Have scientists been wrong about Alzheimer’s for decades?

Brain scan of a patient with Alzheimer’s disease.
Photo: BSIP/UIG Via Getty Images

Less than two weeks ago, a scandal broke out in the normally placid world of Alzheimer’s research. Report of investigation of Science revealed that a Vanderbilt University researcher, Matthew Schrag, found the slides included in a highly influential 2006 paper on the disease published in the journal Nature were fabricated. The discovery cast doubt on a popular, if increasingly contested, theory of how Alzheimer’s disease takes its toll. I spoke with Nobel Laureate Thomas K. Südhof, a professor of molecular and cellular physiology at Stanford and an expert on the disease, about the implications of the news and how our understanding of Alzheimer’s is changing.

Are you absolutely convinced that this seed Nature produced images with paper included?
I have to answer this cautiously. I would say that the data that has come out of the forensic analysis of the images that I have seen strongly supports the idea that there is a fabrication. What worries me more is that there are multiple accusations against the author of fabricating images. I don’t actually know if it happened. But if I saw this in a review process with modern image analysis technology – which is not standard in journals and wasn’t standard before – it would certainly cause the article to be rejected.

Apparently I’m a layman on this subject. But as I understand it, the allegedly fraudulent data reinforced 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 are a key marker of Alzheimer’s disease.
Yes, they are not just a key tag. They are probably also the causative agents of the disease. The question here is not whether they are important — I think everyone would agree that they are important. The question is whether they alone drive the disease process or are part of a larger set of events that cause the disease. They used to be thought to be the key drivers, but in the last ten years that has changed. I think most people in the field now would say that they are one aspect of the disease process. However, I don’t think the importance of beta-amyloid is in doubt.

It seems to me that there are two separate stories going on here. One is about the alleged fabrication itself, why someone might do it, academic pressure, etc. The other is a much broader story about Alzheimer’s research and where it stands. If the data does have the problems it claims, what do you think the wider implications are?
To be honest, I don’t think there are any – or not many. Let me explain why. In science, fabrication usually happens when people publish high-profile papers that nevertheless largely confirm what everyone else thinks. This is why most fabrications go undetected. In this case, there was a strong belief in the community that the beta-amyloid proteins that accumulate in the brains of Alzheimer’s patients play a central role in the pathogenesis of the disease. And I think that belief will remain, because this data somewhat confirmed, but did not really add anything significantly new.

I think the problem we have in science is not necessarily fiction or people falsifying things. The problem is that as scientists we are human and as humans we tend to agree with each other and try to find further supporting evidence for something that is believed to be correct. And the peer review process that leads to the publication of articles has become very problematic in recent years, exacerbating this problem.

Were there any promising avenues of Alzheimer’s research that were abandoned, at least to some extent, over the past 20 years as a result of the preoccupation with beta-amyloid proteins and plaque buildup?
Absolutely. And I think that’s still the case today because the field moves almost 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 certainly very important as well. In Alzheimer’s disease, you have inflammation of the brain, and that inflammation is mainly carried out by a type of cell called microglia, which is involved in immune responses and which is obviously very important to the disease. And so a lot of resources are now going into microglia, justifiably so.

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

So I think there’s more to disease and that we, as a field, have to keep an open mind and study all the components of the disease process, especially the cell biology of the nerve cells, because they’re 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 is so difficult to come up with any kind of treatment for it?
No, no — think about it: Do you think the brain is simpler than a cancer cell? And we’ve put, what, 50 times more money into cancer research than into brain research? And we still can’t cure most cancers. Why would we expect Alzheimer’s disease to be simpler than cancer? Is not.

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

I didn’t know 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 biotech is dedicated to cancer. You can probably count those doing research on Alzheimer’s disease or Alzheimer’s drugs on one hand. So there is a huge disparity in effort. And the reason for this is structural. Because if you have cancer and you know you’re going to die in a year or two, you’re much more motivated to do something about it than with a disease like Alzheimer’s, which is very chronic and takes much longer.

Is there any indication that new avenues of research may lead to something even incrementally better than current Alzheimer’s treatments?
I think it will. I am an eternal optimist. And the reason is not that there is a little bit of progress here and there that there is. The way science works, you can’t plan scientific discoveries. You never know when they will happen. Otherwise, you’d already have the discovery, wouldn’t you? Basic curiosity means that a scientist is trying to solve a problem. They are curious about a problem because they don’t know the solution, and in trying to find it, they will discover things that have the potential at any moment to open a completely new perspective on an illness.

And so it’s very, very important to support science that is targeted in the sense that it solves a disease problem, a biological process problem, but not targeted in the sense that it’s going to create a cure, because you can only create a cure.

In science, if you have a lot of good minds working on a scientific problem, and there’s an open mind in the community that’s willing to look at not just one hypothesis and one direction, but many different ones—things will happen. Discoveries will be made. Funding is much better for Alzheimer’s than it was a few years ago. And I think we’re going to see a lot of progress.

Genetics is leading the way, and we understand genetics better than ever. This is extremely important because it gives us the clues about biology. It does not explain the biology of the disease. It doesn’t tell us how the disease occurs, but it’s kind of like a clue in a murder mystery where you try to identify the culprit. We will get there, and once we do, we will know how to better target our drugs. Until then, the community will try to find some shortcuts, some ways to get there faster. But the best and surest way is to do curiosity-driven research that gets to the bottom of what’s really going on in the disease.

This interview has been edited for length and clarity.

Leave a Comment