Alzheimer’s treatment works best early, so why are patients waiting? [PODCAST]

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Two Alzheimer’s drugs now slow the disease, and they work best when symptoms are still mild. Emer MacSweeney is a neuroradiologist and the cofounder and CEO of Re:Cognition Health. This episode is based on her article “Early Alzheimer’s detection is now a treatment decision,” published on KevinMD. She explains why she calls this a new era, how a simple blood test can start the workup, and why clearing amyloid early matters for the tau protein that tracks symptoms. You will hear what the trials showed: The mildest patients had no decline over the first year, and treatment slows the move from one stage to the next by about half. She makes the case that staying in the mild stage keeps patients eligible for the next medications in the pipeline. She also takes on the cost question, since these drugs slow decline rather than cure it, drawing on patients she treats who are fit, active, and often still working. Press play to hear why she says the biggest risk is not getting treated.

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Transcript

Kevin Pho: Hi, and welcome to the show. Subscribe at KevinMD.com/podcast. Today, we welcome back Emer MacSweeney, a neuroradiologist and cofounder of Re:Cognition Health. Today’s KevinMD article is “Early Alzheimer’s detection is now a treatment decision.” Emer, welcome back to the show.

Emer MacSweeney: Kevin, thank you so much. I’m so happy to be able to talk about this, because it is just so important for so many people. So here’s the really big thing: We have to have a proactive shift in how we think about Alzheimer’s disease now that we have new treatments on the market, we have new biomarkers, and we also have more and more clinical trials for new-generation medications. So we’ve got to think about early diagnosis just the same way as we do about cancer. Actually, more people are worried about getting Alzheimer’s disease than they are about cancer. It’s exactly the same: We know that the reason we screen early for cancer is because early diagnosis and effective early treatment will lead to a better outcome.

Kevin Pho: So how does that parallel work now for Alzheimer’s?

Emer MacSweeney: Well, it starts as soon as someone feels instinctively that something’s not right with the way their brain is working, and it is inordinately strange how sensitive one can be to that. In fact, there was a great piece on the news, on Good Morning America, just literally yesterday, with Sully Sullenberger, the Hudson River pilot, and his wife, and he was saying exactly this: The minute you think something’s not right, trust your instincts and present early.

Why? Because today you can get a simple, quick blood biomarker, a p-tau217 blood test. It’s the simplest thing in the world, and it will give you an initial indication. Does it reflect a high amyloid, an indeterminate amyloid level, or a low amyloid? If it’s high or indeterminate, you go on to further tests, and you confirm with the gold standard, PET or CSF: Have you got high amyloid protein? If it’s intermediate, similarly, because you can’t be certain. If it’s low, it’s highly unlikely your problems are due to Alzheimer’s, but you need to find another reason why you’ve got cognitive symptoms.

The reason it’s important is that we can access these treatments earlier. Kisunla and Leqembi, the two amyloid-targeted therapies and the first two drugs to come on the market, are covered by Medicare and supplementary insurers if you’re over sixty-five, and it’s crazy not to be getting early access to these treatments. Your biggest risk is not getting treated. Whatever the potential side effects of the medication, your biggest risk is still not getting treated.

Now, here’s the most important thing: The earlier you get treatment with these medications, the more effective that treatment will be. So it’s exactly the same as treating cancer. If you treat cancer in stage one or two with a given medication, it’s going to be way more effective than if that cancer has metastasized. What these two drugs are doing is removing the toxic amyloid protein from the brain, which is what we’re detecting with the PET amyloid scan, or detecting indirectly with the p-tau217 blood test.

The reason it’s so important to get rid of the amyloid protein as soon as possible is that the amyloid protein drives another neuroinflammatory process, called microgliosis, which in turn drives tau protein. And it’s the toxic tau protein inside the brain cells that actually correlates with the progression of symptoms. So you’ve got to get the amyloid out as quickly as you possibly can in order to drive down the toxicity and the propagation of the tau protein inside the brain cells. We know that the people who get treated as early as possible, when tau is low, do best. That, I think, is really the most essential message.

It’s so hard, because it’s the same in every country. This is so common; there are hundreds of thousands of people. The key thing is trying to manage people effectively and quickly through this pathway. In fact, at Re:Cognition Health, we’re now doing pretty much direct access, or we’ll work directly with primary care physicians, to accelerate the process of checking whether someone meets the eligibility criteria to start treatment.

Those eligibility criteria are essentially mild cognitive impairment, MCI, or mild AD dementia; an MRI scan that has certain characteristics, which I won’t go into because we haven’t time, but it’s easy to look at the MRI scan; and then proof of high amyloid protein, either via a spinal fluid tap for CSF analysis or a PET amyloid scan. But the p-tau217 blood test gives you a quick indicator. And then we just want to check you’re not on anticoagulants. That’s really all we need to know, and that the individual is otherwise well. Most people with early Alzheimer’s are actually pretty fit and well.

So I really want to emphasize that we’re in a new era. There are a plethora of new clinical trials for new medications, but in the U.S., you are in such a fortunate position, where you have the first two drugs on the market, covered by Medicare for everyone over sixty-five in particular. This is just fantastic. So act quickly. Don’t stay on a waiting list. It’s like being on a waiting list for cancer; it’s mad. You would not be on a waiting list for cancer. Do not be on a waiting list for this, because all the time you’re on a waiting list, this tau protein is progressing through your brain.

So I want to say, look, if you are anywhere near Fairfax, Northern Virginia, or Houston, Dallas-Fort Worth, or Chicago, where we have centers, we are able to see people literally straightaway. We’re expanding our team to bring people in, and you just need to contact recognitionhealthusa.com. But I want to urge everyone: Don’t sit around wondering, don’t wait for it to get worse, act immediately. And if you’re wrong, and it’s not due to Alzheimer’s disease, it may be due to something that is reversible, in which case you want to get it treated as quickly as possible as well.

So there’s a reason now: clinical trials, treatments on the market, and biomarkers to detect the presence of disease when it’s very mild, which is the very time that these drugs are most effective. And I go back to what I saw about Sully, the famous Hudson River pilot. I want to leave it by saying that his wife noted that family members should trust their instincts when something feels off, advising that the key lies in identifying what’s unusual for your partner, your parent, or your friend.

Kevin Pho: So last time we talked, we talked about the biomarkers. In this particular episode, I want to ask more questions about those anti-amyloid treatments. For those who aren’t familiar with the clinical trials, what were the endpoints, and how effective actually were these new medications?

Emer MacSweeney: Great question. The big trials were TRAILBLAZER-2 and TRAILBLAZER-6, the two big trials for donanemab, or Kisunla, which is the Eli Lilly drug. They showed slowing in the progression of disease and symptoms, and the extent of that depended on how mild your symptoms were when you first started treatment.

Everyone had to have mild cognitive impairment or mild AD dementia. Mild cognitive impairment is really managing independently, but having to work stuff out, make extra lists, things like that. And with mild AD dementia, I think most people know it means that you do need some help from someone else with certain tasks, maybe doing your tax returns or other more difficult things.

Now, if you look at everybody in that group and take the mildest 25 percent, those people, relative to the placebo group, did not demonstrate any decline over the first year of treatment. And if they then started to decline, it was very gradual, at about 60 percent less decline relative to the people on placebo. If you look at the people who were around the 50 percent mark, in the second 25 percent cohort, the difference between being on active medication and placebo was about a 60 percent differential in slowing the progression of disease. And if you take the more advanced people, who are still relatively mild, it’s about a 37 or 38 percent slowing in the progression of disease.

But I think what’s really important in thinking about this is that what matters to people is not, “Oh, I’m a tiny bit worse than I was yesterday.” What matters to people is, “Have I moved to the next stage of the disease?” Because that’s where you suddenly think, “Oh my goodness, now I’ve lost a new level of independence.” And losing your independence is what everyone, to be honest, is pretty scared of. So it will reduce by about 50 percent the rate at which you move from one stage to the next, and I think that is probably more important.

The other thing is that Kisunla or lecanemab, and I’ll come to the lecanemab results, is not going to be the only drug that ever comes out for this complex, very common disease. I think the most important way to think about getting on treatment early is this: If you can get on Kisunla or lecanemab now, yes, you’re still going to decline a little bit, depending on how early you’ve managed to start treatment. But there are lots of other new medications in trials, and some of them, though not all, will statistically come on the market. They’ll have different mechanisms of action. They could potentially be synergistic, or they could be additive, working at different stages in the Alzheimer’s neuroinflammatory pathway. They could be anti-tau. They could be anti-microglia, and various other things. And we already know that most of these other new medications coming through are also most effective when symptoms are mild.

So the key thing is that you don’t want to have declined and missed the stage where you could have hopped onto this medication, then the next one, and the next one. By missing out on Kisunla or lecanemab now, you could potentially be missing out on the other new medications as they come through, because you’ve already slipped below the cognitive band where those medications are effective. What will truly change the paradigm for this disease and the outlook for individuals is being able to combine it with other medications as well. That, I think, is the most important way to think about this.

With lecanemab, the mechanisms of action are slightly different, and the results in that short period are slightly less dramatic. But with Leqembi, we also have people who’ve been on it for a really long period of time. I have patients myself in clinical trials in several of our centers, and it does, without question, have an ongoing effect. Keeping down the amyloid, both the protofibrils and the fibrils, which Leqembi also removes, is clearly beneficial.

And with Kisunla, there is now a follow-up study showing that three years after people stop taking Kisunla, once their amyloid plaque has been removed, they continue to gain benefit from the treatment compared to the people who have never been exposed to treatment. I don’t know if you can see this, and it’s not to scale, but say that is the gap at eighteen months. At three years after stopping treatment, the people on active medication will fall a little bit, but they fall much less than the people who have not been on the treatment at all. So if that’s the gap at eighteen months, the gap at three years will be out here. There’s a lot that we’re still finding out about this.

I have treated hundreds of patients, and I have never come across a single individual who was offered an amyloid-targeted therapy, and for whom it was suitable, who chose not to take it because they were worried about side effects. Their main concern is doing anything they can to slow down the progression of the disease.

I do know many people say, “Oh, but it’ll only slow it down for this period of time.” I think the big thing that’s being missed in that context is that this is one of the most active areas of research and development. I was on a program with Alzheimer’s Disease International earlier this week, and I think there are something like 290 new medications currently in the pipeline, active in clinical trials. Obviously, not all of those medications are going to make it, but there are just going to be quite a lot of medications for this disease. As normally happens in life, each new one that comes on the market will, as I said, either be synergistic, or it’ll be better, or it’ll be less expensive, or it’ll be easier to take. It will just get better and better. So don’t miss the boat now.

Kevin Pho: So how does a clinician weigh the benefits of these therapies? I’m going to assume that these therapies are going to be very, very expensive. And you did make that comparison with cancer screening, but isn’t cancer treatment more curative? These treatments aren’t necessarily curative of Alzheimer’s, because there still may be a little bit of decline. So how does a clinician weigh the benefits versus the high cost of these medications when considering them for an individual patient?

Emer MacSweeney: I think it’s actually a more difficult question to pose than it is to answer. Obviously, I’m doing this all day, every day, and I think this is really important: Any individual who is not able to make the decision about whether or not they want access to one of these medications, given that they’re eligible, is basically not eligible for the treatment. If they’re not able to make that decision themselves, they’re already too advanced.

I think it is very difficult to put oneself in the position of deciding who gets treatment and who doesn’t. There is always that sort of awareness in the medical profession of morbidity and mortality. But what throws this into a very contentious area is that, unlike vascular disease or potentially other forms of dementia, most people with Alzheimer’s disease are actually very fit and well. In terms of the disease itself, at the time they’re eligible for these treatments, they’re generally very fit and well; the disease doesn’t cause illness of other sorts.

So you usually have really fit and well people, many of whom are playing a very active role in life. Maybe they’re looking after grandchildren, which is very important to the next generation. They are doing voluntary work. They’ve worked hard all their lives. Many of the patients I treat are still at work; they’re on committees, they’re doing voluntary work, all sorts of things. And they have a very active period of life ahead of them.

I think there’s a lot of work done on actuarial and financial analysis showing that it’s actually more expensive to spend longer in a very dependent position, particularly when you’re perfectly physically fit and strong. And people often say, again when the disease is more advanced, that it’s actually a much bigger burden on the family than, in a weird way, it is on the individual.

And you could say that with cancer, you either get better or you die. This is the destruction of who you are. It is a really bad way to die, which is why everybody is so worried about it. What everyone really wants is almost not so much body span as brain span, if you like. What you don’t want is for your brain to die before your body. That’s not a good scenario.

So I’m not sure it is just doctors who should be making that decision. I think it’s a much bigger decision than an individual doctor’s. I’ve never come across a doctor whose job it is to make that level of financial decision. And particularly in this situation, if somebody is not eligible for Medicare, then they would be self-paying, and no one should be making this decision who is not able to make it with full capacity, because if they can’t, then they’re not eligible for treatment.

Kevin Pho: We’re talking to Emer MacSweeney. She’s a neuroradiologist and cofounder of Re:Cognition Health. Today’s KevinMD article is “Early Alzheimer’s detection is now a treatment decision.” Emer, as always, we’ll end with your take-home messages to the KevinMD audience.

Emer MacSweeney: Thank you, Kevin. It’s how I started: Please, if you are worried, and that’s if you’re a doctor or anyone else, if you’re worried about your thinking ability, don’t sit and wait for it to get worse. Be proactive, do a quick test, even if it’s just a blood test, and get a diagnosis as quickly as you can, because today there are treatments.

Kevin Pho: Emer, thank you again for sharing your perspective and insight, and thanks again for coming back on the show.

Emer MacSweeney: Thank you very much. Thank you.

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