Have Scientists Been Wrong About Alzheimer’s for Decades?

by Intelligencer:

Less than two weeks ago, a scandal erupted in the usually staid world of Alzheimer’s research. An investigative report at Science revealed that a researcher at Vanderbilt University, Matthew Schrag, had determined that slides included in a highly influential 2006 paper about the disease that was published in the journal Nature were fabricated. The revelation has cast doubt on a popular, though increasingly embattled, theory of how Alzheimer’s does its grievous damage. I spoke with Nobel laureate Thomas C. Südhof, a professor of molecular and cellular physiology at Stanford and an expert on the disease, about the fallout from the news, as well as how our conceptions of Alzheimer’s are changing.

Are you fully convinced that this seminal Nature paper included fabricated images?
I have to answer this cautiously. I would say that the data that have emerged from the forensic analysis that I’ve seen of the images strongly support the idea that there’s fabrication. What worries me more is that there are multiple allegations of fabrication of images against the author. I don’t actually know that it happened. But if I saw this in a review process with modern image-analysis technology — which is not standard in journals, and it wasn’t standard before — it would certainly lead to a rejection of the paper.

I’m obviously a layman on this subject. But from what I understand, the allegedly fraudulent data solidified the already-popular theory that plaques made up of beta amyloid proteins are — I don’t know if “cause” is the right word here — but they’re a key marker of Alzheimer’s.
Yeah, they’re not only a key marker. They’re probably also an agent of the disease. The question here is not whether they’re important — I think everybody would agree they’re important. The question is whether they, by themselves alone, drive the disease process, or whether they’re part of a larger ensemble of events that cause the disease. It used to be thought that they are the key drivers, but in the last ten years, that has changed. I think most people in the field would now say that they are one facet of the disease process. Nevertheless, I don’t think the importance of beta-amyloid has been questioned.

It seems to me there’s two separate stories going on here. One is about the alleged fabrication itself, why somebody might do it, the pressures of academia, and so on. The other is a much broader story about Alzheimer’s research, and where this leaves it. If the data does have the problems it’s purported to have, what do you see as the broader implications?
To be honest, I don’t think that there are any — or not much. Let me explain why. In science, fabrication usually happens when people publish high-profile papers that are nevertheless pretty much confirmatory of what everybody else thinks. That’s why most fabrication isn’t detected. In this case, there was a strong conviction in the community that beta-amyloid proteins accumulating in the brains of Alzheimer’s patients play a central role in the disease’s pathogenesis. And I think that conviction will remain, because these data were confirmatory to some extent, but they didn’t really add anything substantially new.

I think the problem we have in science is not necessarily fabrication or people faking stuff. The problem is the fact that as scientists, we are humans, and as humans, we have a tendency of agreeing with each other and of trying to find further supporting evidence for something that is thought to be correct. And the scientific review process that leads to the publication of papers has become very problematic over the last years, which has exacerbated this problem.

Were there any promising avenues of Alzheimer’s research that got sidelined, at least to some extent, in the last 20 years as a result of the preoccupation with beta-amyloid proteins and plaque buildup?
Absolutely. And I think that that’s still the case today, because the field is moving pretty much in lockstep with certain ideas in mind that are the main focus of everybody’s research. It used to be beta-amyloid, and now it’s largely another component of the disease, the inflammatory component, which I think is unquestionably also very important. In Alzheimer’s, you have an inflammation of the brain, and that inflammation is carried out primarily by a type of cell that is called microglia, which is involved in immune responses, and which is clearly very important for the disease. And so a lot of resources are now going into microglia, justifiably.

But what I think we are missing in general in Alzheimer’s disease research is a broader view of the entire landscape. Not just microglia, not just beta-amyloid. If you look at these genes that are associated with Alzheimer’s disease, they have a broad scope of probable function. For many of them, we don’t actually know the functions. The most important gene that’s associated with Alzheimer’s disease is the APOE gene, which is a lipoprotein that transports lipids. And it’s also a signaling molecule that signals between cells, but we don’t actually know what it does in the brain.

So I think there is more to the disease and that we, as a field, need to have an open mind and study all components of the disease process, especially the cell biology of the nerve cells, because these are the ones that die.

That there are so many components to this disease, unlike some others that perhaps have a more specific cause and effect — is that why it’s so difficult to hammer down any kind of treatment for it? 
No, no — consider this: Do you think the brain is simpler than a cancer cell? And we have put, what, 50 times as much money into cancer research as into brain research? And we still can’t cure most cancers. Why would we expect Alzheimer’s disease to be simpler than cancer? It isn’t.

Biology is inherently complex — that’s the nature of the beast. Every cell is complex. We haven’t really spent that much effort and time on diseases of the brain as a community because there hasn’t been that much funding. There’s been tons and tons of funding for cancer, and there’s been some successes, but let’s face it: In spite of the successes, most kinds of cancer — the most common ones people die from — we can’t cure. It’s a fact. So we shouldn’t expect the brain researchers to be that much smarter than the cancer researchers. They’re not.

I didn’t realize it was so underfunded.
It’s much better now than it was. But it’s still much, much less than cancer. If you look at biotech, I would say more than 90 percent of the biotech is devoted to cancer. You can probably count the ones that are doing Alzheimer’s disease or Alzheimer’s drug research on one hand. So there’s a huge disparity in effort. And the reason for that is structural. Because if you have cancer and you know you’re going to be dying in a year or two, you’re much more motivated to do something about it than in a disease like Alzheimer’s, which is very chronic, and takes much longer.

Is there any indication that new paths of research might lead to something even incrementally better than the current Alzheimer’s treatments?
I think it will. I’m an eternal optimist. And the reason is not that there are little advances here and there, which there are. The way science works, you cannot plan scientific discoveries. You don’t know when they’re going to happen. Otherwise you would already have the discovery, right? Basic curiosity means that a scientist is trying to solve a problem. They’re curious about a problem because they don’t know the solution and by trying to find it, they will discover things that have the potential at any given time to open up a completely new perspective on a disease.

And that’s why it’s very, very important to support science that is purpose-driven in the sense that it solves the problem of a disease, a problem of a biological process, but not purpose-driven in the sense that it will create a drug.

In science, if you have a lot of good minds working on a scientific problem, and there’s an open mindset in the community that is willing to consider not just one hypothesis and one direction, but many different ones — things will happen. Discoveries will be made. The funding is much better for Alzheimer’s disease than it was a couple of years ago. And I think we will see major advances.

Genetics leads the way, and we have a better understanding of genetics now than ever. That is crucial because it gives us the clues to biology. It doesn’t explain the biology of the disease. It doesn’t tell us how the disease happens, but it’s sort of like a clue in a murder mystery where you’re trying to identify the culprit. We’ll get there, and once we do, we will know how to target our drugs better. Until then, the community will try to find some shortcuts, some ways of getting at it quicker. But the best, safest way is to do curiosity-driven research that solves the problem of what actually happens in the disease.l.