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Studies Question Potential Alzheimer's Treatment


This is SCIENCE FRIDAY. I'm Flora Lichtman, filling in for Ira Flatow today. Last year, researchers reported a breakthrough in treating Alzheimer's disease. They'd found a drug that appeared to reverse the symptoms of Alzheimer's in mice. The drug was already on the market, approved by the FDA to treat a type of skin cancer, meaning Alzheimer's patients could ask their doctors for a prescription, and some did.

But this week, four papers appeared in the journal Science claiming that last year's study could not be replicated, at least not in its entirety, casting doubt on the drug's potential. In a field where new treatments are few and far between, what are patients to think? And do we even know what Alzheimer's drugs should be targeting, exactly?

That's what we'll be talking about, so give us a call. Our number is 1-800-989-8255. That's 1-800-989-TALK. Or tweet us @scifri. Let me introduce my guest. Ronald Petersen is the chair of the Advisory Council for the National Alzheimer's Project Act and the director of the Mayo Alzheimer's Disease Research Center at the Mayo Clinic in Rochester, Minnesota. Welcome back to SCIENCE FRIDAY, Dr. Peterson.

RONALD PETERSEN: Thank you very much, Flora.

LICHTMAN: Walk us through what these new papers are saying about this drug Bexarotene.

PETERSEN: Sure, Flora. To put this in context, about a year ago, a study was published in Science by Dr. Gary Landreth and colleagues at Case Western University in Cleveland that really shocked the field, to a certain extent, with respect to there may be drugs out there that are used for other purposes that could have actions against the underlying biology of Alzheimer's disease.

And they were studying a drug called Bexarotene, which likely resulted from what's called high-throughput screening, where people will put a bunch of compounds that are on the market - other drugs, compounds that are available for other purposes - through a screening process looking for any hits at an assay that may be relevant for Alzheimer's disease.

So the amyloid protein that's deposited in the brain of people with Alzheimer's disease was thought to be a relevant target. It certainly is. It's a hot area in the field for investigation. So people run a variety of compounds through the screening process to see if it has any action on the deposition or the removal or the biologic processing of this amyloid protein.

And in doing that, Bexarotene - which is on the market for a form of skin cancer called cutaneous lymphoma - actually had a hit. That is, it affected the processing of the amyloid protein. So the investigators at Case Western then took it to the next step and said, OK, let's put this drug in an animal model, so-called mouse model, of Alzheimer's disease.

And these are mice who have been genetically altered to develop this protein, amyloid, in the brain by giving them genes from humans who have the genetic form of Alzheimer's disease to see if, in fact, the mice produce this amyloid protein. And lo and behold, they do. So this becomes a human - not a human but an animal, living model of the biologic process.

Go they gave this Bexarotene to these mice that were genetically programmed to develop the amyloid protein in the brain, and lo and behold, it reduced the amount of amyloid in the brain. And also, they had behavioral tests. That is, they put the animals through some various tasks that are thought to reflect what's going on in the brain, and, in fact, when you gave the drug Bexarotene, these animals performed better on these tasks than they had done formerly.

So the implication was that this drug may be useful in the treatment of people with Alzheimer's disease. Now this is a basic science study, it's in an animal model, and one has to presume that there is an implication for Alzheimer's disease in the human, but that's a leap.

So the four papers that are being published this week in Science have tried to replicate that study done at Case Western, and these are very reputable scientists from around the world who have been in the Alzheimer's field for years and years and years. So these are solid citizens, so to speak.

And the papers in general said, gee, we can't replicate this. We can't reproduce exactly what they found at Case Western a year ago when we did this, that and the other thing. However...

LICHTMAN: So this is why we have the scientific process, right?

PETERSEN: Exactly. This is science at its best. I mean, so this was a study that was published in a very reputable journal in the field, and now the journal is saying, well, let's let the process play itself out, and let's try to actually see if, in fact, the elements of that original paper were replicable. And so the other papers now that have been published this week raise questions about certain aspects of the study.

LICHTMAN: Although some of them were - some of the aspects were replicated, the samples.

PETERSEN: Absolutely. In fact, Dr. Landreth and his colleagues have replied to these four and said no, no, no, wait. I mean, while the general tenor is you've got four papers that didn't replicate our findings, there are elements of these papers that, in fact, do replicate their findings.

So, in particular, some of the behaviors improved in some of the animals that were tested in these other studies, and a particular form of the amyloid - the so-called soluble amyloid, or the oligomeric form of the amyloid - was in fact replicated in these other papers.

So Dr. Landreth and colleagues are saying no, no, no. I mean, some features weren't, but in general, the basic premise was replicated.

LICHTMAN: Since that original study came out, did you have patients that actually came to specifically asking for this drug based on the reports they heard in the news?

PETERSEN: Absolutely. I mean, I think the field of Alzheimer's disease therapeutics is starved right now for a real effective treatment. And consequently, when you see a study like this that may, in fact, have more immediate applicability to treatment of patients than, say, a molecule under development in a pharmaceutical company, that people came and say - as I mentioned, I just had a patient last week whose home physician had said let's try you on this drug, because I've heard it might be good for Alzheimer's disease.

So it does happen that, in fact, patients interpret these findings as immediately applicable to their condition.

LICHTMAN: And how do physicians handle that kind of request?

PETERSEN: Well, at the risk of trying to be a naysayer and living in an ivory tower, I think you have to be honest with patients and say yes, this is very exciting. It may be important. It may prove efficacious down the road, but I think it's premature to take either an amyloid study or a test tube study and directly translate that to the human model.

There are safety issues. There are ethical issues, and we really don't know whether it's going to be efficacious.

LICHTMAN: Did some of these reviewers - do I have this right - caution that this drug particularly is a little - has bad side effects?

PETERSEN: Yes. One of the papers talked about the possibility of some side effects developing from the study that were not outlined in the original paper and perhaps could be of concern. But again, Dr. Landreth in his response said, gee, this is a different form of the drug. You take - you've taken and manipulated it somewhat differently. You've given it at different doses than we would recommend in the human condition.

Nevertheless, it doesn't mean that just because a drug is approved by the FDA, on the market for another indication - in this case, cutaneous lymphoma - that it is going to be safe using it for another indication in another population. One can imagine in Alzheimer's disease, you're dealing with patients who, in general, are older - 70s and 80s is where the disease manifests itself. And you may have to take it for a long period of time - years - to get the effect of the drug.

So to say that the drug is absolutely safe because it's already on the market is a bit of a presumption. So we have to be concerned about that. So I think physicians will bring all this information up to the patients and explain to them why this may be premature.

LICHTMAN: Do we understand or is there a consensus among physicians and researchers about what the mechanism is for actually causing the cognitive symptoms in patients with Alzheimer's - that is, are plaques the thing we should be worried about? Is it the dissolved beta amyloid?

PETERSEN: Right. Very, very good point, Flora, because in general, many people - not all - but many people in the field believe that this amyloid protein is a central player. Whether it's the end-all, be-all, I think, remains to be seen. But it most likely has an effect on the underlying clinical manifestations.

But it's another issue as to whether - what form of the amyloid protein. So the amyloid protein goes through a various cascade of misprocessed steps to get to the final plaque. And in some of the papers that were reported this week, they indicated that there was no change in the ultimate plaque formation in the brain.

But Dr. Landreth and his colleagues contend that's not the culprit. The culprit is the earlier forms of deposition, the so-called oligomeric stage that is really causing the damage, or the soluble stage of the processing. And the drug may be effective at that stage, and hence may be efficacious.

But this is all within the world of amyloid. There's a whole other research community out there that talks about other aspects of the Alzheimer's disease process. So while amyloid is likely to be a major player, it may not be the only culprit in the disease.

LICHTMAN: And so there may be other ways to treat it, too.

PETERSEN: Absolutely. I mean, I think one - you may be familiar with the National Alzheimer's Project Act that was signed into law in 2011, and eventually resulted in the first United States national plan for Alzheimer's disease, released about a year ago in Washington. And part of that plan talks about exploring other targets for Alzheimer's disease.

Amyloid is a very big one. We need to fulfill our research obligations there to examine it to the hilt. But there could be other proteins, the Tao protein, Alpha Synuclein, a variety of other proteins that could be involved, and hence we need to throw the landscape open with respect to what might be other potential targets in the various cascades that are described to produce the results of Alzheimer's disease.

LICHTMAN: I have about 20 seconds left, but just in this last little bit, there's a clinical test - a clinical trial to test this drug starting soon. Will these new studies affect that trial?

PETERSEN: No, I don't think so. I mean, I think that the phase one trial of Bexarotene going forth in humans to test its safety and efficacy I think is entirely appropriate. So I would not pull back. I mean, there are some cautionary notes in these papers, but I wouldn't sabotage the overall program by this.

LICHTMAN: Thank you for joining us today.

PETERSEN: My pleasure. Thank you.

LICHTMAN: Ronald Petersen is the chair of the Advisory Council for the National Alzheimer's Project Act and the director of the Mayo Alzheimer's Disease Research Center at the Mayo Clinic in Rochester, Minnesota.


LICHTMAN: This is SCIENCE FRIDAY, from NPR. Transcript provided by NPR, Copyright NPR.