Phil Lofton:

Hey, everybody!

All this season, we’ve been talking about life with Alzheimer’s and dementia, featuring perspectives from society, health systems, the patient and the caregiver.

There’s a pretty natural question that gets posed after all of that, though, which is “what can I do to protect my brain and reduce my risk?”.

While there’s no way to completely prevent Alzheimer’s, there are some good habits and behaviors that we’ve found can reduce your risk, and possibly protect your memory.

We’ve got three episodes, all out now, that focus on ways to reduce risks of cognitive decline, including diet and exercise, and delirium.

This episode, we’re talking about medication — specifically, common medicines known as Anticholinergics, which you might not even realize you are taking, and the effect that they can have on your memory.

Welcome to The Problem. I’m your host, Phil Lofton.

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Noll Campbell is a pharmacist and researcher at the Regenstrief Institute. Over the last several years, his research efforts have revolved around anticholinergics.

What are anticholinergics? What is your work shown us about them?

Noll Campbell:
Anticholinergics are medications that block a certain neurotransmitter pathway important to the way nerves talk to each other and the way that nerves talk to muscles that they support throughout the body. So, by blocking these neurotransmitters, which is what they do, because we call them anticholinergics, right? So that means they block these neurotransmitters, they end up slowing down the way that that communication between the nerves can, the speed with which those nerves can connect. And then that ultimately explains the clinical effects that we, that we see. So, these medicines, they’ll come from several different types of classes. So, there’s not an anticholinergic class of medicine. There are different medicines from different classes that have anticholinergic-like effects. So those include depression medicines, medicines for sleeplessness, medicines for allergies, and certain types of pain, even could be considered anticholinergic medicines.  So the other thing that it’s important to know is that these anticholinergic medicines can be both prescribed as prescription medicines, but they can also be over-the-counter products as well.

Phil:
So, how do they affect the brain? What has your work shown us about some of the unintended side effects that they may have?

Noll Campbell:
Right. So, the nerves that these anticholinergics effect that they might block, as I said, occur throughout the body. And those can be, those can include areas of the brain as well. So as I mentioned, the way that these block the nerves to talk to each other that also slowed out slows down several processes normal the brain normally accomplishes. That can be things like maintaining level of alertness, finding the right words, even storing or recalling memories. And that’s why we’ve identified this relationship with dementia that these drugs may be increasing the risk of dementia. However, it’s really unclear whether these, whether these medicines that affect these processes in the brain are considered reversible or not. So if we were to stop these medicines, does the brain go back to functioning the way it normally would?  But there there’s some information that suggests that that one of the byproducts of blocking the communication between these nerves is actually an accumulation of a deposit of proteins that may be causing damage to the brain. And we think that that’s the unintended consequence that might be occurring by blocking these receptors that leads to this accumulation of bad proteins in the brain that looks like dementia.

Phil:
A few years ago, Dr. Campbell had a unique experience with a patient who was taking several Anticholinergic medicines.

Noll Campbell:
When we first met her, she could start a sentence in response to a question, but by the time she hit the relative halfway part of her, of her sentence, she didn’t know where she was going to finish the sentence. And that happened on repeat occasions. And the way she tested cognitive, inner cognitive evaluation, she tested in a stage of moderate dementia. And so we knew that this was complex because she was using 28 medicines–four anticholinergic medicines and two benzodiazepines. And so, you know, the, in this case in particular, I was working with Dr. Boustani and his first move was, “Let’s call in Noll, cause the first thing we need to do is clean out some of this complexity in her medications.” And so we did that. It took time, it took collaboration with physicians across, with physicians all over the city who were helping to helping her treatment. And they, all of those physicians were helpful, collaborative. It was an amazing experience actually. We worked with her over about nine months to get rid of those medicines because we didn’t want to do it too quickly,  and provoke, some withdrawal effects. But we did it over nine months and, and we saw early signs of success that even six weeks where she felt better. She gave us a, a phenomenal quote where she said, “I feel like I’m taking my life back one day at a time.” And after about nine months, her cognitive evaluation put her back into a not demented, cognitively normal category.

Phil: 
Wow.

Noll Campbell:
It affected her mobility as well. She came in the first time in a wheelchair and now she comes, she still uses a walker, but she’s, you know, these medicines can have extra cognitive effects too. And so she’s seen a significant, improvement in her overall quality of life. She’s happy with where her brain is. She’s not perfect. Her brain is imperfect, but it’s better. And what we want to know from our, from our research going forward is, is this transferable? Does this happen to most people? Is it durable?  and, and do these, do the improvement that we’ve seen from her, is that just an acutely reversible or is it, if we change some underlying mechanism in her brain?

Phil:
What was it like for you to be a part of that?

Noll Campbell:
It was, it was meaningful, meaningful to me professionally and personally and emotionally too, because I’m so happy for her.  you know, you always say, “If I could help one person in the world…” and I did. And that felt really, really good and it created a personal relationship that I have with her and her husband.  And that continues, and that’s a really important relationship today. And, and to see someone improve like that through your coordination, through your help, through your effort, is really meaningful. And it creates, you know, enough desire to pursue this to so that everybody else, you know, there are people like her down the street in the city that we haven’t helped. There are people like her in almost every city in the US and around the world. And we now have the challenge to make sure that we can find, we can take that benefit to everyone else.

Phil:
How did she wind up getting on so many medications in the first place?

Noll Campbell:
That’s a good question. She kept, she had complaints that she was trying to solve. She had a symptom that she was trying to treat, and her providers were trying to do right by her by helping her solve that problem, solve that symptom. And no one is really at fault,  in that scenario. But she kept looking for an answer in a medicine. And when one didn’t work, they’d try another one, and then we try another one. And there’s a lot of data suggesting that multimodal therapies for treating many of these symptoms can be effective. And so, when the first one doesn’t work, adding a second one is not unreasonable. And the mechanism of the second one is unique from the first one. The, the mechanism of the second medicine is unique from the first medicine to justify using them together. And that’s how it, it’s pretty easy. That’s how it happened. So there’s a lot of prescribed medicines that she was using. She was also supplementing with something else.  communication physicians may have been, may have been prescribing to her trying to isolate a problem and almost in silos.  but she saw, she saw several physicians and each of her problems were complex. And so there are multiple treatments that were available to her. So they just kept each one in their own silos, kept adding and adding and her primary care physician was concerned and working with her to try to find, you know, to try to try to reduce the burden and did not want to overprescribe her.  and so really, we use the catalyst of her concern about her brain health to start to take those away and take those away. And her primary care physician was very supportive, communicated quite openly despite the fact that he was in a completely different health system. We would have personal phone calls for the betterment of her care so that he was telling her the same thing and not making too many changes too often. And so, I really appreciate that collaboration. And as I mentioned before, every, every one of her physicians that we spoke with about coordinating her deprescribing efforts was supportive and certainly on board with trying to optimize her care.

Phil:
So if that story makes you want to run to your medicine cabinet and throw everything out, hold on a second.

While the thought that these medicines could present a risk to your memory is scary, they’re also medicines that were prescribed for a reason, and it’s not a good idea to start or stop medication without a talk with your doctor, Dr. Campbell says.

Phil:
So a lot of these medications are medications for things that can be pretty significantly affecting a person’s day-to-day quality of life. They are anti-histamines, they are drugs that are supposed to reduce incontinence. They’re, they’re drugs that sound like they’re things that should be making a person’s life better. So an individual might kind of scoff at the idea that maybe they should get rid of these right away. So like how has your work sort of addressed that process of deprescribing? What does that look like?

Noll Campbell:
Yup. So they’re, in a lot of cases, most cases, these medicines have safer alternatives and in most cases them, the alternatives work just as well as these anticholinergic medicines. What we learn and what we know clinically is that we shouldn’t be making quick changes to these medicines. Because they work in the brain, we need to be careful about making quick changes because the brain needs to adjust to the presence or absence of that medicine. And it, those, those adjustments could look like withdrawal effects if they’re, if they’re stopped too quickly.  just as you would slowly start a medicine and increase the dose slowly, you should do the same when you’re taking a medicine away because the brain or other parts of the body could react unfavorably, if you, if you make changes too quickly.  but the good news is for most of these medicines there is an equally effective alternative. It’s oftentimes safer or at least hasn’t been attributed with some of the same side effects that anticholinergics have. And, and they’re readily available and, and only in a few cases do, they actually maybe might cost more money, but in many cases they’re quite accessible and achievable and easy to use medicines as well.

Phil:
Right now, the effort to better understand Anticholinergics is a priority for Dr. Campbell and other researchers at Regenstrief, but we’ve suspected the link between memory and these medications for quite a while.

Noll Campbell:
The relationship between anticholinergic medicines and poor cognition dates back to the 70s. It’s not, it’s not new. And I think, and it’s not unique to just geriatric training, but it’s a longstanding relationship, but it’s such a longstanding relationship that we don’t want to assume that the relationship is correct. It’s a longstanding relationship that lacks high quality data. And that was, I, I saw that as an opportunity to fill a void and to check assumptions. Right?  and I think that’s a role I, I got interested and excited about that role as, as part of my role on the clinical team as being a pharmacist is, is checking assumptions, making sure you know the right answer and if you don’t know the right answer, finding a way to, to answer that question appropriately, scientifically valid with through evidence-based medicine. And that’s consistent with my training and consistent with interest areas of geriatrics. So it was a natural marriage. The opportunity that I had to study this initially started back in roughly 2008 working with the Indi-Ibadan project, which was funded here funded by the NIA I believe, and took place here and in and in Canada and in Africa. By the end it was run by Dr. Hugh Hendrie, and they had data that could help us answer this question in more of a longitudinal fashion, which hadn’t been done sufficiently before.  and so that was a really nice opportunity that one of my first research experiences afforded me.

And it became a unique and quality publication in the Journal of Neurology in 2010 where we were able to study longitudinal exposure to these medicines with a, with a really high-quality diagnostic outcome, that was performed by the Indi-Ibadan study. So, merging those two data points, those two data pieces was, was unique for the field at the time. And the finding that we had almost a 50% increase in the risk of, of dementia or cognitive or worsening cognition among a susceptible, frail group and then up to an 80% higher risk among those who didn’t have a genetic signature or did genetic risk was also a telling finding and novel to the field at that time.

So, we started to introduce that scientific quality into that relationship. And so to me that was exciting and then I needed to close the loop and that’s why I’ve spent now almost 12 years pursuing that because I need to close the loop on this question scientifically and clinically to know if you should, you know, if the associations that we found in prior research hold in higher quality research.

Phil:
What are some of the other studies that are going on right now that are sort of like helping further our knowledge of deprescribing and anticholinergics’ effect as well?

Noll Campbell:
So we have two really exciting studies that we’re just getting off the ground right now,  through support from the National Institute on Aging.  and the first is what we would call a deprescribing trial. And that’s where we do, we design an intervention that’s pharmacist-based, pharmacist-supported with the intent to go out to primary care and find older adults who are currently using these medicines and then give them a support tool to help them find alternatives and safely work to those alternative medicines. And the, the primary focus of that trial is to test, to see if brains get healthier after and they make a change from one medicine to another. Now we’ve, we’ve seen a few smaller studies start to begin to study this in a randomized controlled fashion.  and they haven’t found anything suggestive of improvement yet, but our hypothesis is slightly different than theirs in that we think that the, the really the impact of the intervention might be delayed and it could take up to 24 months. So our, our study period is about 24 months of inclusion and we need to test brains really as far out as 24 months to see if this mechanistic damage that we think is being caused by anticholinergics can resolve over, up to 24 months. So that’s what, what’s a little bit unique there. It’s going to be great for pharmacists, a great opportunity for pharmacists and the practice of pharmacy to support deprescribing.

We’re going to get a pretty good idea of whether medicine these medicines are the causative agent for adverse cognitive effects. So that’s pretty exciting. And so that’s one study. The other study has an, is a deprescribing study as well, but it takes a very different approach. And what’s really cool about it is that it’s a tech-based or tech-focused intervention to support deprescribing in that the tech is available as a mobile application and, and is intended to provide education about deprescribing, education about risks of medicines and an awareness of the availability of alternatives along with supporting conversations with healthcare providers about deprescribing. So, we’re going to see if through these two trials we’re going to be able to compare does one approach to deep prescribing which might be more human intensive, what’s the impact and the and the depth of the effect on that versus a much more scalable tech-based approach on deep prescribing. And you know at the end of the day when we complete these two trials because they started pretty close to each other, they should hopefully end pretty close to each other. We’ll be able to directly compare the impact of these two interventions on deprescribing and then know from there going forward, “Do we need people doing this or can we do it through tech? And what are the pros and cons of each, each approach?” Which to me is, again, pretty exciting.

Phil:
If you’d like to learn more about anticholinergics, head to this episode’s page on regenstrief.org/theproblem, where you can find articles, videos, and other resources.

Listen to our other episodes on prevention, including a look at diet and exercise and an episode on delirium, out now, and join us next time in the season finale.

We’ll see you then, on The Problem.

Music this episode was by AA Alto, Blue Dot Sessions, Everlone, Jahzarr, and Monplasair. Our theme, and additional musical cues were written and performed, as always, by Hecate’s Homeboys.

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