Unlike other inflammatory diseases, asthma typically begins early in life. What could life-long systemic inflammation mean for Alzheimer's risk? UW-Madison's Dr. Melissa Rosenkranz explains her latest research on asthma and the brain.
Researchers have long tied inflammation to increasing Alzheimer’s risk, particularly in how it triggers amyloid production in the brain. Scientists are now delving deeper into the role inflammation could play, examining how systemic inflammation from disease can impact brain health.
UW–Madison’s Dr. Melissa Rosenkranz is studying the connection between systemic inflammation and brain health by examining how asthma and dementia are related.
“If asthma is in the first decade of life, that means there’s a very long window for the damage that can follow neuroinflammation to accumulate,” Rosenkranz explained. “That really worried me and so I started looking for evidence and the data that we had for those connections.”
As the distinguished chair in contemplative neuroscience at the Center for Healthy Minds, her research focuses on understanding the underlying biology of the mind-brain-body interactions of stress, emotion, and the immune system.
Rosenkranz joins Being Patient Founder Deborah Kan to discuss her latest research on how systemic inflammation from asthma impacts long-term cognitive function and the risk for the development of Alzheimer’s disease.
Read or watch the conversation below.
Being Patient: What made you start thinking about putting asthma and dementia together? Where is the link there?
Melissa Rosenkranz: This link occurred to me six or seven years ago because the broader arc of my work is really trying to understand how inflammation in the body impacts the way the brain processes and responds to emotion and cognitive information in terms of increasing risk for mood and anxiety disorders.
I also follow animal research. I was seeing more and more in animal studies, they were showing that inflammation in the body provokes brain inflammation. I knew that brain inflammation was one of the things involved in the cascade that leads to Alzheimer’s disease and dementia. I started to get concerned [that] if asthma is causing systemic inflammation that is impacting the brain, is it causing inflammation in the brain? If so, is this potentially a risk factor for dementia?
The reason that really worried me is because asthma is very prevalent. It affects about 10 percent of the population, and unlike other chronic inflammatory diseases, it begins usually in the first decade of life. Most chronic inflammatory diseases like arthritis, irritable bowel syndrome, or things like that don’t begin until later in life.
If asthma is, in the beginning, the first decade of life, that means there’s a very long window for the damage that can follow neuroinflammation to accumulate. That really worried me so I started looking for evidence and the data that we had for those connections.
“I started to get concerned [that] if
asthma is causing systemic inflammation that
is impacting the brain, is it causing
inflammation in the brain?”
Being Patient: Are you looking into specifically Alzheimer’s or all types of dementia?
Rosenkranz: It is both. We just published, earlier this year, an epidemiological study. The lead author on that was Dr. Christie Bartels and [the] paper [showed] that asthma does indeed increase the risk for Alzheimer’s disease in terms of both incidence and prevalence. But not only Alzheimer’s disease, it can cause dementia as well.
Being Patient: Did you find actually the prevalence of asthma is higher in dementia patients?
Rosenkranz: We looked at it with asthma predicting new diagnoses of Alzheimer’s disease. We didn’t look at it the other way around to see whether Alzheimer’s disease could increase the risk of asthma. We looked at it only in the direction of asthma increasing the risk for Alzheimer’s disease, and we did indeed find that asthma does increase the risk for Alzheimer’s disease.
Being Patient: Could it be true as well that the inflammation within asthmatic lungs means they’re not getting as much oxygen to the brain? Could that also be a possibility?
Rosenkranz: It could be a possibility. I think there are several factors that could underlie why asthma is associated with problems with brain health in general. It could be inflammation. That’s the avenue that we’re pursuing most aggressively right now.
It could be hypoxia. Although hypoxia is generally more relevant [in] people with severe asthma, and we’ve seen the impacts on the brain, even in people with mild asthma, so their hypoxia probably is less likely to be a big contributor to that.
It can have effects on the vasculature, right? I have a colleague here at UW named Matt Tattersall, who [is] a cardiologist. He has studied the vasculature in children with asthma, and has shown that even in children as young as nine or ten years old, they have thickening of the carotid artery already.
If that’s happening in the peripheral vasculature, it’s probably happening in the brain too. That could also be a contributor. We’re trying to understand more about the mechanisms now— what connects those two things, and they’re probably many fold; it’s probably not a single pathway.
“I think there are several factors that
could underlie why asthma is associated
with problems with brain health in general.”
Being Patient: If you have inflammation in one part of the body, why is that bad for the brain? How does inflammation from the lungs go into the brain?
Rosenkranz: That’s a good question. The answer is yes to both. There are pathways through which inflammation in the lung can directly signal the brain, like neural pathways when you have inflammation in the airway. If somebody who has asthma gets exposed to their allergen, we’re talking mostly about allergic asthma here; then they have an inflammatory response to that allergen. That inflammation from their airway spills out, so it doesn’t stay just in their airway. We see increases in inflammatory mediators in their blood.
That is ultimately going to circulate to their brain. Those can bind to the blood-brain barrier. Some areas of the blood-brain barrier are leaky. The immune system can get into the brain, and it can signal through the blood-brain barrier into the brain through a variety of mechanisms. It doesn’t just stay in the lung, which I think is more well recognized, and other diseases, but in asthma, we still think of it really as a disease that’s confined to the airways.
Being Patient: What do we know about different types of inflammation? For example, would inflammation from rheumatoid arthritis pose different risks than asthma? Are there inflammatory states caused by diseases or health conditions that are more dangerous to the brain than others?
Rosenkranz: That’s one of the key questions that we’re investigating right now. We think we have some hints about that for asthma, [but] it might differ for different diseases. I’ll give you an example. You brought up rheumatoid arthritis. Rheumatoid arthritis is also associated with an increase in risk for dementia and Alzheimer’s disease.
There was a study that was published, maybe five or ten years ago, that looked at patients who are on Medicare and the medical records of those patients. with rheumatoid arthritis. It was a similar study looking at whether the prevalence of Alzheimer’s disease [has] increased.
The interesting thing about rheumatoid arthritis is they were way out ahead of other fields and [used] what are called biologic drugs to treat rheumatoid arthritis, meaning they target specific inflammatory cytokines. What they found when they looked before and after those drugs hit the market, the people who are on those biologics who are targeting very specific inflammatory pathways in rheumatoid arthritis had rates of Alzheimer’s disease below the general population. The people with rheumatoid arthritis who are not on those drugs had big increases in the prevalence.
Specifically in rheumatoid arthritis, it was drugs that blocked a cytokine called tumor necrosis factor alpha. That seems to be, at least in that one study, a really important pathway through which RA confers an increase in risk for asthma. It might be a different pathway, but that’s what we’re trying to understand right now.
Being Patient: If you’re taking anti-inflammatory medications, do we know if it is possible to stop the inflammation before it gets to the brain?
Rosenkranz: We don’t know that. That’s another area that we’re actively investigating. We do have a few hints at this because, in a lot of this early research, one of the big criticisms of some of our data was: how do you know that it’s not the medications that are used to treat asthma that is causing problems in the brain as opposed to asthma itself?
There isn’t a lot of data to answer that question right now, but of the data that we do have, it looks like people who use anti-inflammatory medications to treat their asthma as opposed to only bronchodilators like albuterol; those people, their brain is more protected.
Being Patient: We have a question from our audience. Do you think it could be a combination of the MTHFR gene, mold toxins, or an inflammatory diet with stress that leads to dementia?
Rosenkranz: I can’t speak to that specific molecular pathway, but I will say that another arm of my research is looking at how psychological stress changes airway biology. If you are exposed to an allergen, your response to it is different. We have a few studies now showing that, indeed, psychological stress primes the lungs to respond more aggressively in response to an encounter with an allergen.
We have other data that shows that if you train people with asthma in stress reduction techniques, like mindfulness based stress reduction, for example, that can reduce airway inflammation. It can improve disease control, both of which are important factors, we think, in the impact that asthma has on the brain.
We have some evidence that just managing your stress well can be protective. In addition, one of the effects that stress has on asthma is it makes the medications that are used to treat asthma less effective. When people are under chronic stress, their use of inhaled steroids is not as effective at managing their airway inflammation.
Overall, it’s going to be bad for their systemic inflammation. If you can manage that stress, it will help your brain, but it will also make your asthma medications more effective, and protect your brain sort of through that route.
“If you can manage that stress,
it will help your brain, but it
will also make your asthma
medications more effective.”
Being Patient: Why does stress make medication less effective and asthma worse? Do we know the connection?
Rosenkranz: It makes it worse through a few different pathways. One is that stress makes a receptor on immune cells called glucocorticoid receptors. Glucocorticoids are stress hormones. Maybe some of the audience is familiar with the term cortisol. That’s a stress hormone. It is usually glucocorticoids like cortisol that suppress inflammation. That’s actually what inhaled corticosteroids are.
It’s more or less the same thing, but when you are experiencing chronic stress, those receptors on the immune cells become less sensitive. They’re not responsive anymore to the stress hormones, and they’re not responsive to those medications anymore. That’s one way that stress impacts the inflammatory response in the airway.
It also upregulates certain immune pathways that make the glucocorticoid receptor less sensitive. So, it promotes the expansion of T cell populations that are less sensitive to the effects of glucocorticoids. There’s also a route through the sympathetic nervous system where the activation of the sympathetic nervous system promotes the production of new immune cells from your bone marrow.
Those new immune cells are hyper-responsive to inflammation, and they selectively migrate to the lungs into the brain. You get these new populations of cells that are being produced that are kind of hyper-responsive to inflammation.
Being Patient: What’s the next phase for your research?
Rosenkranz: What we’re really trying to do now is to dig into the nitty gritty and find out: what are the immune pathways that are conferring this risk? If we target those immune pathways, do we see the changes that we think might be giving rise to some of the neurodegeneration and neuroinflammation? Do we see these pathways not emerging?
Some of this work will have to be in animals because you can’t do all of this work in people, but [we’ll] really try to understand what the signaling pathways are because if we know that, then they can be targeted with medications to even potentially prevent these effects.
When you think about asthma, beginning in children, that means that there’s this long window of time for damage to accumulate, but there’s also a long window of opportunity to intervene. So, if we know what we need to target, then we can do that before we have the consequences start to show up in the brain.
“When you think about asthma,
beginning in children, that means
that there’s this long window of
time for damage to accumulate, but
there’s also a long window of
opportunity to intervene.”
Being Patient: We obviously don’t want to prescribe anything to people, but how should people be thinking about living their best brain health with a condition like asthma?
Rosenkranz: One thing I do want to emphasize is that these connections that we’re identifying— this is really new research. We’re not sure [how] these things are playing out. I don’t want anybody to be really afraid, “Oh my gosh, I have asthma. I’m gonna get Alzheimer’s disease.” We just don’t have that level of certainty. I don’t want anybody to be really alarmed by this.
What I often tell people when they ask me this question, I say, if I had a child or a close family member with asthma, what I would want to do is first of all, make sure that their airway inflammation was well managed. [I would] make sure that they’re taking anti-inflammatory medications for their asthma, even if it doesn’t seem to bother them very much.
There’s not always a one-to-one relationship between how you feel, how tight your chest feels, and how much inflammation is present. Work closely with your doctor to make sure that the airway inflammation is well managed.
The second thing to invest in and prioritize is your mental health and your ability to manage the stressors in your life. We know that there is this circular relationship between what’s happening, the contents of your mind, and the way that your lungs respond [to] asthma, and also with the ability of your brain to do its job well. It’s this bi-directional relationship, and you really need to pay attention to both.
Katy Koop is a writer and theater artist based in Raleigh, NC.