- What you need to know: In our Q&A, Huntington Potter, PhD, explains the progress being made in the battle against Alzheimer’s disease. He discusses the headway in the development of a new drug – an antibody against Alzheimer’s amyloid – and points out the possible treatment benefits of GM-CSF Leukine against COVID-19.
Last fall, we sat down with Huntington Potter, PhD, director of the University of Colorado Alzheimer’s and Cognition Center – one of the major Alzheimer’s research centers in the country – for a wide-ranging podcast conversation about the state of Alzheimer’s research.
As World Alzheimer’s Month 2020 comes to a close, we followed up with Dr. Potter to learn about the progress made over the last year toward better understanding and combating a disease that currently affects over 5.5 million people in the United States at a cost of about $300 billion per year.
CU Anschutz Today: How has the COVID-19 pandemic impacted your research?
Dr. Huntington Potter: COVID-19 has impacted all research around the world. The university shut down in the middle of March, and our research essentially was shut down. Then [as part of the phased university return-to-campus protocols], the laboratory was re-opened by a set of restrictions having to do with mission critical research that really needed to continue. And then over time, the amount of additional work that was allowed was increased, but we never returned to what was pre-COVID norm.
“The University of Colorado will be one of the sites
where people can get treated with the first new
treatment for Alzheimer’s disease in 20 years.”
– Huntington Potter
We're at what we call 50% density. So that means that at any one time, the total number of people in a certain space in the laboratory has to be no more than half of what it was before. And that was not as devastating as we were fearful of, because of changes in timing of when people come to the laboratory, and the fact that at least some people like myself don't need to come in at all. We could work remotely. That reduces the density naturally, and we've been able to open up slowly over the last couple of months to almost equal efficiency as we had before.
CU Anschutz Today: When you spoke with us last September, you were in the middle of conducting a clinical trial involving a drug called Leukine. How did the halting of research on campus, and the reduction in density adjustments your team had to make in order to return to the lab, affect the Leukine trial?
Dr. Potter: The Leukine trial is an interesting question because we actually stopped it in December, but then when COVID-19 hit in March, we had not finished the complete analysis. So we submitted a paper reporting the Leukine trial in April, but it was rejected because it was incomplete. Our blood biomarker analysis, for instance, had not been done because we couldn't get into the lab to do it. So we're now back in the lab, we've carried out those assessments, they're looking extremely promising, and we will be re-submitting the paper with the complete data very soon.
CU Anschutz Today: Can you share any details regarding those assessments?
Dr. Potter: I can say that we'll be reporting at the Clinical Trials for Alzheimer's Disease meeting, which is a virtual meeting this year in November. There's an abstract submitted already, and the data that we've gotten from the blood work look very promising.
CU Anschutz Today: The Leukine trial was based on a theory you and your colleague Tim Boyd developed around the fact that people with rheumatoid arthritis tend not to get Alzheimer's disease. You theorized that a protein called GM-CSF, which is increased in the blood of people with rheumatoid arthritis, may inhibit Alzheimer’s disease from developing in their brains.
Dr. Potter: The main gist of the Leukine trial is to take this hypothesis about GM-CSF and actually test it in real people with Alzheimer's disease. We didn't ask whether they had rheumatoid arthritis or not. We just recruited people who had Alzheimer's disease and asked whether GM-CSF would improve or at least maybe slow down their decline. But it was a very short trial. It's only three weeks of treatment and a couple of follow-ups a couple months later. And so in that situation, we were very pleased to see that there was apparently an improvement in certain aspects of Alzheimer's disease in people. And that's basically telling us that we need to treat for longer and with a larger number of people in a bigger trial. We've submitted the application to the FDA, and we have just been given permission to start that trial (after it goes through the university approval process).
CU Anschutz Today: When do you hope to start the new trial, and how long will it run?
Dr. Potter: This [new trial] will be 24 weeks. We hope to start maybe before the end of the year, but certainly in the first weeks of January.
The FDA is rather distracted right now with COVID-19, and that brings up another fact you might be interested in. We published a paper in F1000, which is a peer-reviewed journal, in which we proposed that GM-CSF Leukine would be a treatment for COVID-19. The idea was based on some preliminary work that Ken Tyler's lab and ours found – which has not been fully published yet – that GM-CSF prevented the death of mice that were infected with West Nile Virus.
So we made a leap to suggest, for many good reasons based on what we know about GM-CSF, that this natural protein might be a treatment for COVID-19. And there are now at least two clinical trials being carried out with GM-CSF treatment for COVID-19 right now, one in Belgium and one in Singapore.
One would never necessarily have thought that all of our work on Alzheimer's disease would give us an insight into how to treat COVID-19, but it did. That's one of the reasons why it's so great to be in a university setting where ideas can be tested by essentially moving to the fifth floor from the fourth floor of our research building.
CU Anschutz Today: Have there been any findings regarding how COVID-19 impacts people with Alzheimer’s? Or how it affects the disease itself?
Dr. Potter: There are not yet any published studies relating COVID-19 and Alzheimer’s disease, although, of course, the elderly are at much greater risk for both. However, it is known that COVID-19 has very detrimental and potentially long-term effects on the brain. Also, I participated in a meeting this morning about people with Down syndrome, and at least anecdotally the people with Down syndrome who also have Alzheimer's disease were getting sicker from COVID-19 than those who were younger and didn't have Alzheimer's. But of course, that study is tricky to interpret because people with Alzheimer's disease who have Down syndrome are also older than the people with Down syndrome but don't have Alzheimer's disease, so we would have to look at the typical population to get a good sense about whether Alzheimer's is an increased co-morbidity for COVID-19.
CU Anschutz Today: Last September, you spoke to us about the amyloid deposits and tangles that are universal in the Alzheimer’s disease brain, and how they kill nerve cells and cause dementia. Over this last year, have you made any progress in determining why those amyloid deposits and tangles occur and why they destroy nerve cells?
Dr. Potter: We know quite a lot about how amyloid deposits and tangles arise in the sense that they are composed of proteins that have a natural function or at least are harmless by themselves and aggregate into the tangles and into the plaques. And the nerve cells that are in the proximity of the plaques or have a tangle are very prone to die. We do know a little bit more about why they die, and we're working on drugs to try to prevent that from happening.
CU Anschutz Today: What have you discovered about why the nerve cells die when they are in proximity to the plaques or have a tangle?
Dr. Potter: There are very essential proteins and other molecules in cells that are necessary for that cell to function and live. They also have to be in the right place at the right time in each cell. So there are roadways in the cell and motors that move things around and when those are damaged, then the cell can't function. We are understanding more about how those motors and those highways are damaged in the cell, in the brain of somebody with Alzheimer's.
Over the last year or so, we've discovered a number of normal human drugs that seem to block the toxicity of the amyloid in the test tube and in cells. Some of those drugs actually are taken normally by people for other reasons, and we have found that they may be helpful in reducing or reversing Alzheimer's disease. That's, of course, just from an analysis of current data based on our first search for drugs that block this is a very important step in Alzheimer's disease.
In another approach, the company Biogen developed an antibody against Alzheimer's amyloid, and we helped them to carry out a clinical trial that was stopped in early 2019 because the results looked negative. Then they looked at the data a little more carefully and they actually found a benefit. So they have now applied to the Food and Drug Administration for permission to market this drug as a potential treatment for Alzheimer's disease, and the University of Colorado will be one of the sites where people will have access to this first new treatment for Alzheimer's disease in 20 years.
Now it's not a magic bullet. It only slows the course of the disease in people who are in the mild cognitive impairment stage. We don't know how many people would really be appropriate for this treatment, but Biogen is very hopeful that the FDA will allow this to be one of the treatments for Alzheimer's disease. That would be a huge advance that represents 20 years of work to try to develop an anti-amyloid drug. Finally one looks promising enough to actually submit to the FDA.
CU Anschutz Today: Does this new drug slow progression of the amyloid?
Dr. Potter: Yes. Actually, it is capable of removing the amyloid from the brain, and the cognitive effect is that the disease progresses more slowly. We helped them find this by being a site for the trial, and we will be one of the sites where the new drug, if it's approved, will be available.
CU Anschutz Today: That’s exciting news. Not a magic bullet, but it sounds promising. You’ve cautioned us in the past not to expect a “one pill cure” for Alzheimer’s. Do you still foresee combination therapy as the most likely approach for effective treatment?
Dr. Potter: It's not only the likely approach based on the history of almost every other human disease that people have studied, but Alzheimer's disease in particular is very complex and has many aspects of the disorder that affect the clinical symptoms of people with Alzheimer's disease. Thus just as there are many steps in the pathway, each of which could be a target for a new drug. Furthermore, the pathway is even more complex that many disease precesses because it's almost three dimensional. So it's very likely that we may need drugs for different aspects of the disease.
The other problem of course, is that the disease is progressive and different interventions may be more beneficial at certain stages of the disease—early, middle, late. Furthermore, people are different and some people may respond to certain interventions better than other people. There may even be people who can't take a particular drug for one reason or another. In sum, we will have to have a toolbox of options because people are different and the disease is complex.
CU Anschutz Today: This harkens back to something you talked to us about last year, but many people may not be not aware of – that you consider Alzheimer’s to be a disease of the middle aged, not of the “aged.”
Dr. Potter: Yes, I think that is the expectation – that Alzheimer’s should be considered to be, if not a lifelong problem, at least a middle-age problem that should be addressed as soon as we have biomarkers that can identify people at risk.
Now, being at risk doesn't mean you're guaranteed to get the disorder if you do nothing. Some people who smoke their whole lives don't get lung cancer, and some people who have high cholesterol don't get a heart attack, but there's no reason to play the odds in your disfavor. You might as well go ahead and start treatment prophylactically as soon as we have a way to identify those at risk..
CU Anschutz Today: And what does it look like in terms of finding those markers?
Dr. Potter: The markers are numerous in the sense that there are cognitive assessments, but of course, somebody in middle age will not show those. even subtle ones. Then there are imaging biomarkers such as a PET image or an MRI image of the brain. Those do show very early signs of Alzheimer's disease in some people, but it's not necessarily a guarantee that they will convert. And then there are blood biomarkers that we and others are working on, and those are looking more and more promising in terms of being able to mimic the brain imaging. The reason that's important, of course, is that brain imaging is not a practical population-wide biomarker to use. We need something cheap and easy, and a blood biomarker would be the best. Indeed, the data are beginning to come in that blood biomarkers of the right kind seem to reflect the amyloid and tau pathology in the brain, which are the precursors for full-blown Alzheimer's disease, including cognitive decline.
CU Anschutz Today: So we’re talking about a simple blood test?
Dr. Potter: The only thing is that, again, whatever biomarker we measure in the blood will identify people at risk, but some people at risk never go on to develop Alzheimer's disease. Even some people who show a negative biomarker may, given enough time, still develop Alzheimer's disease. Even if not perfect, a biomarker would be a tremendous help to the physician and the family trying to decide what to do once we have treatment possibilities.
Of course, as we've discussed before, exercise and eating right, are interventions that you can carry out right now, which are relatively easy, and also benefit you in other ways. Most of the time we recommend people who feel they may be at risk or are at risk to take up a change in lifestyle.
CU Anschutz Today: When we spoke last year, a study had just been published about how weightlifting might help protect areas of the brain that are vulnerable to Alzheimer’s. Over this last year, have there been any other insights about specific exercises that are helpful?
Dr. Potter: The ones that I'm aware of largely go along the lines of cardiovascular exercise recommendations, namely high intensity, several times a week, cardiovascular stimulating exercise. Weightlifting...I know the New York Times had an article that suggested that might be also helpful, but that also depends a little bit on how you lift weights. I think that that's an interesting finding, but the mice and the people suggest that more cardiovascular exercise may be more broadly beneficial.
Now the question, of course, is how long? And there's been some indication that the longer the better, but some more recent data suggest for instance, that 10,000, 12,000 steps of walking a day may not be so necessary; that something along half of that is still beneficial to people who are at risk.
There was a study that just came out that said even a few minutes of exercise right before you're going to study, or do a learning episode, is beneficial.
CU Anschutz Today: So the bottom line for all of us remains: exercise and eat healthily. It's good for you on a number of levels and it's not going to be harmful.
Dr. Potter: Correct. And keep your brain active.