Editor’s Note: Dr. Richard J. Hodes is an eminent immunologist and director of the research program of the National Institute on Aging (NIA) at the National Institutes of Health (NIH). He is a featured expert in the new HBO documentary series “The Alzheimer’s Project,” which began airing on HBO on Sunday, May 10. In 1995 Dr. Hodes was elected as a member of The Dana Alliance for Brain Initiatives; in 1997 he was elected as a Fellow of the American Association for the Advancement of Science; and, in 1999 he was elected to membership in the Institute of Medicine of the National Academy of Sciences. Dr. Hodes is a graduate of Yale University. He received his M.D. from Harvard Medical School. As author of more than 200 research papers, he is an influential scientist in and contributor to the field of immunology. For more about HBO’s “The Alzheimer’s Project,” click here.
LESLEY STAHL: Dr. Richard Hodes, director of the National Institute on Aging, welcome to wowOwow. And thanks for joining us to discuss the four-part HBO documentary on Alzheimer’s, which is running right now. I watched this documentary, and one of the messages that is loud and clear in the series is that the hopelessness people have felt about this disease is turning into hope. And I wonder if you can tell us, in a nutshell, why you think there is cause for optimism since, as far as I know, there still is no cure.
DR. RICHARD HODES: It’s a great question – probably the question. I think the reason for hope, which you rightly perceived, came through in the comments of many of the lead investigators in the field, reflecting the progress that has been made over the past 10 and 20 years from the very little we knew to what we now understand, in terms of basic molecular and cellular mechanisms underlying the disease; what we’ve been able to learn from animal models; the way we’ve been able to improve our ability to image events that happen in the brain, both of normal individuals and of those with Alzheimer’s disease. However, given all this optimism and excitement that’s been generated by progress, I think it is important to note, precisely as you have said, that we still do not have an effective means of treating, preventing or delaying progress of disease. And the most challenging question is how long it is going to take us to translate this excitement in research into such a success ultimately. And the answer to that, we truly do not know.
LESLEY: Before we get into what to do about the disease, since so much of the science that is shown in the films is about the progress made in understanding it, I was kind of surprised – if not very surprised – to see the connection to vascular disease and a connection to insulin. Now explain that.
DR. HODES: The connection to vascular disease has come from a variety of lines of evidence, a lot of it having to do with risk factors – that is, epidemiologic studies – that show the relationship between multiple variables and the risk of having Alzheimer’s disease. And so for some time it’s been known that diabetes increases the risk of Alzheimer’s disease, and this relates both to the vascular disease, really, and the insulin story that you mentioned. It’s been known that a history of high blood pressure – hypertension – in midlife is associated with an increased risk of developing Alzheimer’s disease. It’s been shown that some of the variables, such as levels of physical activity and fitness, which are closely related to cardiovascular risks, are also associated with the risk of Alzheimer’s disease. And in addition to this line of association to risk factors there are some interesting studies that included those that came from the Religious Order Study, in which a group of individuals had committed to being followed through life with close histories and examinations, and then to post-mortem examination of their brains.
LESLEY: Now when you say religious orders, we’re talking about priests and nuns –
DR. HODES: Yes. Correct.
LESLEY: — who live in these closed communities?
DR. HODES: Correct.
LESLEY: Yes, go ahead.
DR. HODES: Dedicated individuals who in this case had their dedication extended to participation in these studies. And one of the observations was that at death, when one compared what was seen in the brain to the level of cognitive function, including dementia that was apparent at death, that in addition to a correlation of dementia and memory loss, with the lesions associated with Alzheimer’s disease – that is the plaques and tangles that I’m sure you’re very familiar with – that correlation was imperfect and that part of the imperfection was explained by the influence of vascular changes in the brain. So if one took individuals who had equal amounts of plaques and tangles they might have very different levels of cognitive function and the prediction of cognitive function was associated with not only the plaques and tangles, but also the status of the cerebral vascular lesions. So from the pathologic point of view it appeared that the symptoms of Alzheimer’s were the product of the pathology we commonly call Alzheimer’s, but also the pathology of cerebral vascular disease.
LESLEY: Does science know yet whether vascular disease, high blood pressure or even diabetes causes Alzheimer’s? Or do they both come from the same root problem?
DR. HODES: The short answer is that we don’t know. It is likely that Alzheimer’s disease involves processes that are not identical to those that define diabetes or heart disease. But if, when one talks about the cause of Alzheimer’s disease one is talking about the symptoms, the way an individual is affected, the loss of function, then the possibility is real – but not definitively established – that high blood pressure, diabetes, et cetera, do contribute. So what ultimately is the way in which research aims to determine whether there is really a cause and effect relationship? The most direct and probably the most meaningful way to do that is through clinical trials that would determine whether controlling blood pressure or controlling the level of insulin control and blood sugar control, or by controlling cholesterol level, for example, will have an impact on the generation of disease and its symptoms. And some of those studies are currently in progress.
LESLEY: Right. I learned so much by watching this series. One of the things I learned is that there are 91 new drugs being tested right now, in trials around the world – 91 new drugs – some of which do what you’re just saying, some of which try to see what controlling insulin will do, and other things related to vascular and heart disease. I guess the one that really intrigues me, that the series sort of honed in on, was the development of a vaccine to try and immunize us against the disease. You’re an immunologist, right? How promising do you think that approach is?
DR. HODES: Well let me say, in the beginning those who pursued this approach really deserve great credit for innovation. The results, as you know, were from a study that began in mice – mice that carried the human Alzheimer’s disease and therefore had the brain lesions of Alzheimer’s disease and had the memory loss that parallels Alzheimer’s disease. And investigator Dale Schenk and his collaborators immunized them against the amyloid peptide that is a part of the plaques.
LESLEY: OK, you have to stop right there. We’ll get back to the vaccine. Amyloid? These are big words. What does that mean?
DR. HODES: In 1906 Professor Alzheimer defined the disease, which now bears his name. He noted two principal types of lesions in the brains of those affected. One was called “plaques” and the other “tangles.” Now, the plaques were, over the years, determined to consist of a protein that consists of amyloid protein fragments. So amyloid is a gene product, or protein, that’s normally found in the brain. With patients who have Alzheimer’s disease there is a collection of clumps, aggregates of fragments from this protein.
LESLEY: So they … it clumps together?
DR. HODES: It clumps together.
LESLEY: And creates a plaque?
DR. HODES: And creates a plaque.
LESLEY: Like on our teeth.
DR. HODES: Yes.
LESLEY: We all know that’s not good.
DR. HODES: Right. Of interest in trying to understand whether this observation really relates to the cause of disease is that in the rare but very tragic families who have Alzheimer’s disease inherited with an early onset – this is estimated to be perhaps five percent of the people with the disease, onset may occur in the 60s, 50s, 40s, even 30s – in these families the inheritance is clear and simple. So if a parent is affected there’s a 50/50 chance of each child being affected. And years ago, investigators were successful in identifying the gene which causes this disease.
LESLEY: So if a woman’s pregnant and she has an amniocentesis, will they tell her this child has this Alzheimer’s gene?
DR. HODES: If a woman is known to be in a family with early onset disease and chooses to undergo genetic testing, if that woman finds that she does not have the gene, then there is no more risk of Alzheimer’s than the considerable risk in the rest of the population. But if she does have the gene, then she knows that there is a 50 percent chance of passing it on to offspring, in theory. In principal, this could be tested in utero.
LESLEY: OK. But most people who have Alzheimer’s don’t have that gene.
DR. HODES: Absolutely. And as I said, usually it’s quite clear, because people know from multiple generations there’s a history of early onset at a high frequency in families. When the genes were identified, one of them turned out to be the gene that encodes this amyloid protein that is found in plaques. So it’s a very striking finding. So in these families, a mutation – a change in the gene that affects these plaques – actually causes the disease. Two other genes turned out to be genes that are not themselves encoding the amyloid, but they code for proteins which modify the processing of the amyloid. So all three of the genes, mutations of which can cause the inherited early onset disease, all affect this amyloid product. And this contributes to one hypothesis, the so-called amyloid hypothesis, which says that the amyloid protein and abnormalities in its production or clearance or aggregation, are actually causal for the disease. So this brings us back to the reason that the vaccine approach was thought to be a useful one, if it might prevent or alter or reverse the collection of amyloid. So experimental mice were made by taking the mutated gene from families who have this early onset disease and introducing it into the chromosomes of a mouse. So one now has a mouse carrying the human amyloid Alzheimer’s gene. And these mice, in a variance of this model, develop the amyloid plaque that can be detected in the brain and, as they age, they undergo detectable losses of memory at an accelerated pace.
So it was in this model that the immunization was tried. And the results were actually quite striking. If one took young animals, young mice, and began the immunization, it was possible to prevent the accumulation of amyloid plaques. If one waited until a time when they had plaques and treated them then, it was actually possible to reverse the deposition of amyloid. And in either case, in addition to these changes in the pathology of the brain, there was an improvement in cognitive function; memory, as measured in these mice.
LESLEY: So very hopeful.
DR. HODES: So this, of course, was a very exciting finding. And then the challenge was to determine whether it could be translated into a clinical approach in humans. So the investigators appropriately took it through some studies in non-human primates, importantly looking to be sure there was no unsuspected toxicity that would create a danger to human subjects. And the studies in non-human primates did not reveal a problem, and thereafter progression to human trials occurred. And the unfortunate outcome of the study was that a small proportion – I believe it was about six percent – of the individuals, as they were treated, developed an meningoencephalitis. This is an inflammation of the brain and its linings and spinal cord. That’s a serious problem; serious enough to lead to the conclusion that the study had to be discontinued, that it was not ethical to continue a study putting individuals at risk for treatment that was not yet known to be effective. Since the time the study was ended, there has been suggestion by investigators that there were signs of possible positive effects of the vaccine, even though the study could not be taken to a definitive completion. And so the current circumstance is one in which investigators are pursuing a number of approaches, still trying to use immune therapy. They are altering this immune therapy in such a way as to avoid the side effect, this encephalitis, and yet to preserve the possible, positive effects of an immune response in clearing amyloid.
LESLEY: Right. When you say there’s hopefulness out there, that, to me, is a pretty hopeful sign – if they can figure out how to not cause encephalitis, obviously. I wrote a book several years ago about my experiences covering the White House. And when I got to the Ronald Reagan chapter I wanted to find out if there were any signs of Alzheimer’s when he was actually president. And I interviewed several doctors about this. And some of the things I remember in those interviews have stayed with me. And one was when one of the doctors said, and this is a quote, “It’s a very ragged disease.” And by that he meant that it kind of comes on in fits and starts. So you could see a person, in the early stages of Alzheimer’s, who one day is perfectly, totally normal, and the very next day – or even within the same day – is spaced out. They have huge bursts of clarity where they remember everything and everything’s just fine. And then, within an hour or so, they slipped into kind of a daze. Is this typical, in your opinion, of what you would see in the early stages?
DR. HODES: Quite honestly, it is consistent from what I’ve heard from many, anecdotally as well. But I hesitate to say more since I’m not aware of an evidence-based research study that actually documents it. So let me not go further, if that’s OK.
LESLEY: OK. But in the documentary there are several people who you meet and actually watch as the disease develops to some degree.
DR. HODES: Yes.
LESLEY: And one of the things that really struck me was the very person we meet, who’s an 87-year-old woman who has the early stages of Alzheimer’s, but she’s been diagnosed. And there are many things she can’t remember and she’s losing the ability to recognize faces and things like that. But she’s still driving her car.
DR. HODES: Yes.
LESLEY: She’s living alone, and she sings in a choir, and it really struck me that this idea of raggedness – I like that word – seems to be borne out; that until the disease really, really develops quite a bit, that people can go along and lead their lives.
DR. HODES: Yes. And this very ability creates a number of very special challenges. For example, you mentioned that in the case shown the woman was still driving, a very difficult, real-life decision for individuals affected and their families. At what point is it no longer a reasonable and safe thing to do? An individual case precisely identifying the right time to make that decision is very challenging. And this relates to many other areas of self-sufficiency in which the desire for independence and the very positive spin that we all put on independence is weighed against risk. And it makes every case, every family, every individual a very special challenge.
LESLEY: Well this is one of the real cruelties of this disease, that all the people we meet in the documentary – and there are many whom we meet as it’s four hours plus – where we look at all different aspects of the disease, we meet many people with it. And, obviously, the ones we meet are able to talk about it. They haven’t lost so much of their cognizant powers that they can’t. And they’re watching their own brains deteriorate, and it’s horrible. It’s just horrible. It’s ghastly.
DR. HODES: That it is. That it is.
LESLEY: And that’s one of the sadnesses if you’ve ever known anybody. Here’s something else I wonder if you know about, and it struck me over and over. You would meet people who are pretty far along – some have trouble even recognizing their wives – and yet they can sing a song and remember all the lyrics, going back. And I wonder: Why do we remember music when we can’t remember someone we know? Isn’t that funny?
DR. HODES: It is. in fact, what this points out is the way in which disorders, diseases such as Alzheimer’s, actually challenge and teach us a lot that we don’t understand fully about normal function – in this case memory. It clearly tells us that not all memory is the same and there are ways of recognizing patterns, be it in song or habitual physical activities that are able to sustain themselves, certainly after there are serious defects in the ability to acquire and store new memory, or to remember other past memories.
LESLEY: Right. Well you’re learning an enormous amount about the brain through all these studies about memory, about insulin, about all kinds of things, as you hone in on Alzheimer’s. Let me ask you one final question, and it goes back to something you brought up – the study of the religious orders, of the priests and nuns who live in these closed communities, who’ve been studied for the effects of aging, for I forget how many years, forever and ever, many years. One of the things that’s brought out in the film is that lifestyle and behaviors seem to have an effect on the course of this disorder. For instance, exercise seems to make a difference; diet seems to make a difference; having a social network seems to make a difference. Now that’s very interesting.
DR. HODES: Yes. And so you’ve learned and summarized very well some of the lifestyle associations that have been identified. Just as you’ve said, in large, well-controlled studies that demonstrate association, it’s been shown that individuals who have a history of extensive intellectual activity that is reflected in part but not entirely by formal education, those who have extensive social networks, those who are physically fit and have a high level of physical activity, those who are not obese, are all less likely to develop Alzheimer’s disease, as a risk. Now the challenge, of course, is determining if this is true cause and effect; and if it is, to design interventions that will actually decrease the risk of Alzheimer’s disease. These are not easy studies to carry out since the effects of these lifestyle changes are likely to exert themselves over decades.
DR. HODES: The approach to defining a clinical trial or study that will show unequivocally that one’s identified intervention, which can have an effect, is extremely challenging, but also very important. This is a case in which some of the advances in brain imaging and in identifying biomarkers may prove helpful. That is, there is intent and realistic hope that by identifying the changes in brain structure and function, for example, which can occur years before there are symptoms of Alzheimer’s disease, one may be able to – still hypothetical – track these changes and, in a much more sensitive way, identify interventions that alter the course of disease. And then one could achieve this by following the symptoms of individuals over many years.
LESLEY: Let’s say you have someone who gets Alzheimer’s at the age of 80, which seems to be a common time to get it, how early do you think – once a lot of the studies that you’re working on now are pursued – you might be able to tell someone, “You’re going to get Alzheimer’s, you ought to exercise more”? That kind of thing.
DR. HODES: Well, first it is likely that the information is not going to be all or nothing. That is dichotomous. It’s not going to be that you are going to get Alzheimer’s disease and need to do something and another person will not get Alzheimer’s. It’s more likely to be an ability to say that you have an increased risk of developing Alzheimer’s disease; you might even be able to say it’s so many times greater than others because of these risk factors. And the other point to make –
LESLEY: But how early?
DR. HODES: There are clues to this that suggest if one looks retrospectively at psychological testing for tests of memory change, that at least ten years – and perhaps more – prior to the onset of any signs of Alzheimer’s disease, in retrospect that is, by people who’ve been followed in studies every year for many years, one can find early signs. In terms of how early brain change will predict, well those are the studies that are just happening, because many of these brain imaging techniques are relatively new. And so what is being done now is to study people who are relatively normal or who have very mild memory changes, and to repeat these tests year by year. Some of them will develop Alzheimer’s disease; others will not. And by studying this and the pace of change we should, in a few years, then be able to answer your question more precisely as to how early some of these tests can predict and track the progression of Alzheimer’s disease.
DR. HODES: And the one other point to make is what do we do now, if we’re being so cautious about indicating that we can’t be 100 percent certain that increased social networks, or increased physical activity, or better control of blood pressure, or of blood sugar in diabetics – if we’re not 100 percent sure that these things will prevent Alzheimer’s disease, what do we say for the present? And I think a very reasonable perspective is that since we know with fair degree of scientific rigor that these very same lifestyle changes are helpful in improving a number of other aspects of health and in preventing a number of other diseases, that it ought to be quite straightforward – and is – to recommend that these be undertaken by the population at large. These are not high risk interventions of the sort that might be involved in medication.
DR. HODES: So while we in parallel do the best we can to provide the most rigorous evidence about what does and doesn’t work, there is a lot that people can do to improve the likelihood of their overall good health, their cardiovascular health and perhaps will also be decreasing their risk of Alzheimer’s disease as well.
LESLEY: Great. Thank you so much. So interesting. And this documentary is going to run now for the next couple of weeks, right?
DR. HODES: Yes. And we’re up to 18 supplementary videos online as well. [Click here for HBO's supplementary videos.]
LESLEY: Great. Thank you so very, very much, Dr. Richard Hodes. We appreciate it.
DR. HODES: Thank you very much, again, for your interest.
“The Alzheimer’s Project” is a presentation of HBO Documentary Films and the National Institute on Aging at the National Institutes of Health in association with the Alzheimer’s Association®, Fidelity® Charitable Gift Fund and Geoffrey Beene Gives Back® Alzheimer’s Initiative. The series’ producer is John Hoffman; the executive producers are Sheila Nevins and Maria Shriver.