Vol. 2, Special Issue
| Marilyn S. Albert, Ph.D. |
Huntington Potter, Ph.D. |
The wonder of the brain is that if any of these events are of particular interest to you, you may remember them for months, or years or even for the rest of your life. But if an Alzheimer's patient is among us, who is even in the early stages of the disease and even if he or she thinks that the events are very important, it's very unlikely that they will remember for more than a few hours and certainly not more than a few days.
As the disease progresses, the span over which Alzheimer's patients can remember things gradually shrinks--from days and hours to minutes, then to seconds and then to nothing. Unfortunately, this is not only a devastating disease but an extremely common one. We estimate that it affects six million people in the U.S. alone and costs 100 billion dollars a year.
But, for the first time there is really hope. In fact I think the progress in Alzheimer's disease over the last 20 years is a model of the enormous advances that can be made when large numbers of neuroscientists work together on a common problem.
Alzheimer first described the disease in 1906. He had a patient who was young, who had a progressive dementia and declines in memory, languages and other mental abilities. When this patient died, Alzheimer looked at the brain tissue, using a new silver stain that had just been developed, and for the first time described the abnormalities in the cells that we have come to call plaques and tangles. We now use these as the hallmark of the disease.
For 70 years it was thought that Alzheimer's disease only affected people over the age of 65. This is important for you to know, because in that age range it is an extremely rare disorder. However, in the early 1970's, investigators began to realize that the changes they saw in the brains of young patients who had died with a progressive dementia were exactly the same as those that they found in older people who had a progressive decline in mental abilities. When they realized this, it made Alzheimer's disease the fourth leading cause of death among adults.
We are now much better at diagnosing the illness. A definite diagnosis still requires an examination of brain tissue, and, since we don't recommend brain biopsies for most people, we are limited to clinical diagnosis. The accuracy of diagnosis of the clinician compared to the autopsy in now 85 to 95 percent, but it is still extremely tricky. It still takes a great deal of knowledge about the early symptoms and course of the disease to make an accurate diagnosis. We have learned that the major hallmark is the memory disorder-a dramatic loss of information. The rate of forgetting in Alzheimer's disease turns out to be greater than in any other dementia we have examined.
After the memory problem begins to develop, one typically sees problems in handling abstract ideas and complex tasks. Then they begin having trouble with talking, dressing, eating, and finally they require total care. The ability to identify this pattern early in the disease is what has led to improved diagnosis.
Many researchers are looking for a simple test for Alzheimer's. It is important because we are beginning to make progress in treatment. And when we have effective treatment, we want to intervene before a considerable amount of brain damage has occurred.
But we are a long way from preventing the progression of the disease that I described. Dr. Potter is now going to describe to you the changes in the brain responsible for those dramatic changes in behavior.
DR. POTTER: Thank you, Marilyn. Alzheimer's is indeed a disease of the brain; nerve cells in the brain die. If you look at an Alzheimer's brain, you can even see the results of this yourself. In a normal brain, the tissue areas are fat and healthy-looking; the spaces between are fairly small. In contrast, in an Alzheimer's brain, the tissue areas are contracted and the spaces in between have gotten bigger. Essentially, a large number of nerve cells have died.
You can think of nerve cells as traffic lights controlling communication in the brain. If a single traffic light in Boston went out, nothing much would happen. But, if ten, twenty, or thirty percent all went out at once, there would be gridlock and complete chaos. Boston can't afford to go without traffic lights anymore than you can afford to go without your neurons.
If you looked at a piece of this brain, a small section of it, you could actually count the neurons. You would find that there are actually many fewer than there should be. You would also see curious structures in this Alzheimer brain: neuritic plaques. These are totally abnormal and absolutely unique to Alzheimer's disease. Scientists looking at these plaques came to a hypothesis that perhaps they caused the cell death that led to the devastation. That has turned out to be largely true.
The first step in the analysis of neuritic plaques was to try to understand exactly what the components of these deposits are. We have identified three important such components. One is a small protein called the beta amyloid protein, which you may have read about in the newspaper. In addition, we and others have discovered two other proteins. One is called A-C-T or ACT and the other, apolipoprotein E. These associated proteins are important for the formation of the amyloid deposits.
The reason for identifying these proteins is to get an idea of what is going
wrong in Alzheimer's disease. This slide (right) shows a summary of our
current state of knowledge. Nobody could have put this slide up on this podium
five years ago; everything on this slide is new.
The beta protein, the major component of the amyloid, turns out to be a very small fragment of a large protein that sits on the surface of many cells all over the body, including neurons. This is true of normal patients and Alzheimer's patients. Also normal is the cleavage of this small fragment out of the larger protein. What is abnormal is that, in Alzheimer's, these fragments link up to make long filaments in the brain. When these filaments aggregate together, they form what we call the amyloid plaques that are characteristic of the disease.
So essentially, the beta protein and two associated proteins are created normally, but for some reason in the Alzheimer's brain are present in the wrong place at the wrong time and perhaps in the wrong amounts. They aggregate and form amyloid plaques, and in a way we don't yet understand, kill neurons.
Marilyn, can we design a therapy based on this new knowledge?
DR. ALBERT: Well, one of the first approaches was aimed at the dying cells. The first drugs were designed to increase the amount of acetylcholine in the brain. A few weeks ago the FDA approved the first drug, called tacrine, which works in this way. Unfortunately, this drug is really only marginally effective. So, people are looking at other ways of preventing the cell death--for instance, substances that help in the repair of cells.
Obviously, it would be better if we could intervene in the production of amyloid. That's the area that people are working on now most aggressively, trying to develop drugs.
Of course, when we have a reasonable treatment we are going to need to have a really accurate way of diagnosing people early in the course of the disease.
DR. POTTER: You remember that acetylcholine is an important neurotransmitter, and that acetylcholine is decreased in its efficacy and amounts in Alzheimer's patients?
Two facts gave us an idea about how to use this information to develop a diagnostic for Alzheimer's. It turns out that Alzheimer's patients lose their neurons and develop plaques and tangles in a very similar way to Down's syndrome patients; that is, all Down's syndrome patients get Alzheimer's. It also turns out that Down's patients have a defect in their acetylcholine neurotransmission system.
This is not well appreciated, but that defect can be detected with a simple eye test. A physician or scientist can place a drug that inhibits acetylcholine into the eye of a Down's patient, just like your ophthalmologist would, and the pupils will dilate more than those of a normal patient. We thought maybe this would be true of Alzheimer's patients and we approached our colleagues at the Beth Israel Hospital. The data so far are very encouraging, but they are still preliminary and we have a lot more work to do.
DR. ALBERT: We are going to take some questions from the press.
MS. TOUFEXIS: What makes some people vulnerable and others not; is it genetic, an environmental insult or what?
DR. ALBERT: The first risk is, unfortunately, aging. You are at greater risk of getting the disease the older you are. There is in fact a geometric increase in the prevalence of the disease as you get older.
MS. TOUFEXIS: But not everyone who ages gets Alzheimer's disease.
DR. ALBERT: That's true. We know now that there is clearly a genetic risk. At least three chromosomes have had markers identified on them. One on chromosome 19 appears to be related to risk for the more common form of Alzheimer's, which occurs in the elderly. Now people are trying to find out how much of that risk is totally related to genetics, or to the impact of environment and the interaction of environment and genetics.
MR. RAEBURN: Where are you on that eye test, and what are the next steps before you can expand the test?
DR. POTTER: With any diagnostic test, you have to be very careful to be sure you don't get any false positives--normal people who would test positive and therefore be worried they might have Alzheimer's disease. At the moment, we have too few patients tested and too few controls tested to be absolutely sure that we aren't going to run into another neurological problem that would give the same result.
MR. RAEBURN: Are false negatives a problem too?
DR. POTTER: That is also possible, although one very interesting thing about Alzheimer's is that it is surprisingly uniform in its characteristics. Even though there are at least three genetic mutations and perhaps some sporadic causes of the disease, their clinical and biochemical characteristics are identical. That suggests that the same problem is going on, and all patients are going to show the same kind of sensitivity to this eye test. So, I would suspect that false negatives will not be a problem. *