, CU School of Medicine, neurology) had a poster and it was a fascinating poster on viruses. And on the fact that viruses actually may be involved in Alzheimer's formation of amyloid. Amyloid is a protein that's found in the brain of Alzheimer's patients. 

We started talking about this and because of my interest in Alzheimer's, it became clear that we should try to understand whether the loss of smell, which happens very early on in Alzheimer's, and could be useful for diagnosis, for example, early diagnosis and treatment. Could it be that the loss of smell is also a causative agent or maybe that it accelerates Alzheimer's, the loss of smell by viral infection?

Maria Nagel: I actually had a great time collaborating and discussing each other's projects with Diego after that meeting. It was amazing to me. I had never had any intention of doing Alzheimer's research, but when Diego and I started talking about how smell loss is one of the early symptoms in Alzheimer's patients before they get demented and what are the possible triggers that could cause this smell loss that may potentially accelerate Alzheimer's. 

Then we were like, ‘Wait a minute, maybe VZV and HSV-1, which resides in the sensation neurons around the head, could potentially be a reservoir for the virus that would then enter the nose and affect the sense of smell.’

Diego Restrepo: It became very interesting also from the research point of view because these neurons that are in the nose, we can actually biopsy. Our lab was the first lab to actually record from human olfactory neurons. And to actually set up the cultures of human olfactory neurons. That is wonderful because you can do that from a patient that has Alzheimer's – or control – and you can actually see what happens when you do the viral infection.

Maria Nagel: One of the kind of important aspects of this collaboration is that when you look at previous researcher’s reports, they were looking at end-stage Alzheimer brain, when patients were already demented, and were looking for different bugs or pathogens that might be associated or seen more frequently in Alzheimer's brains by the time they're already demented. 

Diego and I were thinking, well, maybe that virus contribution occurs very, very early on. We might be able to detect infection and disruption of signaling to the brain from those smell neurons before patients are demented. And if our hypothesis that viruses can contribute to smell loss, thereby accelerating Alzheimer's, holds true, then maybe we could treat patients with early cognitive problems with an antiviral to prevent them from actually becoming demented.

Diego Restrepo: The other thing that's fascinating is we knew about the work of Francisco Lopera, who had found families in Colombia that became demented at about 45 years old, which is very early for Alzheimer's. That's called familial Alzheimer's disease. These are patients that you can actually study before they get Alzheimer's and you know they're going to get Alzheimer's very early on.

Thomas Flaig: It's really fun to hear about the collaboration. And sometimes they say that the collaborators that have the most different backgrounds come up with the greatest solutions and the greatest insights. You really do come at this from your different disciplines. 

In some ways you had that first meeting and you decided that this was something that required more investigation. It almost becomes a detective story, where you look at your sources and your evidence and how you're going to put those different things together. Is that the way you think about it?

Diego Restrepo: That's correct. You know why that is clear to me is because I teach them at school about Alzheimer's. I've been teaching for 20 years about Alzheimer's. At the beginning, I thought in five years I'm going to be teaching about the therapy. That's not what I teach. And that's frustrating. There have been how many trials?

Maria Nagel: Yeah, over 400 drug trials that have all failed for Alzheimer's disease.

Diego Restrepo: Yeah. And what happens is that the hypothesis then 20 years ago … but about the same, is that it's amyloid that does it, amyloid or tau, and/or tau. There've been a lot of drugs that have been tested. 

What we thought is, you know, this is something that we can actually look at and see whether this loss of smell through viruses actually accelerates Alzheimer's?

Thomas Flaig: Do you want to say a word about amyloid and tau and what those are clinically or otherwise?

Maria Nagel: You could just think of them as proteins that we make, that humans make, that have misfolded and formed these aggregates, and these aggregates are toxic to the cells surrounding them. And they also cause inflammation. So if these aggregates form around neurons involved in memory, you can have loss of those neurons. 

Then as I was learning about the amyloid field, I was amazed that diabetes – adults with onset diabetes – was also an amyloid disease, where you have amyloid accumulating in the pancreas, contributing to the death of the cells that produce insulin.

Diego Restrepo: You find amyloid in the olfactory epithelium as well in Alzheimer's patients.

Chris Casey: And the epithelium is?

Diego Restrepo: The epithelium is the mucus. It's the mucus layer in the nose, inside the nose.

Chris Casey: Diego, I've heard you refer to this, the biological area in which you concentrate your study, as almost a railroad track to the cognitive center of the brain, if you will. Could you expound on that?

Diego Restrepo: So, we have five senses. The interesting thing is that all of those, except for one, one exception, go through the thalamus. The thalamus is a central place in the brain, except for olfactions. Even when olfaction was first studied, Santiago Ramon y Cajal thought it was going to the hippocampus and that the hippocampus was part of the olfactory system. The hippocampus is actually, we learned afterwards, it's important for learning and memory. It's the place that's affected in Alzheimer's patients. 

Olfactory systems go with a couple of what we call synapses, a couple of stops, goes all the way to hippocampus. The question has always been why is that something different? So Li-Huei Tsai from MIT has shown that oscillations in the brain are important in Alzheimer's. They have a system, and they actually think that flickering the electrical activity in the brain actually decreases the cognitive problem. Well, this olfactory system, the olfactory bulb actually is a train to the hippocampus. It's well known to be trained to the hippocampus through that railroad in oscillations.

Thomas Flaig: You've been studying the olfactory or the smelling system, if you will, in individuals that have Alzheimer's, and you have identified as part of this, as I understand it, that there's been infection in the olfactory system. Do you want to talk more about that and what that leads you to next?

Diego Restrepo: Yeah. What we did is when we talked about what to do, we targeted these families that get early Alzheimer's and controls in Colombia, and this is a collaboration with the neurologist there, Dr. Francisco Lopera. What we thought is we would actually see, look at the transcripts, these are what's called RNA transcripts. They're basically a string of letters that tells the cells how to make proteins like amyloid and see if they were different between Alzheimer's patients and controls. They sent us all olfactory bulbs from postmortem patients, these are donations. We did what's called a BioSyder analysis, which is an analysis of those RNAs. 

We found they were very different. The difference was really interesting in the olfactory bulb, which is the first part as you come into the brain through the olfactory system, the start of the railroad track. What we find is differences in viral responses. The Alzheimer's brains have signatures of viral responses and then downstream in what's called the olfactory tract, the tract that goes over to the hippocampus, it's inflammation. Basically what this is the signature of viral infection that then produces inflammation.

Thomas Flaig: It sounds like you're studying this in families that have a history of early onset. So we're talking about viruses, which we think are coming from an environmental cause of something. If you look at families, there's a genetic link, but is it the family's genetic response to the virus that you're looking for?

Diego Restrepo: At the beginning, the study with familial Alzheimer's was mostly a control because we were not clear and this is the interesting thing about this being a detective. It was not that clear that the viruses were going to be important for those families; we thought it was going to be important for spontaneous Alzheimer's, which is, the people who get Alzheimer's much later on, and it was not. 

That made it even more interesting that there was an involvement of the viruses. So yeah, it is in these families, there is a span from age 40-something to about 50-something for that onset. The question is, could it be that the onset is actually caused by the viral infection?

Maria Nagel: I would add also that we suspect that amyloid that's talked about a lot for Alzheimer's disease, but that's not the only thing that can contribute to Alzheimer's disease. You could get chronic inflammation in the brain that contributes to formation of tau, complement activation. You can have problems with your baby neurons not replacing the damaged neurons, the neurogenesis. And so when we talk about amyloid, that's just one of the things we're focusing on, but there are other aspects of Alzheimer's, as in many diseases, it's not just going to be one thing.

This will be in combination with host and other environmental factors that may determine whether this toxic amyloid is cleared efficiently, or whether it accumulates, if the inflammation can calm down or not. With this familial Alzheimer's patients, they already have that genetic risk where they have more of these proteins that can misfold and form amyloid. We believe that this virus exposure will be that trigger to cause this large amount of protein to misfold and form amyloid in this familial group. Whereas in normal people, we'll get a virus infection. We are not over-expressors of these proteins. So we tend not to get amyloid, unless we have problems clearing it.

Thomas Flaig: Now one thing we've talked about a little bit here is the association between the loss of smell and Alzheimer's. Do you see that as a symptom of Alzheimer’s, or could it actually be a cause of it?

Diego Restrepo: It's unknown right now. Even as a symptom, it would be useful because it's a very early symptom, but the question is out there. Is it actually part of memory? What's the link between smell and memory? There are some really interesting papers out there. Even breathing slowly actually makes you think better. That's actually been shown in MRI. In some cases, exposure to odors actually allows you to answer questions more quickly. Those are things that are not understood, but the sense of smell is not just a sense of smell. It's doing something else in the body. In fact, what it does is it trains the entire brain in these oscillations and the oscillations are important for cognition.

Thomas Flaig: Maybe this is a question for Maria too. So just clinically, is there any role for a smell test and could you see a future role for something like that? I think that might be considered in other neurologic disorders as well?

Maria Nagel: It's one of those challenges when you see a virus associated with a disease, the question is also raised, OK, ‘was the virus causative or did the disease predispose that individual to have more virus infections?’ 

I think that's still tricky, but with regards to smell loss, I think that that's a really fascinating field. What we do know is, as Diego was mentioning, with regards to smell and how it provides signals to the brain for the brain to stay healthy, that there has been some experiments. Maybe you could describe the results …

Diego Restrepo: Very early on. It was like 40 years ago, they did that. In that case, what they found was depression. In fact, one of the causes of depression is actually taking, cutting the track from the olfactory bulb to the rest of the brain. It's really not well understood what the link is between olfaction and other disorders.

Maria Nagel: Diego, refresh my memory: Were there some studies about where, when they did cut this railroad track, the microglia, which is a certain type of immune cell in the brain, stopped functioning normally?

Diego Restrepo: Yeah. There was a change in microglia also and those are the cells that pick up the garbage, let me put it like that. They're really important for inflammation.

Maria Nagel: Especially if you have amyloid accumulation and then you don't have that olfactory input and then your microglia are unable to do the job and clear up this amyloid garbage, you might end up then getting some cognitive changes. That kind of brings our research together because we do know that HSV and VZV infection can cause smell loss. Then depending on how, again, host and genetic factors, how long that railroad track stays disrupted, that may determine what type of disease in the brain, if any, you would develop. We actually have some amazing prelim data, right?

Diego Restrepo: Also in the human study with the proteomics with Nanostream, we find that in the areas that are highly myelinated, the proteins that are different are proteins that are involved in demyelination and protection against demyelination, which is basically slowing down the railroad track.

Thomas Flaig: Yeah. Well at least you’ve got that coating of the nerve cells.

Diego Restrepo: Coating of the nerve cell allows the communication to be quick.

Chris Casey: And obviously there's a connection between COVID and loss of sense of smell as well. Could you perhaps address that a bit? Is it possible that combining the Alzheimer's sense of smell issues, COVID sense of smell issues, can you extrapolate that perhaps COVID has a tie as well to onset of dementia in some way?

Diego Restrepo: The first way that I found out about loss of smell with SARS-CoV-2, was with a phone call from a cousin of mine. Her son had lost sense of smell in New York. Then it was from emails, because we have a taste and smell center here and this is very interesting. It's well known that other viruses do cause loss of sense of smell, but not as badly as SARS-CoV-2. 

The question is what's going on? And yes, we actually have a project where we're studying the infection of the epithelium of that mucus with the SARS-CoV-2. The question is, why do you lose the sense of smell? It's hard to say, my scientific guess from the literature and what we're doing, is that very likely that's done on purpose that you lose the neurons because it's a very strong infection. You do not want a brain to be infected, but that's just a guess right now.

Maria Nagel: I would say that we're still really early in disease. We need to follow the people that have suffered from smell loss, following COVID and look at what complications they may or may not develop, in particular, those individuals that had recovered their sense of smell. The railroad track is back online. I wouldn't expect them to have as many issues perhaps as individuals that have a permanent loss of smell. 

Diego Restrepo: The most important thing is to look at the long COVID patients and what happens with them and also the small percent (that don’t get it back); about 95% recover their sense of smell. There's a small percent that actually have parosmia, which is actually they smell something fetid.

Chris Casey: Fetid, so kind of just unusual or sour smells?

Diego Restrepo: It smells awful, even when they take some coffee that triggers it. Then some people do not recover the sense of smell beyond six months. The question is what's happening with them.

Thomas Flaig: In the popular press, there's a lot of news about loss of smell early on. I just sort of found that I personally had questions, sort of the friends and families and so forth. There seems to be less of it now, so I don't know if we've just become accustomed to it or do you think there are less incidents of that with the different variants of the virus?

Diego Restrepo: The incidents are still high, so it's not going away. We're more used to it. We still don't have a cure. There are some clinical trials out there, but no, I think we've become accustomed to the fact that's... Even today, I talked to somebody in the lab that had lost their sense of smell.

Maria Nagel: I would say now that the work that Diego and I are continuing to do – testing whether infection VZV or HSV-1 in animals produces smell loss, and whether that's associated with cognitive impairment. And then ultimately it would be amazing if we can test whether an antiviral agent can actually decrease the risk of these animals, infected in the nose, decrease the risk of developing cognitive impairment. Then that would translate to us. 

And for individuals that might be at risk for Alzheimer's disease, like familial Alzheimer's disease individuals, or those that might start having early memory problems, then our research may have a place for looking for potential virus infections, and maybe treating with antiviral therapies to slow progression. If our hypothesis holds true that these viruses can accelerate Alzheimer's disease.

Thomas Flaig: So we think this whole story, going from the initial idea of the meeting, the basic science concepts, working with some different models of disease, getting some samples, bringing that together. Just to summarize … is that we'd like to maybe see this go into using antivirals drugs – antivirals as a way to sort of reduce the chances of developing or having progression of Alzheimer's. Is that where you'd like to see this go or could see going?

Diego Restrepo: Yeah, that's correct.

Maria Nagel: Yeah. There's actually some great support from this by other researchers. There’ve been multiple epidemiological studies where people have found that when you have HSV or VZV infection, you're at a higher risk for developing dementia and that antiviral therapies appear to reduce the risk of developing dementia. Those antivirals are like Acyclovir, Valacyclovir and famciclovir. 

Now there's still some papers where they have opposite findings where they say, "Oh yeah, HSV-1 is associated with cognition changes, but not dementia." Yet, the antiviral therapy still decreases the risk of dementia. We actually think that there will be a role for this in the future. The National Institutes of Health has actually funded a study, looking at the effects of these antivirals with regards to dementia.

Chris Casey: Obviously Alzheimer's is exploding. I can't remember what the estimated number of Americans that have Alzheimer’s. It's a huge number.

Diego Restrepo: One out of nine, 65 years or older and it's going to mushroom because of the aging population.

Chris Casey: Exactly. I'm just curious on a personal level, how satisfying is this for the two of you to be making headway down this road of research?

Maria Nagel: Yeah. We hope that this is a new direction, I think for the field. If you think about the whole Alzheimer's research field in general, people have been focused on amyloid and screening for drugs that will dissolve amyloid. What we are investigating is whether aside from amyloid what can be the triggers for that and what other things can trigger the other changes that are seen in Alzheimer's? Not just amyloid, but neuroinflammation for instance. If we can actually find the trigger for the formation of amyloid and accumulation or one of the potential triggers, then if we stop that trigger, can we slow down disease?

Diego Restrepo: Yeah and importantly do it early on. Because beyond a certain point you cannot recover. There's a lot of loss of neurons. So this has to be done early on.

Thomas Flaig: What a great conversation today. I think the arc of the story here, and the arc has not landed yet, but seeing that it’s going to land is really exciting.

During this horrible pandemic, there's been this engagement from the general public and science and viruses, honestly, then these symptoms such as loss of smell. So in the midst of this horrible pandemic, there's been this engagement in science. I think the way you're able to tie together these changes that we see with the SARS-CoV-2 virus and loss of smell and translating that to other very important human illnesses, diseases is really inspiring to hear. So thank you for sharing that story today.

Diego Restrepo: Thank you.

Maria Nagel: Great. Thank you.

Outro: CU Anschutz 360 is produced by the University of Colorado Anschutz Medical Campus. Story, editing and production by Chris Casey and Matt Hastings, digital design by Sarah Adams. Thanks to the rest of the Office of Communications team for support and edits. Special thanks to Denver band Splitstep, for our theme music featuring School of Medicine, student Matt Golub class of 22, Daniel Carillo, Kevin McKinnon. We'd also like to thank our guests this week, Dr. Diego Restrepo and Dr. Maria Nagel. And thanks to Dr. Thomas Flaig for co-hosting. You can read about the latest stories on our campus at news.cuanschutz.edu. This is CU Anschutz 360.