Solving the Puzzle of Alzheimer’s Disease

Alzheimer's is the sixth leading cause of death in the United States, and it is the only disease in the top ten causes of death that cannot be prevented, cured or slowed. As the most common form of age-related neurodegeneration, it is estimated to cost the nation $236 billion in 2016, an economic burden that could rise as high as $1.1 trillion in 2050. The long-term social impacts are expected to be just as sobering.

With numbers as startling as these, the need to understand Alzheimer’s and to translate that knowledge into effective treatments has never been more urgent. A group of senior scientists, aiming to kick-start a new era of discovery in neurodegeneration research, especially in Alzheimer’s disease, have called for a renewed focus on studying the fundamental biological pathways that underlie neurodegenerative diseases. Writing in the journal Science, they argue that without an understanding of the cascade of events that causes neurons to die, efforts to find cures for these diseases will continue to fail.

The Kavli Foundation spoke with three of the scientists, each of whom participated in a series of salons convened by the Foundation to identify knowledge gaps that must be urgently filled. They discussed new scientific insights into Alzheimer's and related diseases and what the field can learn from the “War on Cancer.”

The participants were:

• KENNETH KOSIK, MD – Harriman Professor of Neuroscience Research and Co-Director of the Neuroscience Research Institute at the University of California, Santa Barbara. He has conducted research on the genetics of Alzheimer’s; his lab currently studies fundamental biological processes, including neural plasticity and the evolution of synapses, the junctions between neurons. He is the author of Outsmarting Alzheimer’s: What You Can Do To Reduce Your Risk.
• MARCUS RAICHLE, MD – Alan A. and Edith L. Wolff Distinguished Professor in Medicine at the Mallinckrodt Institute of Radiology at Washington University in St. Louis School of Medicine. Raichle is the recipient of the 2014 Kavli Prize in Neuroscience for his contributions to the study of cognition through the development and use of brain imaging techniques.
• DAVID BALTIMORE, PhD – President Emeritus and Robert Andrews Millikan Professor of Biology at the California Institute of Technology. He received the Nobel Prize in Physiology or Medicine in 1975 for his discovery of reverse transcriptase, a viral enzyme that copies RNA to synthesize DNA. His research at Caltech is focused on harnessing the immune system to combat cancer.

The following is an edited transcript of the discussion. The participants have had the opportunity to amend or edit their remarks.

THE KAVLI FOUNDATION (TKF): Let’s begin by talking about the state of Alzheimer’s research today. Many say this is an exciting time for the field. What are the discoveries being made that make this such a promising time to be studying these neurodegenerative diseases?

KEN KOSIK: In the past decade, there have been some very exciting discoveries of genetic mutations that can cause rare cases of Alzheimer’s disease and other neurodegenerative diseases. Those mutations point to biological pathways that could be explored in more detail to understand their role in these diseases.

MARCUS RAICHLE: Also we now know that Alzheimer’s begins decades before there are any clinical symptoms. That insight opens up the possibility of thinking very long-term about what it takes to develop this type of disease. Is it a development disorder? Exactly how do we frame it? I think it will be valuable to keep in mind that long-term perspective as we dig ever deeper into the cellular aspects of why Alzheimer’s occurs.

DAVID BALTIMORE: Another major advance has been the focus on the proteins that are thought to be involved in generating Alzheimer’s disease, namely amyloid and tau. But we’re still at an early discovery stage, where we’re not completely clear about what role these proteins play and whether they are the best target for treatment. That’s because, as Marc just said, the disease starts much earlier than when we see two of its hallmarks: plaques, the clusters of sticky amyloid proteins that accumulate between nerve cells in the brain, and tangles of the tau protein. We continue to wonder if we need to look at Alzheimer’s in a very different way to understand its root cause.

TKF: Yet despite all these discoveries, a recent analysis by the Cleveland Clinic showed that more than 99 percent of potential Alzheimer's treatments have failed in the past decade.

BALTIMORE: And that’s exactly what’s troubling—any attempt to take the information that we do have about what’s going wrong in the brains of patients with Alzheimer’s, and then turn it into a therapy, has failed. Now, whether that’s because we’ve got the wrong treatment target or because of the way it is being targeted is always a question. But the fact of the matter is that we’re facing a string of failures. Those are raising the question: is there a deeper way of going at this problem, which would lead to the successful development of treatments?

RAICHLE: There is a mechanism underlying Alzheimer’s disease that really cries out for an explanation. For example, there is a protein, amyloid, that deposits in the brain and creates plaques. These plaques are thought to contribute to the memory loss associated with the disease, possibly by blocking the communication between neurons, or by activating immune cells and triggering inflammation in the brain. Plaques may be dangerous for the brain, but amyloid, when not forming plaques, is actually essential for a healthy brain. It is involved in the transmission of information between neurons, and its concentrations go up and down depending on the brain’s activity level. And at a certain level of neuronal activity, the plaques don’t develop at all.

This raises a very basic question: Is there something amiss with the activity level of cells in the brain in Alzheimer’s disease? Maybe there's a community issue going on here, the depths of which we haven’t really explored.

So we see the evidence of the disease in the form of these plaques, but we have a very poor understanding of why the plaques are there.

KOSIK: One of the difficulties we’re facing in the field is that we don’t really have a deep understanding of the biological processes that underlie Alzheimer's disease—or really any of the neurodegenerative disorders, such as Parkinson’s disease, Huntington’s disease and dementia. So we don’t have a strong foundation to support clinical trials, which take an awful lot of money and time. There’s been amazing work that has gone on, but the fundamental understanding of what’s happening in brain cells affected by Alzheimer’s is just not there.

TKF: You take these issues head-on in your paper in the journal Science, which calls for a shake-up in how Alzheimer’s research is conducted. For instance, you suggest one of the major roadblocks to making real progress is that scientists are trying to find solutions before they really have a handle on the problem. How did we get into this situation?

KOSIK: The experts have a very good understanding of the issues in Alzheimer's. I’ve traveled in their circles, and these experts should definitely have a voice in shaping the future of Alzheimer’s research. But if they’re the only people with a voice, then it’s going to be the same old, same old. So what we really need is to figure out how to strike a balance between ideas from within the field and ideas from outside the field that are really worth pursuing. The challenge is striking the right balance.

RAICHLE: In reading over our paper, I came up with something I call the four Cs: cooperation, collaboration, collegiality and communication. In my opinion, this is what will help the field move forward. We need to break the current mold and get more people who have something to contribute at a basic science level into the conversation. I think we’ve got to broaden the audience of scientists that are potentially able to contribute to understanding Alzheimer’s and get their voices to the table.

TKF: Do other researchers in the field share your belief that to advance our understanding of Alzheimer’s, we need to broaden our approach to look at the problem in fresh ways?

KOSIK: Many Alzheimer's researchers are beginning to see that, as Marc just said, we need to have input from other areas. For example, I’m seeing statements coming from the National Institutes of Health, which funds most biomedical research in this country, inviting computer scientists, engineers and others to enter the field. And I think it is a really propitious moment, in which people are poised to accept new ideas. So even though there may not be consensus about what to do, there’s an opening up in the field toward looking at the problem of Alzheimer’s in different ways.

RAICHLE: And this isn’t about denigrating the work that researchers have already been doing; instead, it’s about developing a dialogue and interest not only among major investigators, but also their students, in very interesting basic science questions that have to do with neurodegeneration. I think part of the solution is conveying the questions of interest to younger people who will see them as a nifty challenge, and who work for researchers who are broad-minded and realize that this is a devilishly difficult problem that we haven’t gotten to the roots of yet.

TKF: Dr. Baltimore, you’ve done a lot of work on the basic biology of cancer, a focus shared by many others cancer researchers and that has led to the cancer treatments we have today. You propose that the field of neurodegeneration should take a similar approach. What are the lessons important to learn from cancer research?

BALTIMORE: Well, the war on cancer led us to many, many discoveries that have completely changed the thinking about cancer research. It took a very concentrated focus on the genetic and molecular processes at work in cancer cells, and without that we wouldn't be anywhere in cancer research today.

We first had to settle the very basic question: Is cancer a genetic disease? We decided it was, and of course, now we’re unraveling that and have begun talking about how changes in gene expression can be passed from one cancer cell to another. Once you’ve settled some basic information about a disease, you can build on that and move into new directions. So if we’re going to make a dent in the very important question of when and how Alzheimer's begins, it’s absolutely critical to think about cells and genes in new ways. To me, that is the most important question we could ask.

KOSIK: There are people who view the war on cancer as a failure because our treatments are still limited. I hold the opposite view. The war on cancer was really responsible for the understanding of biology at the molecular level—the level of DNA, RNA, proteins and their interactions—that we have today.

RAICHLE: One of my basic interests is brain metabolism, and the relationship between energy use and brain function. Glucose fuels the brain, kind of like throwing coal into the furnace to generate heat. The oncology community has been heavily focused on the portion of glucose that isn’t metabolized for energy—a focus that began in 1929 with Otto Warburg’s Nobel Prize-winning discovery that cancer cells dramatically increase their use of glucose. Why do they do this? Glucose is the critical supplier of carbon for making new cells, which is what cancer cells do.

What oncologists have learned about glucose metabolism can help us understand not only cancer cells, but normal cells as well. For example, in the brain, the connections between cells are being continuously remodeled as we learn and develop. Glucose is likely critical for this process, but for us to understand how and why, we need to follow the lead of the cancer biologists and perform the necessary basic research to learn how glucose is used in the brain.

We now know that areas of the brain affected by Alzheimer’s disease seem to have a lifelong affinity for glucose metabolism, at a level above that needed to satisfy their energy needs. We don’t yet know why, but it is clues like this that should stimulate the basic research needed for that understanding.

TKF: What other areas of research do you think are particularly promising, and why?

RAICHLE: In neuroscience, we have been very focused on one cell type in the brain: neurons. But in reality, the brain is composed of many cell types, including critical supporting cells like astrocytes, immune cells like the microglia, and blood vessels.

It may come as a surprise to many to realize that in the cerebral cortex, neurons do not make up the majority of cells. Instead, cells called astrocytes outnumber neurons by a large margin. We don’t fully understand their role in the brain, but we do know they have an intimate relationship with neurons that is functionally important. There still a lot more to learn.

Microglia have been thought to be the immune cells of the brain, but we’re learning that they are also critically involved in pruning synapses, a key process in learning and memory.

What is emerging is a picture of a beautifully orchestrated, intricate process involving not only the biology of neurons but these other cell types as well. We need to get at what is really going on in this little community.

KOSIK: We need to get the word out that researchers should not be afraid of the brain. The brain has often been seen as a very difficult research domain in which the technology to get really big, impactful insights is not there. But that’s changing. The technologies for brain research are really moving fast. We’ve already developed tools to look inside the living brain and to watch it at work, and that’s a very compelling reason to join this field.

TKF: One of the roadblocks you mention is that researchers are working in silos, that there needs to be more sharing of data and discoveries. Can you speak to that? How big of a problem has it been?

KOSIK: Lack of data sharing stymied research on the genetics of Alzheimer’s disease for a long time, but things are changing. Now, some significant and interesting risk factor genes are emerging. To unravel the role that genes play in disease requires big numbers, and the only way to get genetic information from tens of thousands of people is through collaboration and data sharing.

BALTIMORE: In the schizophrenia field, where there is very extensive data sharing, that sharing has produced some really critical leads that have advanced our understanding of the disease. None of that would’ve happened if people hadn’t consciously gone out and collected large, collaborative databases, and been able to mine them for genetic mutations that increase the risk of developing schizophrenia.

TKF: Sharing sounds simple on the surface, but you’re really asking for a culture change in the field. What’s it going to take to bring about that kind of change in the field?

RAICHLE: It means we need to be thinking about creating the informatics infrastructure that will permit this data-sharing.

KOSIK: That isn’t trivial. It’s a really big challenge for biologists, and also for computer scientists. Researchers need to be able to store and combine different types of data, including information about a person’s genetic code as well as health-related information.

RAICHLE: Data sharing was really one of the backbones of success for schizophrenia, and we need to use it as an example for the Alzheimer’s field.

TKF: Money will be instrumental in accelerating progress on Alzheimer’s. What’s the ideal balance between funding basic research and funding the translation of those discoveries into effective treatments?

BALTIMORE: If we look back at the history of cancer research, we see that enormous amounts of money were put into clinical trials long before we had any understanding of what cancer was about. Most of those treatments didn't save people. What they did was put people through terrible procedures that gave them minimal advances in life expectancy.

I think the important thing for the neurodegeneration field is to be able to make a judgment about when ideas are compelling and therefore worth taking to clinical trials. If clinical trials are simply used as a form of early investigation, they’re not valuable. But once we have developed a basic knowledge about a disease, then clinical trials are absolutely required. It’s not obvious the time has arrived to do clinical trials in Alzheimer's disease.

TKF: In your Science paper, you’ve proposed big ideas that are going to require significant changes to the field. How do we redirect a ship that’s been steering the same course for decades? What is the next step?

RAICHLE: I think we need to reach out to young people. The future is in their hands. The issue is to acquaint them with the opportunities this work entails.

BALTIMORE: I agree that we need to reach out to young people, but we also need to develop a collaboration between institutions, individuals and funders, both private and public. We need all of those elements, and then we can begin trying to attract young researchers, because we will be able to offer them a career opportunity—a robust field of research where they can make a lifetime commitment.

KOSIK: We’re not proposing creation of an Alzheimer's institute similar to the National Cancer Institute. The world is a different place, compared to when cancer research began in earnest. There’s a big difference in technology. The ability to communicate across national borders and all over the world is much easier today. And there’s a big difference in the distribution of wealth. Money is in different sectors other than just in government. We hear all the time that “the brain is the next frontier.”

We hear all the time about the gravity of these diseases. I think there are really large sums of money sitting on the sidelines now, just looking for an opportunity to use these new technologies and to give young people a direction to go in. I think the community can be clever about creating new structures, whether they’re institutions, or settings without walls, or different ways in which we can shuffle the deck to implement these ideas.

TKF: Looking ahead 20 years at where Alzheimer’s research and treatment should be at that time, what do you think is the most important message for researchers working in the field today?

BALTIMORE: We’re in a crisis situation, and we have to act like it’s a crisis. If you project ahead a couple of decades, the amount of resources that will go toward supporting people with Alzheimer's is astronomical. We can’t wait that long. We can’t take a couple of decades to make a serious dent in the Alzheimer's disease epidemic. We have to see 20 years as a long time and that means putting very concentrated resources into new research at the beginning, so we make up for time lost by increased focus.