The Decibel - How a new kind of drug could change the future of Alzheimer’s

Episode Date: April 16, 2024

There are an estimated 650,000 cases of dementia in Canada right now. The last 20 years of research into the treatment of Alzheimer’s have been, as one expert put it, “agonizing.” But a new drug was approved in the United States and is being tested in Canada to see if it can delay or slow the progression of Alzheimer’s symptoms. And it’s giving researchers and patients some hope that a breakthrough could be on the way.Kelly Grant, health reporter for The Globe, has been looking at this drug more closely. She’s on the show today to tell us what these trials mean for patients and the future of Alzheimer’s research.Questions? Comments? Ideas? Email us at [e-mail]

For the last 20 years, Alzheimer's drug development has been disappointing. But a new drug that was recently approved in the U.S. is being tested in Toronto in a new way. The hope is that it will delay, or even prevent, the symptoms of Alzheimer's disease. Tyson Haller is a participant in that drug trial. It's a risk that I take.

It's almost like gambling. It's calculated, right? I can do something for society or myself, right? People are finding a lot of hope in these trials. But the research still has a long way to go. Kelly Grant is a health reporter at The Globe, and today, she's here to tell us what we know so far about this new class of Alzheimer's drugs. I'm Mainika Raman-Wilms, and this is The Decibel from The Globe and Mail.

Kelly, thanks for being here. Thanks for having me. So you spoke to Tyson Holler, who is part of a clinical trial for a new Alzheimer's drug. Can you just tell us about him? So I met him at the Toronto Memory Program, which is one of the locations for a trial called AHEAD. And we spoke while he was actually receiving his infusion of either this drug or the placebo. He doesn't know because he is in a double-blinded clinical trial. And does he have symptoms of Alzheimer's at this point? Tyson does not have any symptoms of Alzheimer's. He learned in his 50s that his father, who had left when he and

his sister were children, had died after a long battle with Alzheimer's at the age of 75. So Tyson started to pay extra attention to when he noticed things like forgetting names he should remember. But that's also a pretty run-of-the-mill part of getting older. He asked his family doctor to give him some of the standard visual, verbal, written cognitive tests that medicine does to identify dementia. He passed all those tests. But given his family history, his doctor agreed to refer him to the Toronto Memory Program, where he was again tested and found to be cognitively normal for his age. Nonetheless, because of his family history, the memory program told him about this trial, and that's how he wound up joining the study.

Okay. And we are obviously going to come back to this trial because this is an important part of what we're talking about today. But Kelly, I think maybe we should just get into some of the basics here before we get too deep into the trial. Really, basically, what exactly is Alzheimer's, and do we know what causes it? So Alzheimer's is the most common cause of dementia. And dementia is an umbrella term that connotes a loss of memory, thinking skills, eventually the ability to do activities of daily living like dressing and feeding and orienting yourself. Alzheimer's, like I said, is its most common cause. And although there's still a fairly robust scientific debate about what the exact cause is, the biological hallmark is the buildup in the brain of a substance called beta amyloid, which forms sticky plaques in the brain and sets off a cascade of events that leads to brain cell death.

And do we know how common Alzheimer's is? Well, we know that in Canada, as far as dementia goes, there are about an estimated 650,000 cases right now. That's according to the Alzheimer's Society of Canada. We know that Alzheimer's is the most common cause of dementia, but for reasons that we can get into, it's not always entirely clear whether Alzheimer's is the cause of the dementia that a person might be experiencing. Yeah, so let's talk about this. I think maybe I should just ask you, like, how do we usually diagnose Alzheimer's? This may be a way to talk about that. In Canada, Alzheimer's is really diagnosed as a disease of exclusion. So what will happen is somebody at a memory program, maybe a neurologist, maybe a nurse,

will administer these tests that are written and verbal and visual. So you may have heard, like, being asked to draw a clock, memorizing a series of words, then being given a new story and asked to remember those words, say, 10 minutes later. Those are the kinds of cognitive tests I'm talking about here. So if a person fails those cognitive tests and is deemed to have dementia at any stage, then the next thing that doctors will do is try to figure out what is causing this dementia. So they'll do things like CAT scans, potentially MRIs and blood tests to see is there any other obvious cause of this person's dementia, such as a stroke, a severe vitamin B12 deficiency, a brain tumor. And if they can't find any other cause, generally the assumption is that this person has Alzheimer's disease. Okay. So what you're saying, it's basically a process of

exclusion instead of like finding something that actually points you in the direction of Alzheimer's is if you don't have any of these other things, it's probably that. And that is how the disease is currently diagnosed in Canada. That I I think, is about to change because it is already being diagnosed in a bit of a different way in the United States. Medicine now has the ability to determine whether a person has amyloid buildup in their brains before death. You may have heard people say that Alzheimer's is a disease that could only be diagnosed upon autopsy. And that did used to be the case. But now we are able to use PET scans with amyloid tracers and tests of cerebrospinal fluid obtained through a lumbar puncture. That fluid can be analyzed to look for

biomarkers of amyloid and of tau, which is another substance that sort of accumulates into tangles in the brains often of people who have Alzheimer's disease. So those two technologies are now, they're available on a very limited, mostly research basis in Canada. In the United States, they're being used a bit more widely. And the big change that is coming is blood tests to detect these biomarkers for amyloid and tau. Let's say a person is diagnosed with Alzheimer's today. What can they expect, Kelly?

I guess I'm thinking about like symptoms and then also treatment. As far as symptoms go, Alzheimer's looks very different for different people. As a general rule, it moves from a mild cognitive impairment stage where you might have trouble with short-term memory but are still capable of functioning in your day-to-day life to more serious forms that progress from mild dementia to moderate dementia to severe dementia due to Alzheimer's. By the time patients get to the end of that road I just described, they're often in a place where they can't dress themselves or feed

themselves or bathe, where they don't know the names of the people they love or may not recognize where they are. As far as how patients behave once they develop later stage Alzheimer's, it can be very different depending on the patient. Some are very paranoid, very angry. There's, you know, can be a fair number of outbursts. Some become sort of fairly calm and incredibly happy and seem, you know, that even though they may not know the people who they once loved or still love if, you know, if they were able to recognize them. So that part of it, it really differs from patient to patient. But on the whole, it's a very sad and difficult disease for both patients and their families. Yeah. And so I guess it's really managing those symptoms is kind of what it comes down to then through those stages.

There do exist in Canada right now a couple of treatments. The most recently approved treatments were approved almost 20 years ago. And they really only help around the margins with symptoms. I guess if we can broaden this out a little bit, like the impact on Canada's health care system, what do we see as the impact of Alzheimer's? The impact is huge. themselves and on their immediate family and caregivers because this disease is one that does require so much hands-on care. As far as the system itself, it really has its heaviest impact, I think, in terms of the need for long-term care and home care for people who require the round-the-clock care that sometimes happens with dementia. The system in general right now in Canada is already struggling to deal with the number of people who have Alzheimer's and other related causes of dementia. And that extends not just to the availability of proper

memory care units in long-term care homes, but it also extends to access to neurologists, for example, to get diagnosis. There's some good efforts to try to extend those services more into primary care, but we already have a huge shortage of primary care in Canada. So on the whole, it's a disease that is hard on patients, hard on families, and hard on the healthcare system. Yeah. And I mean, for all these reasons, right, we've been doing research for decades to try to figure out how to prevent and treat Alzheimer's. I guess, what has the field, right, we've been doing research for decades to try to figure out how to prevent and treat Alzheimer's. I guess what has the field of research been like so far?

One of the experts I spoke to for this story put it this way. He said it has been, in a word, agonizing. It has been agonizing to watch trial after trial after trial of new potential compounds for Alzheimer's disease just fail. There have been basically two decades of every trial failing. Now that has started to change. We'll be right back after this message. So let's go back to the clinical trial that Tyson Holler is in, the one we talked about off the top. So what exactly is this trial testing? This trial is testing a drug called licanumab, which is a monoclonal antibody that is designed to clear the brain of amyloid, that sticky plaque substance that we spoke about earlier.

The head trial that Tyson is taking part in is using that drug in prevention. So what that means is they are testing this drug in people who do not yet have outward cognitive impairment, but do have evidence of amyloid in their brains through the PET scans and the cerebral spinal fluid tests that we talked about earlier. The interesting thing about this drug is that it has already been tested and has been approved in people who have mild cognitive impairment or mild dementia due to Alzheimer's. And this drug was approved last year by the FDA. It's also been approved in Japan and China for people who are in that early stage. So that's in the US, Japan, and China, then it's available.

Yes. And it's available not as a drug for prevention. We do not yet know whether it works for that. That's what this AHEAD trial is all about. It is available in those countries that we just mentioned for people who have either mild cognitive impairment or mild dementia due to Alzheimer's. And the reason this drug was approved is because it showed some disease slowing. So when you compared people who received this drug to people who were on the placebo, those who were on the drug got worse slower. That being said, it is not a cure. It did not stop progression. It did not reverse the effects of Alzheimer's disease on the people who took part in the trial. But it did slow down modestly how quickly they deteriorated. And when we say modestly, I guess, how much slowed down are we talking? So that trial that led to the approval of lacanumab found that there was about a 27%

slowing of disease over 18 months versus people who were on the placebo. To put that into more understandable terms, on average, it slowed down the progression over this 18-month period by about five months. So like I said, it's very far from a cure, and it does come with costs and with risks and side effects. Okay. Well, I guess we should talk about those then. So yeah, what are the side effects? What are the risks? And how much does this cost? In the United States, licanumab is selling for $26,500 a year on average. It is being covered there by Medicare. So there are people who are getting the drug through public drug plans in the United States. And as far as the side effects and risks of the drug go, I mean, they are considerable. The biggest risk is something called amyloid-related imaging abnormalities or ARIA.

And that is a reference to either microbleeds or swelling on the brain that can develop and that is linked to these anti-amyloid drugs. I mean, that sounds pretty serious, no? It does. And I would not in any way want to play down the seriousness of that. However, as a general rule, they're finding that these ARIA often resolve on their own without any symptoms. I think the really important thing to know is that because there are cases where the swelling or the microbleeds can be serious, that patients who are on this drug have to be monitored with very frequent MRIs. So in the trial that led to licanumab's approval, the participants were given an MRI before they started the drug, and then four MRIs over the first year. Four a year, okay.

And if you know anything about the Canadian healthcare system, you will recognize that that is a lot of MRIs. So it sounds like, you know, there is some promise here, but there are a few things to think about as well here, Kelly. What are experts' initial reaction to the trial? So they've been very mixed. I would say that some of the experts I spoke with felt very hopeful, I think in part because there was such a long history of failure, that here is a drug that met the endpoints or goals of the trial and was good enough that it managed to obtain FDA approval. That is a breakthrough, right? And I would not want to that it would be hard for patients and their families to really notice. And who said, like, is it worth the risks of the possible brain bleeds and swelling? With that risk, is it worth giving people this drug that might only minorly slow down

their progression? So it's unfortunately not a slam dunk, not a home run, but there is a little bit of hope there. And this is also how science often works. Here's a drug that at least has shown some benefit, even if it is modest. And so now future trials will try to build on that. And one of the questions that is being asked through the AHEAD trial is, well, maybe if this only works modestly in people who already have cognitive impairment, maybe it will work much better if we give it to people before they have cognitive impairment. And we talked about Tyson off the top, who's in this clinical trial. It's interesting because his sister actually

couldn't be in the same trial, right? Even though they're both concerned about Alzheimer's? How does that work? Yeah. So for Tyson and his sister, Whitney, they were both interested in entering this trial. Tyson had gotten in first. And another sort of layer of complexity here is that they both underwent some genetic testing before their entry, his entry, I should say, into the trial began. And they both have two copies of something called the APOE4 gene. And that is not a deterministic gene for Alzheimer's. It doesn't guarantee that you will get it, but it does raise your risk. And after getting those genetic results, they then both went through the process of testing to see how much, if any, amyloid they had in their brain. So the lumbar puncture and the PET scan. And it turned out he had enough amyloid buildup in his brain to qualify for the trial.

And she did not, despite being a year older. So I think their case is just a real reminder that, you know, this disease, especially in its early stages, does not follow a predictable course. And different things happen to different people, even if they have similar risk factors. So it sounds like there is or there can be a genetic component here too? There's definitely a genetic component to Alzheimer's disease, although I should say that by far the biggest risk factor is aging. So if you're lucky enough to live to an old age, you'll have some risk for dementia and Alzheimer's. But when it comes to the genetic side of things, I would really divide them into two

buckets. There are a handful of deterministic genes that researchers have identified that really raise the likelihood to a very high level that you will develop early onset Alzheimer's. These genes are quite rare. And there is a genetic component in there in that there's a gene called APOE. Everyone has it, but there are different kinds. And if you have two copies of a version called APOE E4, that raises your risk of late onset Alzheimer's by something in the neighborhood of 10 times. And that is the version of APOE that both Tyson and Whitney have. We've been talking about medical solutions, drugs to slow Alzheimer's here. But I guess, are there any non-medical things people can do that we know can help reduce

the risk of Alzheimer's? We know more about things that can be done to reduce the risk of dementia generally. And those include a lot of the same pieces of lifestyle advice that we give everybody about how to live well and long. So that means eating healthy, getting lots of exercise, remaining social, high educational status really seems to help. A couple of other ones that have been identified that I always really like to talk about are hearing aids, right? Like, if your hearing starts to go and not being able to engage with the people around you means you sort of withdraw from social connection. That's a bad thing and it contributes to dementia. Avoiding head injuries. Air pollution is another

really interesting area of study right now that seems to have a pretty strong link to dementia. So those are things that through a personal responsibility perspective and a public policy perspective we can do to reduce risk. At the same time, I think probably all of us know people who lived very healthy lives and still got Alzheimer's disease. And when can we actually expect results from this trial? The head trial is expected to release results not until 2029. There is a second very similar trial going on with a drug called Denonimab. That drug also showed promising results in patients who

already have mild cognitive impairment. And it's also being tested as prevention in a trial called Trailblazer. That trial is expected to produce some results by 2027. So both of these trials of anti-amyloid drugs in prevention, we were a few years away from getting any kind of answer. But if those trials are positive and considering the history, I would emphasize the if there, right? We just don't know what these trials are going to produce yet. to either prevent or even delay the symptoms of dementia, then the future that people in the Alzheimer's research field imagine is one in which we could test people fairly early in life using a blood test looking for those amyloid biomarkers, not dissimilar to the way we test people for diabetes, right? We look for their hemoglobin H1C markers.

And if they're above a certain cutoff, then we start treating them with medication in order to prevent all of the bad outcomes of untreated diabetes. So the long-term sort of dream here is if you can detect amyloid using a blood test, which we can already do and is already being done in the United States, and then you had drugs that were really good at preventing or delaying the symptoms of Alzheimer's, you could begin to treat people before they develop cognitive impairment. Again, I would stress that is a big if, but that is what is riding on these prevention trials. Kelly, thank you so much for being here today.

Thanks for having me. That's it for today. I'm Maina Karaman-Wilms. Our producers are Madeline White, Cheryl Sutherland, and Rachel Levy-McLaughlin. David Crosby edits the show. Adrienne Chung is our senior producer, and Angela Pachenza is our executive editor. Thanks so much for listening, and I'll talk to you tomorrow.