Recent research shows Alzheimer’s disease can be present up to two decades before symptoms occur; a phenomenon known as preclinical Alzheimer’s disease. Comparing the disease to a burning building, some scientists believe treatment needs to happen well before significant foundational damage occurs. Guest: Paul Aisen, MD, Professor of Neurology and Director of the Alzheimer’s Therapeutic Research Institute, Keck School of Medicine, University of Southern California
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Intro: Welcome to Dementia Matters, a podcast created by the Wisconsin Alzheimer's Disease Research Center. It's our goal to humanize Alzheimer's research so that our community, our patients, our participants, and anyone else interested can get a better understanding of the work that's happening to fight back against this disease. My name is Nathaniel Chin, and I'm a geriatric memory clinic physician at the University of Wisconsin. I'm also the family member of someone living with dementia. I'll be serving as your host for this podcast and asking the questions I believe are in the minds of many in our community. Thanks for joining us.
Chin: Today, I'm speaking with Dr. Paul Aisen, professor of neurology and the director of the Alzheimer's Therapeutic Research Institute at the Keck School of Medicine at the University of Southern California. Dr. Aisen has been a leading figure in Alzheimer's disease research for more than two decades and we're very lucky to be joined by him today. With that, I would like to welcome Dr. Paul Aisen to Dementia Matters.
Aisen: Thank you.
Chin: Scientists have successfully cured Alzheimer's disease in mice using various techniques. Why haven't we been able to translate our findings from mice into human beings?
Aisen: That's an excellent question. First, mice don't get Alzheimer's disease. These are entirely artificial conditions. There is no natural Alzheimer's disease in the mouse and the artificial conditions that we create are quite different from the disease in humans. So, it's an experimental system that I think can be useful, but we should not think that this is Alzheimer’s disease in a mouse and even if we can eliminate what we create as a model system in a mouse, that may or may not be applicable to humans. On the other hand, we've learned some very intriguing notions that seem to be translatable into humans.
Chin: Well, knowing that, why do you think the current or the most recent drug trials have failed?
Aisen: That's a question we could spend a lot of time discussing, but I'm going to give a brief answer, which is that one of the things we've learned along the way—really in the last 10 to 15 years—is that Alzheimer's disease is very different from what we had initially thought. We have always discussed and described and studied Alzheimer's disease as a dementia. Dementia is a syndrome where there are changes in the brain that become extensive enough to interfere with brain function so that normal activities become difficult and people lose their independence. That’s what dementia is and Alzheimer's disease is certainly the most prevalent dementia. Well, we've learned in the last 10 or 15 years that dementia is the end stage of a very long process and that by the time dementia is present, the damage to the brain, the loss of brain connections, is very, very extensive. You can think about Alzheimer's disease as a destructive illness and think of it in terms of a building that's burning where the burning is the nerve degeneration. Well, if you wait for the structure of the building to be severely damaged, just pouring water on the flames is not going to do much, and that's what we think the problem is in the application of therapies to Alzheimer's dementia. Now, what our focus is, bringing these very promising therapies—and we still very much believe in them—bringing them to a stage of the illness that can be identified very accurately, but is before there is any significant nerve degeneration—and this is what we now call preclinical Alzheimer's disease—and we are confident that bringing these very exciting anti-amyloid therapies into people before they have extensive loss of brain function is going to be the way to change the disease.
Chin: Wow, so now a lot of the people in the community know about mild cognitive impairments; we spend a significant amount of time explaining the difference between mild cognitive impairment and dementia—not many people know about preclinical. So, what you're suggesting is, potentially, these therapies that have been designed, we would actually use them on people who have no symptoms—who feel fine.
Aisen: Exactly.
Chin: How would we find these people?
Aisen: We've learned a great deal about what it is and how we can identify who will develop Alzheimer's disease and who won't, but I'm going to tell you what I think is the most exciting finding to come out of this ADNI study in the normal group—the control group. So, we wrote people with MCI and then we enrolled two control groups to help us understand MCI. One was more severe with dementia, that was a control group, and the other was entirely normal people who were aged-matched. So, these were older individuals, over 65, but were completely free of any memory symptoms or any even subjective memory concerns, as a reference group, to allow us to characterize MCI. What we found was that of that normal group, when we incorporated amyloid scanning in 2005, we found that one-third of the normal control group had amyloid in the brain. That's kind of a shocking thing. These are people who were as normal as could be—that's how they were recruited—and yet fully a third of them had amyloid in brain that looked like the amyloid that is present in people with Alzheimer's disease, and that became the notion of preclinical Alzheimer's disease, and that suggested, well, this is not just an incidental finding. When we looked further, we found, in fact, that all of the abnormalities of Alzheimer's disease were beginning in these normal people and we even found that if we did very sensitive cognitive tests, they were declining, and amyloid in normal older people is not an incidental finding—it's an early stage of Alzheimer's disease, but in order to really establish this, we need to follow those people year after year. We published the first long-term follow-up of that group, and what we find is that, over a 10-year period, we can now say that over 80% of the people with pre-clinical Alzheimer’s disease that are entirely normal, but with amyloid and brain, have developed symptomatic disease. So, I think that we now have very strong evidence that this is an early stage of the disease, and we have initiated clinical trials of anti-amyloid therapies.
Chin: So, as you talk about clinical trials and people who are normal with amyloid, the key aspect is that we need the public to come in for these studies, to undergo these treatments. So how do we keep the public focused on Alzheimer's disease, despite these setbacks that we've had, despite the delays?
Aisen: I very much agree with you that the best way to accelerate the development of therapies is to have everybody working together, and the best path to innovation is collaborating and sharing, but part of that collaboration involves the general population. We can't do any definitive tests of our ideas without volunteers from the public. So, we need to have a collaboration that extends into the population. Now, what part of the population? Well, the entire population that's aging. This is a hugely prevalent problem—I just said that a third of the population over 65 has preclinical Alzheimer's disease. I think we need to talk about this, to inform the public, to bring everybody into a common conversation so that we can discuss strategies together and talk about how people can work together and even volunteer for clinical studies so that we can make progress as quickly as possible. I actually think that all the tools are in place, and we're ready to really make huge progress in the therapy of Alzheimer’s disease, but probably the single biggest roadblock, now, is getting volunteers into clinical studies—people who are completely normal and people who have cognitive issues. We need to continue and increase the involvement of the public. So, we need to effectively communicate and educate, and we need to ask people to join us and to participate in studies, and that will accelerate our development. So, I very much hope that we can communicate that message.
Chin: I think that's well said, well Dr. Aisen. I want to thank you again for joining us on our podcast. We very much appreciate you being here.
Aisen: My pleasure. Thank you.
Credits: Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center. The Wisconsin Alzheimer's Disease Research Center combines academic, clinical, and research expertise from the University of Wisconsin School of Medicine and Public Health, and the geriatric research education and clinical center of the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. It receives funding from private, university, state, and national sources, including a grant from the National Institutes of Health for Alzheimer's Disease Centers. This episode was produced by Rebecca Wasieleski and recorded and edited by Alex Wehrli. Our musical jingle is "Cases to Rest," by Blue Dot Sessions. Check out our website at adrc.wisc.edu. You can also follow us on Twitter and Facebook. If you have any questions or comments, email us at dementiamatters@medicine.wisc.edu. Thanks for listening.
