Lou-Ellen Barkan interviews
Dr. MONY de LEON

LOU-ELLEN BARKAN (LEB): Let’s talk about the National Institutes of Health (NIH) for a few minutes. We know they have cut funding, due to the obvious competing interests in Washington. But “the perfect storm” is coming anyway. The “baby-boomers,” the largest cohort in our history, will live longer than any previous generation and half of them are predicted to get Alzheimer’s disease. The idea that we can just ignore this is ridiculous. The NIH cuts are, at best, counterproductive. At worst they're disastrous. How is that affecting your work?

Mony de Leon (MDL): At the congressional appropriations level, the amount of available funding has been flat for several years. Costs for previously funded projects naturally increase and with money diverted to other health and defense related issues, the NIH is forced to use across-theboard project cutbacks in aging research in the neighborhood of 10 to 20% per year. The last few years have been an extraordinarily difficult time to get new grants. Funds are decreased while the competition for funding has increased. So, who pays the price? The hardest and first hit are young scientists who are trying to get started. This will have a great negative impact on the next generation of scientists. It will also have an impact on innovation and the mission.

Our own group has had to cut back in those development areas that are most speculative. Our organization is relatively strong, because we've had diversified support for a number of years and we have a very solid team that has come together to pool the resources. But this is only a temporary solution for us. It is getting harder and harder for us to do our work.

LEB: The issue with young scientists is very concerning. Unless we can encourage the best and brightest to go into the field, we will lose all this terrific talent just when we need it most. We need the new generation, the folks who can think out of the box.

MDL: Scientists have to go where they can access resources of talent, opportunity, technology, and money. I often get requests from young people who want to work in our lab. This year I had to turn down two very bright candidates because we didn't have the revenue to fund the positions. One was a highly qualified neurologist from South Korea who wanted to spend two years at NYU and only needed partial support of his salary because the Korean government was going to pay the balance. We had plenty of work for him, but no funds to guarantee his salary for two years. The other was an intelligent young basic scientist looking for a first job.

LEB: Although you work largely in the area of diagnostics, I am curious about your opinions on progress in developing medications for prevention, treatments and, of course, a cure. Lately I am hearing much more optimistic projections. Do you think anyone is on the right track?

MDL: These are extremely exciting times. Recent claims that there may be a cure on the horizon are justified. These are based in part on animal evidence for clearing the “bad guys” out of the brain and improving cognitive performance. In some animal studies they were actually able to prevent the disease from occurring in animals at genetic risk. But, the proof that exists so far is restricted to animal models with features of the disease but not identical to the human form.

There are a number of technical issues there that are quite important. One is that the amyloid depositions in the mouse model brain is of a different size and is more soluble than the amyloid in a human brain. The challenge remains to learn if amyloid can be taken out of a human brain as readily as in a mouse brain and what are the consequences. Until very recently, the tools weren't there for making a direct observation of brain amyloid during life. Only recently is there an amyloid imaging capability, one based on the PET technique using what is referred to as Pittsburgh compound B or PIB.

Thus, for the first time we have a potential for viewing if the amyloid is cleared out of the brain. But, this important observation has yet to be reported. To date, there are a few examples of amyloid clearance available through post-mortem examinations following the aborted Elan vaccine trial, with not enough cases to give a clear picture. Of course, there is no information on how much amyloid there was in the brain at the beginning. This study suggested that amyloid was cleared, with only little evidence for a beneficial treatment effect in the late-stage patients enrolled. Nevertheless, with improved medications to clear amyloid without side effects, there is optimism in the field that the new drugs will have an impact on Alzheimer’s disease. It can be expected that after the first trials in AD patients are completed, an evaluation will be made as to the potential for treating milder (earlier) cases.

LEB: Some time ago, a doctor told me the cure could be as much as one hundred years away. Recently, the same doctor reassured me that we would have something meaningful in less than ten years. He suggested that whether it is a single drug or a cocktail approach – similar to what is used for HIV/AIDS – remains to be seen. He suggested that in the early stages of developing these drugs, people with Alzheimer’s disease will need to assess if they want to take a chance on a new drug. Would you agree?

MDL: These are really two questions. What is the timeline? And what is the risk-benefit ratio for an intervention. The timeline is hard to project. In a best case scenario, I think that in the next two years we'll probably know if we're marching along the right track with respect to amyloid therapy reversing the course of the disease, instead of just holding the line as with cholinergic system drugs. This is not to say that in two years we will have possibly cured the disease, and it's also not to say we will have prevented the disease. I hope we may be able to bend the disease curve for some people, if not all. At that point, it will be of great interest to study who benefited, who did not, and why.

In terms of risk-benefit, the first set of amyloid immunotherapy trials produced encephalitis in about five percent of the individuals. Some people actually died and others were impaired. So the trial was stopped. Now the approach to removing amyloid has changed so that the anti-bodies are delivered in a different way (passively vs. active). With passive anti-body treatment the adverse immune system reactions previously observed are not as likely. The new trials underway have a good safety record so far, but risks still remain.

LEB: Recently, I heard from an old friend. His relative was just diagnosed with the early-onset form of Alzheimer’s disease. My friend tells me that he has nothing to worry about because there is a new study that is going to find the cure very quickly. I asked, “Wait a minute. Why would you even begin to think that?”

What I am concerned about is that people are receiving false hope to encourage them to sign up for trials. We agree that these trials are critical and we must have more people participating at every level. But we have to be honest about the status of drug development and the outcomes.

“Another friend told me that she didn’t have to worry about Alzheimer’s disease because she had been taking vitamin E every day. Other folks tell me that they are eating blueberries and doing crossword puzzles. And I tell them, “That’s great, but please read the research material very carefully, so you have realistic expectations.”

MDL: I agree. I guess we are all guilty of being overly enthusiastic – and of course it can color our perspectives. The ideal is to be neutral, balanced, informed, and self-critical, but that is not always easy to do.

LEB: So on that note, how do you feel about blueberries and almonds and crossword puzzles? Because notwithstanding what we tell everyone about the progress in science, someone who reads this will call and ask, “What does Dr. de Leon think about eating almonds and blueberries?”

MDL: I like blueberries because they taste good. I think one needs to weigh the information and the source. Animal studies can tell us a lot, but they can’t tell us everything. Animal studies have been valuable in terms of looking at the relationship between brain activity and brain plasticity. The very first evidence that parts of the brain are plastic - meaning that some brain areas can grow new cells and can restore cells that are either getting sick or injured or just wearing out - was amazing. When it was shown that the process could be enhanced through exercise and then shown that that process could be further enhanced through diet, particularly by dietary restriction and by ingesting antioxidants, this was received as fabulous information. But the question is how do we apply that information to our lives and does it really work for a disease like AD? What evidence is there that this will actually work for you and me? We can make a mouse a little bit smarter. We can make a fruit fly live twice as long. We have the capability of manipulating the genetics of these animals, but what about our own system? How malleable is that? And how do we find out the relevance for humans? Not by guessing. We have to collect the data. So how do we get that data? It brings us back to the most important single issue for anyone reading this – participation in research.

People talk about calling on their elected officials to get more money. That is easy. It's a lot harder to go to a hospital and put yourself on a treadmill, stick your head in a scanner and go through memory and other performance tests to see how well exercise is improving your brain. I think the most important thing is clinical research participation. Everyone who is at risk needs to realize that if there's really going to be a breakthrough, it's going to come through teamwork, including their own participation. There is no amount of money that's going to replace the participation of healthy and at risk individuals who can teach us how to recognize disease. There's no shortage of sick people who will come in for help,but that does not replace the need for healthy people to volunteer for these trials.

LEB: What is the age in which the ideal person should start a trial? In their 20s, in their 30s?

MDL: In our studies, we have seen evidence of pathology in patients in their early 60s who we subsequently observed with cognitive impairment in their late 60s. We have eight to ten years of advance notice. Does that mean that when you're only 55 you should not consider participating in AD studies? We do not know how far back we need to go for usable evidence. Clearly,we have not gone back far enough. There is evidence from the APOE genotype studies that indicate early change or predisposition. It was found that young individuals – even in their 20s – showed altered brain metabolism. To date, no one knows if it's indicative of a change from when they were 18 or if they were born with different brain wiring. The really important questions reflect the specific

The really important questions reflect the specific nature of what you want to address. How early should we begin to treat? How early should we begin to diagnose? How early should we begin to explore for mechanisms of disease? Each one of those questions will take us back earlier than where we are today until we ultimately arrive at the day you were born, under what stars, with which genes.

LEB: A neurosurgeon told me that less than 50 years from now, a doctor will take a blood sample on the day you are born and give you an analysis of what you can expect from your health for the rest of your life. And while there will be some changes along the way, because things are not entirely static, you will have a pretty good idea of the possibilities – and it will help you create a healthier lifestyle.

MDL: It is possible that an estimate of risk for Alzheimer’s could in the future be addressed by a genetic test. It is most likely that a diagnostic test will be available to test for proteins that are promoting the pathology that has yet to be clinically recognized, and whose genetic contributions remain obscure. If some constellation of genes has to get together and gang up on you, and it doesn’t occur until you're exposed to some environmental event, then your specific risk may not be known until that exposure has occurred. You will need to do another blood or other diagnostic test at that point.

LEB: Of course, this process will be managed by internists, so they will need to be very knowledgeable about a number of diseases. Unfortunately, very few internists are really knowledgeable about Alzheimer’s disease. We know that one reason is their discomfort in referring their patients, because even some neurologists are less educated than we think they need to be. Given the growing epidemic, it is a frustrating struggle for us to help them recognize the need to learn more and work more closely with us and the research community.

MDL: I agree that patient and doctor education is vital to the effective management of the dementias. This is a big issue for all of us, because we really don't have any therapies that stop the progress of the disease. Patient choices are extraordinarily limited and much more research is needed.

LEB: I am hoping that more physicians will start to attend our Annual Meetings and see how lucky we are that so many brilliant scientists are working on this problem. Maybe then we can get more of their patients into these studies.

MDL: That is extremely important.

LEB: Before we leave, I have a couple of questions from my own observations. First, I did notice that years ago, when I had a general anesthetic, my brain was very fuzzy for a few weeks. On the other hand, I recently took up horseback riding – a new skill for me – and I had to learn a tremendous amount of new information about horses, about equipment and about riding skills. Once I started this, it seemed to me that my mind was generally sharper. I know these are not clinical tests, but I think we are all asking ourselves, what is it we should be doing – or not doing – to keep ourselves sharp as we age? Many of us are operating at a professional level where we have an obligation to apply the scientific method in a very disciplined way. But most of us are also operating in our daily lives based on what we think makes us more effective.

MDL: This is an active area of research and there is much to be learned of the effects of anesthetics on cognitive function, particularly for older persons. This complex arena includes consideration of the diseases that the patient has at the time of surgery, the duration of the surgery, and the physiological monitoring of the patient during the surgery. Moreover, there are recent reports that the postoperative period is of considerable importance in preventing cognitive decline associated with procedures.

Like you and like a lot of people, I feel better when I exercise and eat well. Even before Fred Gage at UCSD published the definitive studies showing that a mouse running the treadmill improved the plasticity of its brain, I always had the feeling that exercise was actually good for my brain. I felt it increased my capacity and offset the effects of stress, by producing better regulation of the hormonal and metabolic changes that stress produces. Today,we are all aware that a good diet, such as a so-called Mediterranean diet is important, not only for the known relationship of excess triglycerides and cholesterol to poor cardiovascular health, but also to promote the good feeling of being energetic and engaged. Keeping weight under control, especially in middle-age, is important for the body and not being too stuffed and avoiding feeling sleepy from overeating is definitely a plus.

There is a popular and useful concept that what's good for the heart is good for the brain. Excellent evidence for this comes from the Framingham study, which started with cardiovascular observations and evolved into looking at brain health. Ultimately, the brain is dependent on its blood supply. The heart delivers it and the vessels are the proximal suppliers. We need to protect that system. If one has vascular disease of the brain – and MRI has taught us that many older people and the majority of patients with Alzheimer's do – it may be particularly important to attend to this issue.

LEB: Mony, thank you so much for this terrific opportunity to visit your exciting world. You’ve given us a wealth of information and I know our readers, like me, greatly appreciate it.

MDL: Lou-Ellen, this was my pleasure and I am most grateful for your efforts and under your leadership, the Alzheimer’s Association’s contributions to the cure and prevention of Alzheimer’s disease. My colleagues and I can be reached at the NYU Center for Brain Health at 212-263-7563 and at www.med.nyu.edu/cbh.

Dr. Mony de Leon is Professor of Psychiatry at the New York University (NYU) School of Medicine and Scientist at the New York State, Nathan Kline Institute. He received his Gerontology doctorate from Columbia University in 1980. His published doctoral dissertation described, for the first time, the cortical atrophy of Alzheimer’s disease in living patients. For over 25 years he has continued to develop imaging and biomarker approaches for the early diagnosis of Alzheimer’s disease (AD). Among his qualifications, he has published over 200 papers in AD research and founded both the NYU Neuroimaging laboratory and the NYU School of Medicine, Center for Brain Health (CBH). The CBH is an interdisciplinary clinical research center, funded by the NIH, with a team of 25 clinicians and scientists. Dr. de Leon is a reviewer and/or editorial board member for 22 journals and has served on both national and international NIH advisory panels in the area of the early diagnosis of AD. In 2006, he was voted “Worlds pioneer in the brain imaging of Alzheimer’s disease” at the Alzheimer centennial in Tubingen, Germany.

Among the research highlights of CBH scientists are: 1980, the first report of brain glucose metabolism reductions in AD using FDG-PET; 1989, the first study showing that the transition between Mild Cognitive Impairment (MCI) and AD could be accurately predicted by estimating hippocampal atrophy on CAT scan; 2001, the first report that entorhinal cortex glucose metabolism reductions in normal elderly predicted 3-years in advance, future MCI; in 2003, using NYU developed MRI software, the first 3-year MRI prediction of future MCI in normal volunteers; in 2005, the advance prediction of MCI was extended to 8-years using automated PET image analysis software developed at NYU; and in 2007 it was shown that cerebrospinal fluid biomarkers contribute to MRI imaging in the 3-year advance prediction of the transition between MCI and AD.

Current objectives entail using the early imaging and biomarker diagnostic capacity to define presymptomatic candidates for Alzheimer prevention.

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