David Bennett on Identifying Risk Factors for Alzheimer's
Special Topic of Alzheimer's Disease Interview, September 2011
According to our Special Topics analysis of Alzheimer's Disease over the past decade, the work of Dr. David Bennett ranks at #9 by total papers and #12 by total cites, based on 209 papers cited a total of 9,577 times during the analysis period. One of these papers ranks among the top 20 over the past decade. In Essential Science IndicatorsSM from Thomson Reuters, Bennett's work ranks among the top 1% of researchers in the fields of Neuroscience & Behavior, Clinical Medicine, Psychiatry & Psychology, and Social Sciences. His total record in the database includes 263 papers cited a total of 10,357 times between January 1, 2001 and April 30, 2011. Bennett is the Robert C. Borwell Professor of Neurological Sciences and Director of the Rush Alzheimer's Disease Center at Rush Medical College in Chicago, Illinois. |
Below, he talks with ScienceWatch.com correspondent Gary Taubes about his highly cited work in Alzheimer's.
One of your two most-cited articles was a
clinical trial back in 2005 testing a drug called donepezil and vitamin
E on Alzheimer's disease (Petersen RC, et al., New Engl. J.
Med. 352[23]: 2379-88, 9 June 2005). What did that study find and
why do you think it's so highly cited?
That was a trial of people with mild cognitive impairment to see if a drug would delay the onset of Alzheimer's disease. The way this came about is through a series of drugs, donepezil being one, that appeared to slow the decline in people with mild-to-moderate Alzheimer's disease. We had been doing work on mild cognitive impairment, which is defined as having cognitive difficulties but not meeting the formal criteria for dementia. There was a lot of thought that many people with mild cognitive impairment really did have the beginnings of Alzheimer's and that led to thoughts about intervening earlier with the same drugs being used in Alzheimer's.
The donepezil study was funded jointly by Pfizer and the National Institute on Aging. This was the first of a series of studies trying to intervene on mild cognitive impairment and it was ground-breaking in that regard. That's why it was published in the New England Journal of Medicine and has so many citations.
What did you find?
What we found is pretty complicated. Fundamentally the study was null. We did not find that the drug delayed the onset of Alzheimer's disease. That was disappointing. A couple of subgroup analyses were done that suggested maybe subgroups of people might have responded to the drug and that put a little positive spin on the paper, but the basic finding was that the main hypotheses was not supported. And it turns out, if you look at that whole class of drugs, they all struck out. Other studies failed to find an effect in similar populations. So that was all rather disappointing.
You also tested vitamin E in that study. What
was the thinking behind that?
We had done an earlier study, also published in the New England Journal of Medicine, with people with Alzheimer's disease and it show a pretty interesting effect. The outcome was a whole variety of mortality and disability and suppression of disease measures, and there seemed to be some delay in this outcome. So the thought was to try donepezil and vitamin E in a 2 x 2 trial. That allowed us to examine two drugs at only an incremental cost to one drug alone. There was nothing magic about these two drugs together, only that by studying both drugs in the same trial we could test two drugs in a more cost-efficient manner.
Was the vitamin E trial null as
well?
Yes, null as well. That's the story of Alzheimer's disease drugs, by the way—unfortunately.
Why do you think that is?
For a variety of reasons. First, 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. Sometimes we're trying things with a hope and a prayer. And then, where the biology is worked out well—say, with the amyloid modulators—a lot of us think that we're giving them too late in the disease process and that interfering with amyloid metabolism probably needs to be done way before people have dementia, possibly before they have mild cognitive impairment.
"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. "
Unfortunately, we don't know how to do prevention trials in a cost-effective way. When you try to figure out what it would take, they become hugely expensive. This is one of the factors driving biomarkers studies. The thought is that if you can follow a biomarker, rather than following the clinical course itself, you can do these studies with a smaller sample size and a shorter duration.
A good example is in HIV research. Researchers used to take people who were HIV positive and wait for them to get AIDS. When they started using CD4 counts as a proxy, the sample sizes came down, the duration of the studies came down, and the costs came down. The speed with which they could work their way through various agents markedly increased. It would be great if we could find something like that for Alzheimer's disease. So far we have found some markers, but not markers that could be used as surrogate outcomes in clinical trials.
What do you consider the most interesting or
significant finding from your research in the past five years? The
finding that excites you the most?
It's hard to point to one piece of work. I do mostly epidemiology and so we do what I would call studies in parallel rather than studies in sequence. I can point to a corpus of work around a couple of cohorts that I run.
One of the things we're particularly interested in relates to disease prevention. If you have a risk factor for Alzheimer's disease, then the risk factor has to be doing something to the brain because Alzheimer's is a disease of the brain. It's a cognitive disorder. By contrast, if you look at motor dysfunction, the problem could be brain, spinal cord, nerve, muscle, or joints.
What we pioneered is studies of risk factors for Alzheimer's where we get the brains post mortem. This has limitations, of course. You can only get the brain once and only at the end of your study. But, on the other hand, the things you can do with actual brain tissue are virtually limitless. This is not the case with brain imaging, which is the other way to look at the brain, where the number of things you can measure is relatively small and finite. We do brain imaging too. But when we get the actual brain, the number of things that are potentially measurable just keeps growing and growing.
So we have a whole series of papers identifying various risk factors for cognitive decline, looking at the biology of cognitive decline, and then trying to model how different risk factors lead to brain pathology and to cause cognitive impairment.
What have you learned from this comparison of
cognitive decline and risk factors?
Some pretty interesting things have emerged from this body of work. One is that a variety of genetic factors associated with the clinical diagnosis of Alzheimer's disease seem to be related to the typical pathologies we think of as causing the disease, which is amyloid deposition and neurofibrillary tangle formation. Traditionally Alzheimer's is somebody with cognitive decline, dementia, and these two pathologies in the brain at death. We generally think that risk factors for Alzheimer's dementia as causing this pathology.
That's true for genetic risk factors. It turns out that when we get to experiential risk factors, such as cognitive activity, physical activity, social activity, education, and psychological factors that also predict clinical Alzheimer's disease, such as depression, neuroticism, conscientiousness, loneliness, and harm avoidance, and we've reported a large number of these factors related to cognitive decline and getting clinical Alzheimer's, none of these seem to be causing amyloid deposition or tangle formation. None of them.
So what role are they playing if it can't be
directly linked to the relevant pathologies?
Some of them just seem to have a totally independent effect. Others have an interaction with the pathology, which means that they're good or bad for you only in the presence of the pathology in the brain, but they're not causing the pathology. So we've come to the thought—to put it as simply as I can—that the accumulation of Alzheimer's pathology is largely under genetic control, but how that pathology expresses itself as clinical disease disease—to memory loss, etc.—might be related to how you use your brain over your lifespan.
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