Lou-Ellen Barkan interviews
Dr. Bob Green

Lou-Ellen Barkan (LEB): Welcome to New York, Bob. It’s great to have you here — and as part of the Alzheimer’s research community. How did you start your career in the field?

Bob Green (BG): Even as a child, I was fascinatied by the brain and behavior. In college I studied neuroscience and in medical school struggled to choose between psychiatry and neurology. During and after neurology residency, I trained with Dr. Norman Geschwind and Dr. Marcel Mesulam in behavioral neurology, studying dementia, stroke, epilepsy and language disorders. When I arrived at Emory University, where I spent ten years on the faculty, I began to exclusively focus on Alzheimer’s disease and dementia.

LEB: What made you specialize in genetic epidemiology?

BG: Like many neurologists who see patients and work in academic centers, I both saw dementia patients in clinics and worked on industry and NIH clinical trials through the years. A few years after I arrived at Emory, I returned to graduate school to obtain a Masters degree in Public Health, which gave me some additional skills in epidemiology. Shortly after this, I moved to Boston University where I was fortunate to work with Lindsay Farrer, one of the world’s best genetic epidemiologists. We worked together on a large project called “MIRAGE,” that has enrolled over 3,000 families around the world with Alzheimer’s disease. The MIRAGE Study has been responsible for discovering a number of genetic and nongenetic risk factors for AD and exploring the ways in which they interact. That has been part of my primary focus
since 1999.

A few years ago, we utilized MIRAGE Study data to begin a new study. We called this study “REVEAL,” which stands for “Risk Evaluation and Education in Alzheimer’s Disease.” You see, we have known for a while that the APOE gene is a risk factor for Alzheimer’s disease, but not a definitive predictor. Over the years, many family members have requested this information. However, there were a number of consensus conferences from the 1990s that suggested that APOE disclosure would not be a good idea since there is no treatment available. There was concern that the impact of such information could be misunderstood and might have serious psychological consequences. The REVEAL Study has been asking the question, “What is the impact of disclosing APOE risk information on family members of patients with Alzheimer’s disease?”

We designed the REVEAL Study as a randomized clinical trial. In one arm, they received APOE information as part of their risk assessment, and in the other arm, they received risk information based only on their family history and age.

Our preliminary findings of the initial randomized trial suggested that many family members are very eager for this information. For example, when we asked family members of patients in our research registry, we found that 24 percent of them not only expressed interest, not only came out to visit with us and hear about the study, but actually rolled up their sleeves and became part of the study. This was astounding because it shows that so many people really do want to know more about their risk, even in the absence of a treatment to slow the progression or prevent the onset of Alzheimer’s disease.

LEB: I often meet people who don’t believe that they have Alzheimer’s in the family, but still want to participate in a broad-based genetic screening to learn more about themselves. These folks believe they are on the cutting edge, taking advantage of every opportunity to do things that they hope will positively affect their longterm health.

Other than for the very unusual families who have the rare genetic form of the disease which pretty much guarantees that they will get Alzheimer’s, many people think that if they are identified in their 20s or 30s as being genetically predisposed to get Alzheimer’s, they can impact the course of the disease by moderating their behavior. Maybe they are not entirely incorrect as more and more, there are articles about the impact of drinking coffee, getting enough exercise and rest and taking vitamins.

That’s the basis of the questions we get asked all the time. Does it matter if I get enough exercise? If I take my vitamins? Do you believe that if we can identify a predisposition for Alzheimer’s early enough that we can make a difference by taking better care of ourselves?

BG: As we conducted randomized trials in the REVEAL Study, we found that not only were there a high percentage of people who were interested in their result, but those who learned that they had the e4 allele handled the information quite well. The people who learned that they did not have the e4 allele were relieved, although they understood that they were not risk-free.

These were people who genuinely understood that we had nothing medical to offer. But, our survey data also suggests, in agreement with your question, that most people seeking riks information hope to eventually find ways to reduce their risk.

“We are moving rapidly towards a time when I believe there will be disease-modifying treatments available to slow the progression of AD and possibly delay its onset.”

There are many theories from epidemiological studies about the potential beneficial effects of physical exercise, mental stimulation, vitamins and diet on the risk of AD. Epidemiology is fascinating in this respect. It helps you tease out the clues, but doesn’t tell you which ones are true. It them becomes essential to do randomized trials to prove that the clues are meaningful.

There is no better example of this than the estrogen story. Epidemiologic studies suggested that estrogen was protective against Alzheimer’s disease, but to date, both treatment studies of patients with the disease and a primary prevention study of normal elders suggest that estrogen does not protect Alzheimer’s disease and might even add to short-term risk. Right now, we have lots of clues about physical and mental exercise, reduction of vascular risk factors and various vitamins or diets that may reduce the risk of AD. Most of these intervention are good for our health, regardless of their impact on AD, but none of them have yet been definitively proven to reduce that risk.

Lou-Ellen, as the director of a major chapter of the Alzheimer’s Association, I’d be interested in your thoughts on the Alzheimer’s Association’s “Maintain Your Brain” campaign, which suggests that vascular risk factors may have something to do with increased risk of Alzheimer’s disease and that intervening with these may lower risk. Are you concerned that this sends a message that goes beyond the data we actually have about the efficacy of such interventions?

LEB: We are very cautious. It’s one thing to say that you know something works. If I have bacterial pneumonia and I take penicillin, I get well. If I have leg cramps and I take quinine, the cramps stop. But we don’t have any definitive confirmation that people can prevent or treat Alzheimer’s disease with the same medications that prevent and treat heart disease. So we are very cautious about what we say.

Fortunately, we are in a time where health issues are taken very seriously and the media covers the story extensively. We all know — or at least believe — that if we exercise regularly, eat sensibly and are moderately careful about stress and getting enough rest, we’re better off, regardless of our genetic profile. That’s our message. We can’t confirm that any health regimen is going to prevent someone from getting Alzheimer’s disease. It wouldn’t be fair and it wouldn’t be correct based on what we know at this time.

BG: This brings us to the medications that are out there in clinical trials right now. It’s an exciting time. We are moving rapidly towards a time when I believe there will be disease-modifying treatments available to slow the progression of AD and possibly delay its onset. I recently reported the results of the Flurizan Phase III trial and unfortunately, this drug did not show efficacy, but the trial itself demonstrated that we can successfully conduct largescale trials of patients with mild AD and obtain robust results.

LEB: We focus a great deal on the challenges of delivering services to so many diverse communities. Do you notice differences between the acknowledgement and acceptance of the problem in the various ethnic and
cultural communities you work with?

BG: That’s an interesting question. I have been doing research with several cultural communities in New York and across the country and there are some economic and demographic issues related to recognition and diagnosis. For example, the risk of dementia seems to be higher with lower education, which may be lower in some ethnic communities, particularly among the elderly of that community. In a national study we completed several years ago, we reported that cognitive and behavioral symptoms reported by caregivers of patients with dementia were similar among English and Spanish-speaking communities across the U.S. In general, I am more struck by the similarities than the differences.

It’s an exciting time, because once treatments appear to be efficacious, you can then test whether they work earlier and earlier, particularly if they have a low side effect profile. And then we may get to the point where those at increased risk begin to take these compounds at a very early age in order to delay the disease — to the point where they die of something else before they ever get Alzheimer’s. That would be a wonderful place to be.

LEB: There are some diseases — non-Hodgkin’s Lymphoma is one I am familiar with — where recent advances in treatment have created exactly that situation. If someone is diagnosed in their 50s and reacts well to the new treatments, there is a good chance they will die of something other than non-Hodgkin’s. So now, when people are diagnosed with this very serious disease, they are also very hopeful.

BG: If we get disease-modifying treatments that slow the progression, we’ll be able to extend the life of patients with Alzheimer’s disease. Of course, as the population ages and we extend the life of patients who have the disease, we could get an even greater prevalence of the disease than we anticipated.

LEB: In such a scenario, Alzheimer’s would be classified as a chronic disease. This also implies that Alzheimer’s is a single disease. But the more we talk to your colleagues in the research community, the more we hear about Alzheimer’s as a disease category within which there are many variations including both the powerful genetic form of the disease and the more common form that we see in those over the age of 85. Do you believe this is one disease? It has always seemed odd to me that they would be considered the same illness — even though they both present the same symptoms.

BG: We use the term “Alzheimer’s Disease” as a meaningful and distinctive construct for clinical diagnosis in treatment and in research. But it is not a perfect construct. There are genetically determined variants, and they are obviously different than the more sporadic forms, but the sporadic forms have a variable heritable component. And even within the vast majority of sporadic forms, there are huge differences in the aggressiveness of the disease, the presence of other neurological symptoms or the frequency of behavior problems. I suspect there are dozens, maybe even hundreds, of genes acting in ways that create variants.

Of course, that makes it difficult to pin down the genetics of the disease. It could also potentially make it difficult to treat unless there is a common pathway for the entity we call Alzheimer’s disease. This is what we suspect is the role of beta-amyloid, the leading contender for such a pathway.

It’s quite interesting that we talk about amyloid all the time, but what we don’t talk about is that even neuropathologists disagree about whether a certain burden of amyloid constitutes the disease or is just part of the normal aging process. Sometimes we see patients who have a dementia that looks clinically like Alzheimer’s disease, but when we examine their brains at autopsy, they have no excess amyloid. At other times, we see people who are clearly documented to be normal cognitively, but when we examine their brains after they die, they have large amounts of apparently pathological amyloid. Although these situations are not terribly common, they are worrisome and there is concern about what we are missing. I think we’ll all be very relieved if the amyloid-based treatments work because they’ll be a proof of concept that our intensive focus on amyloid pathology has been well-placed.

“We have also found a number of new genes that may offer
new avenues for potential treatment.”

LEB: Some of us worry that the amyloid hypothesis may be the wrong paradigm. I sometimes think that in science, like in so many other disciplines, everybody begins to move in the same direction until all of a sudden, one person sitting on the outside of the mainstream says, “Wait a minute, maybe there’s another way to look at this.” I call it the “Emperor’s New Clothes” syndrome, when the outsider is the person who comes up with the new idea that solves the problem. I suppose it’s possible that the person who is going to solve the Alzheimer’s mystery is now a junior at Bronx High School of Science.

That’s not to say that this current work isn’t immensely important, because to get to the end point, we know you have to do the preliminary work. But it does continually raise the questions of whether Alzheimer’s is a single disease and what are the effects of genes and behavior.

BG: Well, there are certainly other clues from epidemiological studies. For instance, the effect of head trauma and the curious and unclear links between thyroid disease and cognitive impairment have not been well explained. The observation that women are at greater risk than men, even adjusting for their increased longevity is not well understood. Some data suggest that depression in early life is associated with a greater risk of Alzheimer’s disease later in life. There are all these fascinating clues from these studies that are very hard to tease apart.

We have also found a number of new genes that may offer new avenues for potential treatment. One of these discoveries was led by Lindsay Farrer, Richard Mayeux and Peter St. George-Hyslop who discovered the SORL1 gene, an important new gene that increases risk for AD in a large number of ethnic groups.

Alzheimer’s research has generated a large amount of interest and funding, thanks to the advocacy of the Alzheimer’s Association and the National Institute on Aging (NIA). Much of this activity is focused around the Alzheimer’s Disease Research Centers. I suppose there is some risk of institutionalizing the research in these arenas if data collection and questions are imposed in a top-down manner, but there’s also a rich tapestry of researchers at these Centers and at numerous institutions looking at things in many different ways.

LEB: As genetics become more sophisticated, whether t’s about Alzheimer’s disease, or any disease, it does sound as if we’re going into an era of individualized medicine. We’ll have knowledge of the genes we are born with and recognition that, as we age, we also change from day-to-day. We’ll start to make changes in lifestyle when we’re twenty, not when we’re seventy. The current trend to start taking baby aspirin in our 50s, even in our 40s, is a great example. For many of us, it’s become part of our daily routine and we may start taking it earlier, if we have a family history of heart disease or stroke.

BG: I agree. We are entering an era where we’re starting to have access to our own genetic markers. There are now consumer-oriented companies that sell genome scans. These companies and their products are both interesting and controversial, but because of our work in disclosing APOE, we have some of the richest science about what it means to disclose genetic susceptibility risk to people, how they react and what they do with the information.

For example, we were the first group to show, that on the basis of genetic risk information, people make selective insurance purchases. In 2005, we demonstrated that people were five times more likely to buy long term insurance if they had learned they had the e4 allele. So this finding is of great concern to the long term care insurance industry because it affords the opportunity for adverse selection; for consumers to “game the system” and may actually put the insurance carriers out of business.

Genetic testing has many other interesting implications but we are running up against the society’s general ignorance about genetics. People have this notion that genetics is very deterministic, but those who order these genetic tests find out that, while the tests provide information based on epidemiologic studies, they are not giving people the kind of risk information that they expected. So, for instance, you might learn that there is a risk of a particular disease in the general population of 6 percent. Your genetic profile indicates that your risk is 5.2 percent. Is that meaningful information?

However, this is just the beginning of these services, and the beginning of a science that’s going to grow and become more and more useful over time

LEB: There will also be an expansion of genetic counseling. These services are already used extensively in counseling couples who decide to have an amniocentesis. My daughter went through this during her last pregnancy. When she and her husband went to get the results they were appropriately anxious. They saw a counselor before the amnio, which my daughter thought was a more frightening meeting, because she was being educated on what she might learn and what, if anything, she could do about it. The most important part was that when they got the information back, they didn’t just receive a printout. They returned to the same genetic counselor to learn the outcome and what it all meant.

BG: Some of these companies have employed genetic counselors, and others feel as if that should not be a required part of the information they provide.

LEB: So have you been genetically screened?

BG: I was offered the opportunity to be tested by several of these companies. One of the companies had an Alzheimer’s disease checkbox, so I just checked it. And it came back as lower than average risk. If it’s accurate, it presumably reflects APOE status without giving you your APOE genotype itself. It would suggest that I don’t have a copy of the e4 allele.

LEB: And were you relieved?

BG: I felt a slight sense of relief, yes. But I’m also aware that this is just one of many risk factors and that it doesn’t guarantee anything. I found the experience interesting and I’m quite curious as to where this industry is going.

LEB: I continue to be fascinated by your optimism and that of your colleagues. You work, as we do, with people who are struggling with something that is very difficult and where the impact on the family is so profound. We spend our days talking about palliative care and hospice care. It gets very, very hard for people to do this work every day. However, we find that the research community generates this tremendous sense of optimism and excitement. It feels like watching Louis Pasteur, searching for the cure for rabies or Columbus looking for new land. This wonderful optimism really appeals to us — and we’re grateful for it because it seems to keep the momentum of the work going.

BG: Sometimes, it is terribly sad to see patients and it can be a pretty awful day when you have to tell three or four families in a row that their loved one has Alzheimer’s disease. But I do think that it’s an exciting time and I am very optimistic about the near future. In less than one hundred years, Alzheimer’s disease has moved from being a poorly-understood syndrome to the focus of genetic detective work and targeted therapies now in clinical trials. One of the antibody or gamma-secretase therapies currently being tested may soon prove to be effective and if so, we will truly be entering a new era. For me, after 20 years of working with patients and having to say over and over again that there is no treatment to slow down the disease, I can’t tell you how eager I am to tell patients and families better news.

At one level, simply being involved in research helps maintain one’s optimism, because you feel like you’re helping this vast enterprise of new knowledge production. And the kind of research that I’m lucky enough to be involved in, involving both genetics and clinical trials, gives me a front row seat on the the developments that will change the field. Finding the solution to this disease involves a vast and interactive collection of people and organizations, and I’m thrilled to be part of that enterprise.

LEB: We’re very grateful that you’re part of it too and we look forward to hearing great things from you and your colleagues — hopefully in the very near term. Thank you so much for taking time to talk with us today.

Dr. Bob Green graduated from Amherst College and the University of Virginia School of Medicine before completing a residency in neurology at Harvard Medical School’s Longwood Neurology Program. Following this, he completed research fellowships in Behavioral Neurology and Neurophysiology at the Beth Israel Hospital and Children’s Hospital in Boston, winning both the William B. Lennox Research Fellowship and the Wilder Penfield Research Fellowship. Dr. Green obtained additional training in Epidemiology, receiving a Masters in Public Health from the Rollins School of Public Health at Emory University.

In 1999, Dr. Green joined the faculty of Boston University School of Medicine where he founded and currently co-directs Boston University’s Alzheimer’s Disease Clinical and Research Program, and is the Clinical Director of the NIA-funded Alzheimer’s Disease Center. Dr. Green is the author of over 130 publications, serves on a number of advisory, editorial and grant review boards, and is past President of the Society for Behavioral and Cognitive Neurology. He has been continuously funded by NIH since 1990 and was voted one of America’s “Best Doctors” by his peers.

Dr. Green’s research interests are in early and preclinical detection, treatment and prevention of Alzheimer’s disease. He is Principal Investigator and Director of the REVEAL Study (Risk Evaluation and Education for Alzheimer’s disease) a multi-center project funded by the National Human Genome Research Institute and the National Institute on Aging to develop genetic risk assessment strategies for individuals at risk for Alzheimer’s disease.

Dr. Green is also co-Principal Investigator on Boston University’s NIH-funded MIRAGE Study (Multi-Institutional Research in Alzheimer’s Genetic Epidemiology), co-investigator on the NIH-funded Framingham Dementia Study and NIH-funded Georgia Centenarian Study, and is the Boston site director of the NIH-funded ADAPT Study (Alzheimer’s Disease Anti-Inflammatory Prevention Trial), one of the first large-scale intervention trials to prevent the development of Alzheimer’s disease in at-risk family members. He is national co-lead investigator on the industry-sponsored phase III trial of tarenflurbil, a compound being evaluated for disease modification in patients with mild Alzheimer’s disease. He is a consultant on the following NIH-funded studies: the Cache County Memory and Aging Study, the Epidemiology of Alzheimer’s disease in Twins and the Wisconsin Registry for Alzheimer’s Prevention Study.

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