LOU-ELLEN BARKAN (LEB): I am especially curious about the early onset form of the disease, the genetic form. I have heard people say that in these families if the family members lived long enough, you will find the disease if you go back far enough into the family history. In our family, we have one person who developed the disease when he was 48 and died at 54. But previously on this side of the family there had never been Alzheimer’s disease. Is this an example of a mutation? Are there two different kinds of early onset Alzheimer’s?

RICHARD MAYEUX (RM): There are two forms of genetic Alzheimer’s disease; Mendelian, after Gregor Mendel, which is inherited, forms a pattern and is dominant. This means that in every generation there’s at least one person who carries the disease. It can be passed on by either the mother or the father. A child born to an affected parent has a 50/50 chance of having the disease. This is rare, but the mutation alters the protein dramatically. If you have the mutation, almost invariably you get the disease.

The other type of genetic Alzheimer’s disease is characterized by ApoE4, a normally occurring variant of the gene. We are not entirely clear on how having an E4 increases risk, but there are theories. Weisgraber, from the Gladstone Institute, suggested that E4 may affect the processing of amyloid beta in a very subtle way, much like the way SORL1 affects the processing.

Inheritance of E4 is just like inheritance of any other variant and you may not always get the disease. It is just a genetic risk factor. Like any other risk factor, it’s not completely distributed in the population. About 25 percent of the population has E4, but they are overrepresented in people with Alzheimer’s.

However, if you look at the total population of people with Alzheimer’s disease, there are more E3s than E4s, because E4 is not as common. This means that there may be other genes that are important.

The late onset form is not inherited in a Mendelian pattern. Perhaps whatever genes are there are just not penetrant, so that you inherit the gene but you don’t inherit the disease. Perhaps, it just affects risk in some other fashion. Perhaps it takes several genes to trigger the disease or it takes a gene and a risk factor. These are the kinds of things that we need to know because they complicate discovery.

Think about it this way: if 25% of the population has an E4 and I want to look at the effect of having an E4 and head injury. Well, the lifetime risk of having a head injury is about 10%. If I want to look at people who have both E4 and a head injury, it is 10% times 25% or 2.5%. In other words, whatever the size of that population, only 2.5 percent are likely to get the disease. To study this, I need a large sample.

LEB: As you know, we believe that in less than fifty years, one out of every five New Yorkers will either have Alzheimer’s disease or be taking care of someone who does. How do you keep your optimism in the face of all this?

RM: I was talking with a colleague and we asked each other what we would do if the vaccine worked and cured Alzheimer’s disease? We agreed that we could find something else to do. And we both said,“Wouldn’t it be nice not to have this problem to deal with? We could have plenty of other problems to work on.”

I still see patients, so I get a lot of satisfaction out of helping people figure out what their problem is and working through it. Sometimes, a husband comes in and says, “I don’t want to tell my wife that she has Alzheimer’s.” It is satisfying to help the couple work through this. In rare situations where the person does not have Alzheimer’s disease, we can make them very happy. But, most of time, its helping them adjust to a difficult situation. I form long attachments to certain families, because I get to know the whole family. That’s the good thing about being a neurologist as opposed to a psychiatrist. Everybody likes us.

The field has changed. Years ago, we only had hydergine, which did nothing. Now, some of the current drugs are somewhat helpful. And we can help people maintain a good quality of life by telling them to live their life and not hide in a corner.

LEB: It sounds like you’re trying to treat other people the way you would want somebody to treat someone in your family.

RM: We are all at risk for this disease by virtue of the fact that we are living longer. As Clint Eastwood said,“We’ve all got it coming.”

JED LEVINE (JL): I heard at our recent public policy forum that there is more optimism about a disease modifying drug. What are your thoughts about that?

RM: I think that the animal work on the antiaggregates and the vaccine is impressive. I suspect one of them will come through — and this is only the first generation of these therapies, so they will improve. There is already improvement on the original vaccine.

However, I also think that the therapies that stop the disease progression are not going to be very affective in improving memory. Some of the drugs that we are using for memory might actually work better if we could stop the biological progression of the disease.

There is some weak evidence suggesting that current treatments slow the progression somewhat, but it is hard to measure change in progression because you measure it in terms of cognitive performance. And while we know that cognitive performance declines, the way those studies have been done is to compare people on treatment versus off treatment. Of course, these are mostly observational studies, so you don’t know why people aren’t on treatment. They may have a slightly different disease, or lack funds or have some variable that we can’t measure.

I suspect that we’re looking at multiple drugs; a combination of drugs that stop the biological process, plus a drug for symptomatic treatment. But think of it this way. In your 50’s, you get your cholesterol checked, have a colonoscopy and in my example, you’ll also get your amyloid checked and have a “gene screen” for Alzheimer’s disease. If you are told, “I’m sorry to tell you, but it looks like you’re carrying one of these genetic markers. However, there are some preventive things we can do. Do you want to do them now?”

Instead, maybe they say, “Gee, you don’t really have to worry about Alzheimer’s disease. What you really have to worry about is colon cancer. You’d better work on that.” Or they might tell you,“You are also carrying five of the six genes involved in Alzheimer’s disease. You should see a neurologist and go on one of these more aggressive therapies now.” Right now, we think this is a 1,000 piece jigsaw puzzle and we are putting together big patches of the puzzle. Of course, it might be a 5,000 piece puzzle. We don’t know yet

LEB: You know, three years ago I asked one of your colleagues in another institution how long it would be until we had a cure or a treatment with real efficacy. He said, “One hundred years.” Now this same scientist tells me that we will have something within five to ten years. A very different story.

RM: What we need are a few successes and a little excitement in the field to get everyone to ramp up a little. But we are all facing the NIH crunch, which puts a damper on things.

JL: If we want to keep the research momentum going, that is a big issue. It is paradoxical; as more people are at risk for dementia and Alzheimer’s disease, federal funding for Alzheimer’s research is decreasing.

RM: Every minute and a half a new person develops Alzheimer’s. How can these people in Washington not be devastated by that? And that’s just Alzheimer’s disease. Think of all the other health problems.

LEB: Richard, what do you think reduces the risk of Alzheimer’s? Getting enough sleep? Keeping active? Crossword puzzles? Almonds? Blueberries?

RM: Almonds are good. I’m a big almond fan.

LEB: I have exercised almost every day my whole life. Now I tell myself I also need to eat lots of almonds and blueberries. To date, I am not demented. But when people ask me about exercise, certain foods, crossword puzzles, I have to say we really don’t know. We think it’s better to exercise and eat blueberries than watch TV and eat ice cream. Is there any scientific evidence to support this?

RM: In some recent studies in mice, they showed that when the mice exercised, it stimulated the neuro-progenitor cells in the ventricular lining and the mice performed better. This suggests that there is some real benefits to exercise.

There were also one or two clinical studies that looked at healthy people who exercised and showed that they performed better. Of course the caveat in all these observational studies is that you don’t know if people are exercising because they’re healthy or they’re healthy because they’re exercising.

JL: I did read a story about hippocampal growth and it’s relationship to exercise. I always try to explain that while we can only control some things, we should make the effort to control these; things like lifestyle issues including smoking. And there are some factors over which we have no control.

RM: Smoking, obesity and insulin resistance, in both diabetics and non-diabetics are connected to higher risk of Alzheimer’s disease. In fact, we don’t really understand it yet, but the best bio marker we may have right now is rising insulin.We’re trying to figure that out.

JL: So people who are diabetic have twice the normal risk?

RM: At least double the risk and insulin resistance increases with age, even in non-diabetics. You can measure it by just looking at free insulin. We are trying to understand if insulin resistance causes these changes in white matter in the brain, which then predisposes you to Alzheimer’s disease or is this an independent mechanism? We don’t know. But you can affect insulin resistance.

JL: What about homocystine level?

RM: That is very controversial. There is one big study in The New England Journal of Medicine which suggests a twofold increase in risk which does go up with age. But the study was not age adjusted and subsequent studies are not so clear-cut.

JL: So we don’t have to take folic acid?

RM: Well, it probably doesn’t hurt. It’ll reduce your cardiovascular risk. It’s not good to have a stroke. It’s not good to have cerebral vascular disease.

Now several groups are trying to figure out how to interpret changes in the white matter that occur as part of aging and its significance for stroke. And there are three things to be known. First,we learned from one cardiovascular health study that about a third of normal, healthy people over the age of 70 have silent cerebral vascular disease. What is really dramatic in the Washington Heights data, is that 6% of those people have big strokes without any history of ever having cerebral vascular disease. We know that cerebral vascular disease predisposes you to Alzheimer’s disease and most of these people had a mixed-picture postmortem with a history of diabetes, hypertension and hypercholesterolemia in earlier life. So you start to see how your brain picks up changes over time.

LEB: I know you have a family member with Alzheimer’s disease. Can we talk a little about that?

RM: Well, it was a surprise. After I made the diagnosis in more than one family member,we took DNA samples. There is not a large enough sample to make sense of it now, but at some point it may be useful for genetic studies. The disease has had the same emotional impact on my father and other relatives as I see in my patients. I’ve had other people treating my relative. The personal experience was a reality test for me.

LEB: That is when it hits home.

RM: I remember one of my relatives saying, “I just can’t believe that this is happening. She was so outgoing, she was always the life of the party.”And what can I say? This is exactly what I hear from my patients and I have to help them work through it.

LEB: I know our readers would want to know more about you. How do you spend your time? How do you keep yourself going? What do you do with your personal time? Do you garden? Exercise? Eat blueberries?

RM: All of the above… and the good news is that having developed a team with all these good young people, if I walk away tomorrow I don’t worry. There are many people who can step in and take over and run the place very, very effectively. I have two young children and a wonderful wife, and I spend a lot of time with my kids, who are soccer players. I was an athlete in high school and college. In the summer, my wife and I go off to the Adirondacks and cycle on special bikes. We also enjoy the city, particularly the opera. We try to take advantage of everything in the city. But this is what I chose to do for with my life, so I don’t get fatigued, or let it get to me.

I do want to add that we really need better partnerships with foundations. It is really troubling that these are the best of times and the worst of times. The best of times in that we’re making amazing progress, but I’m very concerned about the loss of funds to support young, intelligent investigators who will be attracted to other fields where it may be easier to make a living. I’m very concerned that we’ll lose all the momentum that we’ve worked so hard to achieve if we don’t support these young scientists who come into the field with great optimism and new ideas.

For example, I had one young faculty member who wanted to do some elaborate things with MRIs in mice. And I said, “Nobody’s ever done that. It’s impossible.” When he asked if he could try, I agreed. And, you know what? He has done it. We will lose these creative young people with their enthusiasm and the feeling they have that they can accomplish anything and everything.

LEB: I have been saying for some time now that today, the person who is likely to cure this Alzheimer’s disease is a junior in high school. We must incent the next generation to get interested in this field. The brain, the last frontier, is such an exciting place to do research. But my fear is the same as yours. If we can’t find the funds, the young scientists will go elsewhere. Young doctors and scientists need to pay their bills too and they need lots of education to achieve our goals.

RM: It will have to be a public-private partnership and we have to engage the community. NIH can’t do it alone. The Alzheimer’s Association can’t do it alone. The scientists can’t do it alone. Everybody has to work together. I think the scientists are finally getting the message.

LEB: Richard, thank you so much for taking time to talk with us. Like Jed and me, I know our readers will really appreciate this personal opportunity to learn more about you and your work.

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