NPR

Sifting Genes For Clues To Alzheimer's

Two groups of researchers have scanned the genomes of thousands of individuals, looking for clues to genes involved in Alzheimer's disease. Gerard Schellenberg of the University of Pennsylvania explains how locating those genes could lead to new ways to treat or prevent the disease.

Transcript

IRA FLATOW, host:

This is SCIENCE FRIDAY. I am Ira Flatow. If you'd like to get in our conversation, you can tweet us, @scifri, @-S-C-I-F-R-I. Or you can give us a call. 1-800-989-8255 is our number. Or you can go to our website or our Facebook page at facebook/scifri and ask a question.

Alzheimer's disease is one of medical science's big mysteries, of course. It's difficult to diagnose. We don't really know what causes it, if there is any single cause. We have no real cure for it.

Well, writing this week in the journal Nature Genetics, researchers may have found some new clues to the disease. Two big consortia of researchers, one in the U.S., one in Europe, have sifted through the genomes of thousands of Alzheimer's patients and have come up with a handful of genes that seem to be linked to the condition.

Joining me now is Gerard Schellenberg. He's in the Department of Pathology and Laboratory Medicine at the University of Pennsylvania School of Medicine in Philadelphia. He's an author of one of those two papers. Welcome to SCIENCE FRIDAY.

Dr. GERARD SCHELLENBERG (Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine): Thank you, Ira, great to be on.

FLATOW: Let's go to the big - let me get right to the $64 question that everybody listening to me, and I'm sure you've been asked a million times: Do we have a cure for Alzheimer's here?

Dr. SCHELLENBERG: We do not have a cure for Alzheimer's. There's a few drugs that are, you know, approved and being used as standard of care, but they don't do what we greatly would like to do.

FLATOW: And we have heard of other genes already connected to Alzheimer's, correct?

Dr. SCHELLENBERG: That's right.

FLATOW: How does this set of new genes fit in?

Dr. SCHELLENBERG: Well, we studied late-onset Alzheimer's. There's also a very rare form of the disease called early-onset, when people get it in their 30s and 40s. So there have been three genes that have been found for that. And they've been highly useful in terms of designing experiments to get at what causes Alzheimer's, but they don't apply to the more common form, which is late-onset.

And in late-onset disease, there's been five genes known for over the last, really starting about 20 years ago. And our work that was just published last week adds another five. So we've kind of doubled the number of late-onset genes that contribute to late-onset Alzheimer's.

FLATOW: And so these are basically, you look at all these Alzheimer's patients, and you find some commonality in them, in these genes. And some of these genes are involved in the transportation of fats in the body, are they not?

Dr. SCHELLENBERG: That's right. So we look - we don't go into this with any ideas, with any hypotheses. So we call it unbiased or hypothesis-free research. We saw: What are - we ask the question: Are there any genes involved in Alzheimer's? And try and sample every one of the 25,000-plus.

We came up with five where the genetic variation in Alzheimer's - in patients - is a bit different than in elderly controls. And so we see these five genes. We have very good, solid evidence that they're all involved in your risk for Alzheimer's.

And you're right. There's several of them that, along with what was known before, really point to cholesterol transport and lipid transport in the body. I would say at the moment, certainly, these genes, these proteins that genes make are in the blood and involved in cholesterol transport in the blood, but they're also in the brain.

So at the moment, we're not sure whether is this something that happens in the blood that then affects the brain, or is this actually lipid metabolism in the brain that's being affected.

FLATOW: And if you have these genes, how much does having them increase your likelihood of getting Alzheimer's disease?

Dr. SCHELLENBERG: These are what we call small-effect genes. So each one, you know, if you think of - each one would increase your risk by a factor of about 1.2, not very much. The largest-effect gene is APOE-e, which, depending on what your genetic - your genotype is, can increase your risk four to 10 times. So that's a lot more substantial. These have a small effect.

So the biggest payoff from our study is not particularly prediction. The biggest payoff is really that we're getting new clues, as you put it, into what causes Alzheimer's, new pathways to pursue.

FLATOW: Is there any convergence of all these clues - pointing to something?

Dr. SCHELLENBERG: Well, you know, as a geneticist, when I do this, I hope not. That's an odd thing to say.

FLATOW: Yeah.

Dr. SCHELLENBERG: The first three early-onset genes all pointed to a-beta, which is a protein that's found in amyloid plaques. So, people with Alzheimer's have these abnormal plaques in the brain, and the first three genes all pointed to a-beta being a bad molecule to have and that you want to get rid of.

And there's been a lot of effort, rightly so, in targeting a-beta in terms of developing therapeutics, and we're at a crossroad right now where it looks like those - that approach might not work. And so we need new clues.

I'm actually quite pleased that we can't plug what we find here into our existing hypotheses. So this, kind of, is something new we have to think about.

FLATOW: Well, tell us about why that's a good thing. You know, we hear scientists say all the time: I'm happy to get a negative result or something that doesn't work. Why is that a good thing?

Dr. SCHELLENBERG: Well, it's not a negative result. It's a positive result. So we have positive evidence that - we're not saying that a-beta is not important. We're just saying there are other pathways that contribute to the disease that we didn't know about before, that we now do know about. And that's - you know, if we can't figure out how to remove a-beta in an effective way, then we've got to, you know, take a new shot at something else. So we now have some new things to shoot at.

FLATOW: One of the interesting, I think, outcomes of your study was that it matched another study, another paper, which always looks good. You want to make sure that, you know, people doing the same research have the same results.

Dr. SCHELLENBERG: Absolutely. You know, you like to be first, and you like to be first alone, but on the other hand, when - there are two papers back to back, one ours and one the other group, and it's really nice that they confirm what - we confirm each other's work, and that adds to how solid the results are.

And that, you know, it gives the bench scientist that's going to explore this - biology of this, you know, they're more confident that what they're going to look at is really a true genetic finding rather than an artifact.

FLATOW: And how do you sift through, you said, I think, 25,000 genes?

Dr. SCHELLENBERG: That's roughly the number of genes in the genome. And...

FLATOW: How do you do that? Is that a lot of homework for people, working on different parts, or how does it go, through a machine or computer or what?

Dr. SCHELLENBERG: Well, there's a technology that's been developed, really - so it comes out of knowing what the sequence of the human genome is and then, subsequent work, knowing what kind of genetic variability there is in the human genome.

So there's over 10 million sites in our genome where we differ from other people, that there is common variation.

Four or five years ago, a new technology developed where we can actually look at 500,000 sites - or up to a million sites - in an individual person. We can look at all these sites that vary from person to person. We can get their genotype. We can get exactly what they are at that site. And we can do it for a relatively low cost of about $300 per person.

So we can get the genetic makeup or the genotype at 500,000 different sites in one experiment for a modest amount of money. So that technology, that off-the-shelf, really, technology now allows us to look at every corner of the genome, even where there aren't genes.

And so you can look at genes, as well as the regions in between genes. And once we have that data, we can compare - you know, at every single site, we go site by site. Does this site differ in the population from Alzheimer's versus normal, elderly, unaffected people? And if it does, we explore it further, and that's where we see - that's why we think there's a gene there.

FLATOW: What do you say to people who say: You know, now I've heard about the APOE-e gene, I've heard of these five other genes, a total of 10 genes. I want to get my profile done.

Dr. SCHELLENBERG: A couple things. I mean, it's quite - you will get back a number saying you are four- or five-fold more likely to get Alzheimer's or maybe not. We don't have a treatment for Alzheimer's. There's nothing you can do about it right now. There's no lifestyle modification that we absolutely are sure would change your risk.

I think you've - some people would want to know, and other people would just know and then worry about it. And so at this point, we don't really encourage that.

FLATOW: And so where do you go from here?

Dr. SCHELLENBERG: A number of things. So there were - our research paper had - really was a collection of about 15 different studies, and we all piled them together, and that was pretty much everybody that does Alzheimer's research across the U.S.

And the other two - the other three consortia that were in the other paper, we've all joined forces now into an international collaboration. So we're going to now put all of our data together. So we have the opportunity to see additional genes.

The next thing that also has to be done is the really - you know, the geneticists get some credit right now, and we found something. But the real hard work is saying: Okay, we know that this, you know, ABCI7 is a lipid-transport protein. We know something about how its normal function is. Now we have to figure out: How does it do this in Alzheimer's disease? How does it contribute to Alzheimer's?

And for each of these genes, that's a significant effort that has to be done, but it - that's where the hard work is.

FLATOW: Let's go to the phones. Mike(ph) in Tallahassee, hi, welcome to SCIENCE FRIDAY.

MIKE (Caller): Hi, congratulations on all the things that you found. I'm kind of curious, and this, I guess, has to do a little bit with the philosophy of science. How do you start out without a hypothesis? Doesn't that pretty much limit what you can find, or does it make it very difficult to discover new things? Shouldn't you have a hypothesis? I - you mentioned that you didn't have one when you started out.

Dr. SCHELLENBERG: Well, I have to say we all tell graduate students you've got to have a hypothesis, which is a good idea. But we have been doing - having - doing genetics with a hypothesis, meaning, I think, such and such a gene is involved in Alzheimer's, and then you test it. And you say yes or no.

And we have not been really good at guessing which gene is involved in Alzheimer's. So there is an underlying hypothesis, I guess, in that, yes, there are genes that contribute to risks, but we don't want to predict which one because we have the ability to sample all of them. So it's hypothesis-generating research.

MIKE: Sometimes hard to get past the doctoral committee...

(Soundbite of laughter)

MIKE: ...without a hypothesis.

Dr. SCHELLENBERG: Well, they still want a hypothesis.

(Soundbite of laughter)

MIKE: Thanks a lot.

FLATOW: Do you have to make one up?

(Soundbite of laughter)

MIKE: Thank you.

FLATOW: Yeah. He's not going to say anything about that (unintelligible) listening. 1-800-989-8255 is our number. So you're basically taking a shotgun approach?

Dr. SCHELLENBERG: Right. And it's a - you know, if you do it right, you should come up with answers, and it's just - as I said, we haven't been very good at predicting which genes will be involved without this kind of genome-wide approach.

FLATOW: But you're pretty sure it's going to be a lot of genes, I mean, at least more than one, bang, this is what causes Alzheimer's.

Dr. SCHELLENBERG: Yeah. I think that in other common diseases and diabetes and heart disease, it's very clear that as you increase your sample size, meaning even more patients and more controls, you see more genes, and I don't - you know, it's hard to predict when we will have them all, but there could be a hundred more Alzheimer's genes that we need to find.

FLATOW: And do you take a tact - I know you said you don't have a hypothesis, but do you decide whether you're going to attack it from the fat side, like you found these genes having to do with fat transport, or do you take it from the plaque side, or do you take it from those other kinds of sides? How do you decide which way you want to attack it?

Dr. SCHELLENBERG: Well, I would hope - I know funding is tight right now, but I would hope multiple different groups take multiple different tacks because, you know, we - if we only stick to one idea and the a-beta idea is the one we've been sticking to, and it's very sound - I don't want to just say that was a bad idea. But if we only stick to one track, if we can't figure out a drug to modify that, then we're - you know, you'd like to be having multiple tracks going on in parallel, rather than just sequential.

FLATOW: Because there are always theories - I think there was a new theory just recently about we all get these plaques, but in people who get Alzheimer's, they can't clear a way the plaque-building material fast enough.

Dr. SCHELLENBERG: Right. And the difficulty now is the a-beta, it looks like the plaques develop very early in the disease, even before you have any cognitive symptoms. And once they develop and set in motion a degenerative process, it may be too late to target plaque buildup and plaque disposal. You know, it may have started something that you can't reverse simply by getting rid of amyloids.

So the difficulty now is that if you start early, then you would have to start something to prevent amyloid even before that, when people have no symptoms. So that would be preventative, and that would be great, but it's just so difficult to start at that point if you're trying a drug.

FLATOW: Talking with Gerard Schellenberg on SCIENCE FRIDAY from NPR. I'm Ira Flatow talking about research in Alzheimer's disease.

You dropped a little nugget there that I want to pursue a little bit, and you said funding is tight. What do you mean by that?

Dr. SCHELLENBERG: The - so we're funded by the National Institute on Aging, which is part of the National Institute on Health. And the budget has been going down, so other than the stimulus, economic stimulus, which is coming to an end here, the research money is going down. And NIH supplies most of the budget. There are private foundations that are very important, like the Alzheimer's Association has helped us established this international collaboration. But the bulk of the research money comes from NIH, and that's going down, rather than going up.

FLATOW: And this new budget that's being fought over today in Capitol Hill and the White House is that - is your money in there somewhere?

(Soundbite of laughter)

Dr. SCHELLENBERG: That's a political - I'm a scientist. That's a political question.

(Soundbite of laughter)

FLATOW: Well, don't people need to know where the money - you say the money is tight. And if it's money for research into Alzheimer's, I think we're the ones who vote these people. We should know these things, don't you think?

Dr. SCHELLENBERG: I think so, and that is part of the budget. And it's part of the budget that's being debated. You know, I think some people would like to increase it, and other people want to, you know, across the board, cut money.

So it's - I will say Alzheimer's disease is highly prevalent in the elderly, 80 to 85. Thirty percent of the population has Alzheimer's. We have an aging population, meaning the most rapidly-growing segment of our population is over the age of 65. So by the year 2050, we'll have two to three times more people with Alzheimer's than we do today. So it's a massive health care problem that's looming, and, you know, of course, we're trying desperately to reduce health care costs.

So, you know, if we can come up with a therapy that can delay Alzheimer's onset by five years or just can keep people intact enough so that they can live at home and have a higher quality of life, that will be - not only will it help people and reduce the human suffering, but it will also reduce health care costs. So I think this is a critical point.

FLATOW: Yeah. You know, that's the one cost that people don't think about. They think about drugs and drug therapies and whatever, but they don't think about what it costs to take care of people...

Dr. SCHELLENBERG: That's right.

FLATOW: ...who have these diseases and the family problems and hospitalization and hiring people to stay with your loved ones...

Dr. SCHELLENBERG: That's right.

FLATOW: ...just to take care of them.

Dr. SCHELLENBERG: I think a lot of the interest in this story now is all the baby boomers now have - are going through taking care of their parents and realizing that this is - I mean, it's emotionally devastating to watch somebody develop Alzheimer's and almost intellectually disappear before your eyes while they're physically still there.

FLATOW: All right. Dr. Schellenberg, thanks for taking time to be with us today.

Dr. SCHELLENBERG: Great. Thanks a lot, Ira.

FLATOW: You're welcome.

Gerard Schellenberg is the - he's in the Department of Pathology and Laboratory Medicine at the University of Pennsylvania School of Medicine in Philadelphia and author of one of those two papers that were published this week.

We're going to take a break, and when we come back, we're going to talk about what's so important about April 12th that makes it worth celebrating. No peeking. We'll be back after this break. Stay with us.

(Soundbite of music)

FLATOW: I'm Ira Flatow. This is SCIENCE FRIDAY from NPR. Transcript provided by NPR, Copyright NPR.

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