Dr. Babak Tousi, a neurogeriatrician at the Cleveland Clinic, talks about slowing the progression of Alzheimer’s.
Interview conducted by Ivanhoe Broadcast News in 2023.
We’re talking about brain health. What’s hard is almost everybody either has been affected or knows somebody who has Alzheimer’s, such as epidemic almost right now.
Tousi: There’s a tsunami coming. As we get older, more likely we’re to develop Alzheimer’s. We know people about 80, one out of three may develop dementia, and then people get to 90, one out of two develop dementia. Alzheimer’s is the most common type. We’re dealing with something like a tsunami of Alzheimer’s disease down the road.
And there’s no way to stop it currently?
Tousi: To stop is a strong word, but we know lifestyle modifications, our healthy brain living life as thought might slow down the rate of progression. That includes something like exercise regularly, and healthy habit of diet of eating, but you’re right, just not having to just stop it at this point.
Until recently, you have not had any kind of medication or any way to help patients?
Tousi: For many decades, we have symptomatic treatment, just help with the symptoms, but we didn’t have anything strong to slow it down. The new class of medication developed over the last decade, I would say, and going to different phase of clinical trials. We wondered about a year and a half ago but didn’t get the full approval yet, but this is the first one that received full approval, and hoping to slow down the progression of the disease.
It’s exciting because I think Alzheimer’s and dementia, are getting diagnosed much earlier, so you know you get on top of that?
Tousi: Correct. First, to talk about Alzheimer’s, at least for the time being, our knowledge is that there’s some build-up of protein in the brain. One of them, well-known amyloid plaques build up 10 to 15 years before the onset of symptoms, becoming forgetful. There’s another one also we call it tou, so developing tangles in the brain and the thought process of that, at least as a hypothesis for a long time, that if somehow you interrupt this cascade of amyloid buildup in the brain, you may be able to slow down this progression. That’s our first step in approaching this removal of amyloid plaques. These particular compounds approached the amyloid cascade a little earlier before the plaques were fully formed. Targeting those sealable forms of amyloid that we have. But removing this basically triggers the immune system of the body to remove this. We may be able to slow down the progression and fortunately, the results are positive since yes, it was able to achieve that goal partially.
That’s what tried is doing?
Tousi: Correct.
How early can you use this drug?
Tousi: Currently, the FDA approval is limited to what was in Phase III of a clinical trial, which is what people who have mild cognitive impairment or the earliest stage of Alzheimer’s dementia, what I mean by that is that people who are forgetful or family appreciate they’re forgetful more than usual, but they remain independent or require minimal assistance during their activities of daily living. Such as managing medication, managing finances, maybe a little problem with navigation here and there, but generally speaking, relatively independent, maybe some dependency on some tasks. That’s how far we know because of the clinical trial Phase III trial. But the thought is that if these amyloid plaques start building up earlier, maybe we should go one step before people get forgetful. Actually, there is currently a trial looking at this. We call it healthy patients at risk, and that means people who already maybe have a strong family history for some reasonable concern, and they would like to come at trial, one of them is a head trial, for example, to be ahead of time, and we can measure amyloid plaques in the brain. If the load is high, that raises concern, we start this treatment. Want to emphasize here not everybody who has amyloid plaque will develop Alzheimer’s, but we know people who developed Alzheimer’s, they all had amyloid plaque earlier before that. There’s another step before this one, but it’s not approved at this time for medications, so the trial is happening right now. Hopefully, we know the results in two, or three years and we now approach that way.
This drug is in your trial, can you give me some specifics about the trial results?
Tousi: Correct. It’s a global multi-site trial. The US has been the major site, but it happens in Japan and other European countries. We focus on those features that I mentioned, such as mild cognitive impairment, and early-stage Alzheimer’s dementia, but we have to confirm they have this amyloid pathology involved. That technically usually happens, we have PET imaging- amyloid PET imaging. We also can do cerebral spinal fluid to confirm that pathology and amyloid are one of the causes of the problem. For people recruited to study, of course, some people received a placebo, some people received active medication for the 18-month period, and we followed them over time. We monitor over time, which I emphasize monitoring because medication involves some side effects, of course. After 18 months, we look at how different outcomes that we’re measuring change between those two groups.
Was it a pill?
Tousi: This is infusion, so it’s every two weeks. Based on your weight, you get the medication every two weeks. The infusion takes about one hour. Of course, the first time or second time people receive this medication, elaborate medication monitoring him few hours after the infusion, to make sure they don’t have any rapid reaction, or anaphylactic reaction, which is very rare for this condition and for this medication, but it’s still possible. After that, they go home. They come every two weeks to receive the infusion, and periodically we do an MRI. Usually, it was after 14 fusions or after six infusions, and maybe one after, the current before the 14th infusion. This is because we know that in the process of removing this amyloid plaque in the brain, we remove sometimes amyloid from the blood vessels. We remove these amyloid blood vessels with parts that may make these blood vessels more prone to leaking fluid out or oozing out fluid protein or sometimes red blood cells. That may cause some edema in the brain and sometimes even mini bleeding or micro hemorrhage, we call it. Most of the time people don’t know when they have it, and it resolves on its own over time, but in rare cases, they may become more serious. Due to that, we need to monitor with MRI. If the MRI shows, maybe the size of it much too big, or we have too much bleeding, we hold the infusion, and we repeat the MRI periodically every 30 days to make sure it’s clear up or stable. Then we restart the treatment again. After monitoring and following people, at the end of 18 months, we did all these outcomes again that we did in the baseline visit and compared them. The primary outcome studies and tests are called the clinical dementia rating scale, CDR, for shrt. Basically, they are the assessment of cognition and function and maybe a few behavioral symptoms of the patient. It’s six categories we look at social skills, activities of daily living at home, and memory interaction. It seems people in the primary article on people who are receiving this medication compared to people receiving a placebo had the least decline in those measures. The total added up these numbers, the number was less worsened in that group. The other outcomes of the monarchial, that got my attention the most probably, were activities of daily living. This means who is still able to do laundry? Who is still able to dial the phone number after 18 months? Who is still able to cook as they used to do before? In many of those outcomes was a significant benefit shown for people to receive active medication. About 30 to 40 percent, which is pretty good.
Could you see a difference in the scans?
Tousi: Definitely amyloid is removed, yes. PET imaging.
How much of it? Thirty to 40 percent?
Tousi: More than that. Basically, every person is different from where they start. We expect people are being under 30 to become central. This is the code to use for this one. Then we receive go under 30 or 25 of centroid, basically simply amyloid negative almost. Almost 9 percent of patients went down to become negative results.
That’s really amazing.
Tousi: You’re right. We were able to remove amyloid. We have done it before sometimes, but we have to make sure that can be translated clinically. We remove amyloid plaque. This time for the first strongly we can say yes, we were able to show all these clinical measurements. We were able to reduce the amyloid plaque. Not only that, they’ve been able to show that affects the other harmful protein, we call tangles or tau protein. They were able to show that reduce that. Apparently, reduction of these amyloid plaques has a benefit for reduction of tau as well, which I think correlates more with the degeneration and brain damage and actual cognitive decline than even amyloid plaques. That purpose is more positive. If we see it as a downstream effect then it’s not just removing the plaque amyloid. We were able to show all these changes in this biomarker of disease. There’s another concept of longer-lasting. When I’m looking at the awesome, it’s just not clean to look at someone and say, “We can’t do function well, it doesn’t do well, doesn’t have a stroke. Traditionally the diagnosis of autism was made by exclusion. This is not a stroke, it’s not Parkinson’s, it’s not alcohol induced, should be Alzheimer’s. With the concept of a biomarker that was developed, we can measure these proteins. We can see how amyloid imaging comes down, PET imaging comes down for tau and also cerebrospinal fluid, and even very soon for blood biomarkers. We can measure those changes in blood markers. The study shows that actually changes in blood biomarkers.
Which is nice because then it won’t be all just clinical?
Tousi: Correct. I think that is one of the most important changes. It’s not that we have a new treatment. We have a new way to approach all summer for diagnosis. If somebody wants to receive this treatment, we cannot just set up the old way of diagnosing Alzheimer’s. It always seems like it evolved somewhere because that no, we need some confirmation, some diagnostic biomarker. Currently, we use amyloid imaging and separate spots from it through a spinal tap. I’m not surprised in a couple of years if we use blood biomarkers for diagnosis. Already in research, we’re doing some pre-screening, but I can see them happening very soon, two years from now.
Perfect. Now, for the people who did get the drug and they’re off of it. Did the tangles and blacks come back?
Tousi: Of course, the patient took off a bit. There was not part of a study to follow it over time. In the previous phase of the study, Phase two of this study, when people there gap between the time they finished the randomized phase and phase they started the open-label phase. Open-label phase everybody gets active medication. They realized, yes, that is still building up things happen. The medication effect lasts longer for sure. Not in as much as the amyloid plaques in the imaging but in fluid biomarkers, spinal fluid or blood basically start wrapping increasingly a little bit. The question is going to be, how long do we need to give that medication? Which is a billion-dollar question. At this point, we give mild stage of Alzheimer’s dementia, MCI. The thought is that for now continue it but we will learn or we need to learn when to stop, or is it possible to stop in the first place? Or if you’re stopping it, we have to monitor how often to see this build-up. The buildup of amyloid plaques in the brain happens in the last part. The changes start earlier through the fluid measurement, those changes in the fluid.
Anything I’m missing? Joan thinks that because of this drug, she’s still able to do her life.
Tousi: Of course, I’m glad to hear that. That’s the goal of treatment. Every person is different, the rate of progression is different, for different people. That’s what our goal is. The benefit is there, although it’s small. In different people have presented a different ways. That’s what we hope to achieve providing more good days of independence. We know that this is unfortunate, it’s progressive. I’m not saying we stop the disease. We’re far from a cure, for sure, but just buy more good days of independence.
Do you think this drug will be the start of not an early stage, but a more advanced one?
Tousi: At this point, we only give for an earlier stage. It’s not for patients who are already in the moderate stage of dementia. If somebody already requires help, definitely is not more advanced. Somebody needs help dressing himself or taking a shower, those basic activities of living. That’s not for that group of patients. That’s for a press, the very earliest stage of Alzheimer’s dementia. Keep in mind, I think that’s the first step. We have more medication coming down the road. Amyloid is just one piece of a puzzle we have to approach all other factors involved in developing Alzheimer’s. As inflammatory involves you know vascular changes may happen if we haven’t targeted tau, which correlates even more with damage to the brain and shrinkage of the brain. There are a lot of clinical trials about that, I’m optimistic about it. I think if you want to add something else, is important to look at side effects as well. When we give any treatment, we always look at the benefits versus the risks. To benefit, we have some benefit, small benefit, but still benefit. One of the risks involved is we call it amyloid-related imaging abnormalities for short pieces like edema or manipulation that may happen in some people. But it’s interesting enough. The people have some particular genetic predisposition that happens more often. There’s a gene variant we receive, we call an APOE. The majority of us have Apple E3. We get one from each parent, but there’s another one called APOE4. Some people have it. If you have APOE4, your risk of Alzheimer’s is two to three becomes more. If you get from both parents, is almost like 10 to 15 times more. More likely to get Alzheimer’s. It’s not definite, but the risk is higher. What was noticeable in this treatment and actually can apply to all medication in this class seems like that. If you don’t have APOE4 in this study, you bought a five percent, you may develop this mini edema or mini bleeding. If you have one, the risk was about 11 percent, and we ended up in blue having both APOE4 from both parents. We call them homozygous, which means you get one from parent APOE4 and one from the mother. The risk was almost 30 percent, a much higher risk and if we want to discuss the treatment, I think it’s important to consider APOE measurement. It’s a tiny genetic test. I was glad to hear the FDA actually added this black box just to emphasize that in a group of APOE4 from both parents. It makes it two versions of this gene, and the likelihood of developing scientific is much higher. The other thing is not a factor people consider, if you want to consider this treatment, not only do we have to do some biomarkers to confirm or increase our accuracy of diagnosis that’s due to Alzheimer’s. Considering it may need genetic testing, at least so limited for this particular gene. To see if your risk is higher, so that comes to discussion. I think the decision to start this medication should be always case-by-case. If people are at very high risk of developing a stroke or something like that. Maybe that’s not a good medication for them. People who have a lot of vascular changes have extensive vascular changes.
END OF INTERVIEW
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