David Bennett on Identifying Risk Factors for Alzheimer's
Special Topic of Alzheimer's Disease Interview, September 2011
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We talk about this in terms of cognitive or neural reserve. You have a genetic predisposition to develop amyloid plaques and neurofibrillary tangles, but depending what you do across your life is what determines whether the pathology manifests itself as cognitive impairment and dementia. You may never experience memory loss and another person with the same pathology but a different set of life experiences might develop clinical Alzheimer's disease.
What are you currently doing to explore these relationships and make sense of them?
We're looking to see how these experiential and psychological risk factors actually lead to brain reserve and neural reserve. One thing that we're doing now is looking at the epigenome. Epigenetics is the way the body turns on and off genes so they can be read and the proteins made. The epigenome basically opens and closes parts of the DNA so it can be read by cells at different times.
With a lot of cancers, it now turns out that there are actually problems with the epigenome, such as changes in the methylation of DNA or the acetylation of chromatin. So we're doing a variety of epigenomic studies and looking at epigenomic changes in brain tissue. These are things nobody would have dreamed of doing 10 years ago. We can do it because we have been collecting data on life experiences on more than 2,600 persons for up to nearly two decades and have frozen brain tissue from more than 900 persons to date.
We are also investigating RNA expression, proteins, lipids, and the metabolome. We are in the process of building a series of layers from the genome, to the epigenome, to the transcriptome, to the proteome, metabolome, quantitative neuropathologic traits, quantitative clinical traits, and clinical disease in order to investigate pathways linking risk factors to clinical disease in the hope of identifying potential therapeutic targets for intervention prior to disease onset.
When you look at the field of Alzheimer's research in general, what do you consider the most significant advances in the past few years?
"…a lot of the drugs we tried don't work because we really don't know enough about the basic biology of what's going on in Alzheimer's."
Probably one of the most important discoveries in the last decade was by Bill Klunk and Chet Mathis at the University of Pittsburgh. They created Pittsburgh compound B. It's amyloid imaging of the brain. You put people in the PET scan and you can actually image amyloid in their head. Before that the only way to image amyloid was to take the brain out of the head, cut it up and stain it. Klunk and Mathis published this back in 2004 and it really revolutionized what we can do in living people.
And that's going to change even more soon. The problem with Pittsburgh compound B is you need a cyclotron on site and so it can only really be used in some academic medical centers. There's a variety of companies now making an F-18 amyloid imaging agent, the usual kind of PET compound, a stable agent, that in theory can be used anywhere. There are still delivery problems. But they could be used in any PET scanner. Our group just published a paper in JAMA with one of these new compounds and it's very exciting from a research point of view.
What would you consider a realistic goal for your research over the next five years? An accomplishment that you think is both important and realistic?
I think the way we currently define Alzheimer's disease, which is you have to have a dementia, is really the end of a very, very long process, and I think the field is beginning to come to terms with that. If you think about preventing stroke or a heart attack, you want to prevent atherosclerosis. We know that the heart attack and the stroke is the end result of a long process of developing new atherosclerotic plaques. So the interventions start fairly young. You'd like to find the risk factors for getting atherosclerosis, because by the time you have the stroke or the heart attack, your options are pretty limited.
One of the things that we hope to do over the next five years is to begin to complete the construction of the multi-layer dataset described above, and begin to dissect some of the pathways between these risk factors and cognitive decline. And we're doing that with this epigenetics work, the experiential and psychological factors, and we'd like to extend that work to understanding genetic factors and other risk factors as well.
For example, we've known about apolipoprotein E4 (ApoE4), which was probably one of the most important discoveries of the 1990s, and yet I've never used ApoE in a clinical setting. Even though we know it's a potent, robust risk factor, it doesn't lead to any clinical decision making. If we can understand what links ApoE to cognitive decline, we can find targets for therapy. ApoE4 is common enough that the presence of an intervention could result in screening for the polymorphism.
An optimistic goal for the next five years would be expanding the repertoire of potential therapeutic targets for intervening in the biological cascade of Alzheimer's. We're a long way from any kind of effective intervention, but we're not as far away from perhaps finding some other potential targets.
Are you disappointed by the progress in Alzheimer's disease research, particularly considering the recent high-profile of failure of anti-amyloid drugs in clinical trials?
I wouldn't say I'm disappointed. I would say that this is a very complicated disease and if you think about where things were 25 years ago when Alzheimer's research first started, we were pretty naïve. We've learned a tremendous amount about the complexity of the disease in that time. What we've learned is just amazing.
If there's any disappointment, it's not with the research community and it's not with the funding agencies, it's the fact that I don't think society has grappled with what it is really going to cost to get our arms around this disease. If you think about cancer, with Nixon declaring a war on cancer, it was followed by some real serious money going toward attacking that disease. The same thing for stroke and heart disease.
The National Institutes of Health budget for Alzheimer's is about half a billion dollars, despite Alzheimer's disease being among the most costly and feared diseases in the United States. Estimates from the Alzheimer's Association put the costs, direct and indirect, in the 170-plus billion dollars a year range. The budget for Alzheimer's disease has been flat for years, and flat means sub-inflation growth.
"You may never experience memory loss and another person with the same pathology but a different set of life experiences might develop clinical Alzheimer's disease."
And it's not that we're underfunded and these other diseases are overfunded. Cancer, stroke, heart disease, HIV are all nasty diseases, and they deserve every penny they get. But there's a lot of potentially very good research that's not being done, and other potentially great research that's being relegated to just good or okay, because they don't get funded at the level that's required. I, and many others, would like to see federal funding for Alzheimer's disease increased to about $2 billion per year. That is what it is going to take to tackle this disease.
If you did live in an ideal world for science and you had unlimited funds, what one experiment or study would you do that you couldn't do now?
I'm an epidemiologist. I don't do one-off experiments. We do large longitudinal studies, but if I didn't have to spend so much time figuring out how I was going to pay for things I'd get a lot more done. Overall, I'm very lucky. I'm actually doing the studies I most want to do. However, given funding constraints, I have to put the studies together piece by piece. So, the multi-layered dataset we are putting together is the result of many different grants. If I had a lot more money, then basically I would bring the work I'm doing to fruition much faster. I'd markedly expand the number of people in the cohorts and markedly expand the depth and breadth of brain measures.
I mentioned that I'm doing studies incorporating the accumulation of postmortem tissue. These studies are in people without dementia. We have over 2,600 people without dementia, who agreed to be evaluated every year and they're all organ donors. We collect not only their brains, but spinal cords, muscle, and nerves. This puts us in the position to do a lot of unique things that really no other group can do.
Now 2,600 people sounds like a lot, but think about it. We have to follow them until they die. It's taken 18 years to get more than 900 autopsies done. And then think about the high-throughput data that were collecting—the genomic and epigenomic and proteomic and metabolomic data. Nine hundred people are not very many when you're dealing with hundreds of thousands of variables and millions of genetic markers. Then some of the risk factors may have small effects. When you go back and look at the variety of potential variables we're dealing with, things get pretty messy pretty quickly.
If I had unlimited funds, I would expand the number of people in my study pretty rapidly and I would increase the density of the type of data we have. I would also enroll younger people as some risk factors in mid-life appear to have different effects in late life. You want all these levels of data to put between the risk factors and the things we're measuring in the brains. I would also add the new amyloid imaging and see if we could replicate with amyloid imaging what we see with brain tissue itself.
By the way, I think this would be true of most of my successful colleagues in Alzheimer's research; I don't think any of them would change the direction of their research. They'd do exactly what they're doing, just bigger and better and faster. What we're doing is pretty cutting edge. It's needed. That's why we publish so much and why we get cited so much. But the ability to do it faster is really essential.
People are getting Alzheimer's disease every day, and once they get it, there's no going back. For these people, it's too late to prevent it and I don't think we're going to reverse it. So it really is about prevention and we're a long way from being able to do that. Everything has to move faster. That is really what my colleagues and I would like to see with more funding.
David A. Bennett, M.D.
Director, Rush Alzheimer's Disease Center
Robert C. Borwell Professor of Neurological Sciences
Rush Medical College
Rush University Medical Center
Chicago, IL, USA
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DAVID A. BENNETT'S MOST CURRENT MOST-CITED PAPER IN ESSENTIAL SCIENCE INDICATORS:
Hebert LE, et al., "Alzheimer disease in the US population—prevalence estimates using the 2000 census," Arch. Neurol. 60(8): 1119-22, August 2003 with 651 cites.. Source: Essential Science Indicators from Clarivate.
KEYWORDS: ALZHEIMER’S DISEASE, DONEPEZIL, VITAMIN E, MILD COGNITIVE IMPAIRMENT, CLINICAL TRIAL, EARLY INTERVENTION, NULL, AMYLOID METABOLISM, BIOMARKERS, EPIDEMIOLOGY, COHORTS, DISEASE PREVENTION, RISK FACTOR, BRAIN, POST MORTEM, AMYLOID DEPOSITION, TANGLE FORMATION, GENETIC RISK FACTORS, EXPERIENTIAL RISK FACTORS, PSYCHOLOGICAL FACTORS, EPIGENOME, APOE, POTENTIAL THERAPEUTIC TARGETS, FUNDING.
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