Summer 1995 Volume 4, Number 3

DR. ALBERT: Our goal here is to try to clarify the changes that are part of normal aging and not cause for concern, and the types of memory problems that really might be indications of some serious problems.

As people get older, many have declines in memory, even if they remain physically healthy. These changes don't occur in all older people; however, about a third to a half of healthy older people do develop some changes in memory. For example, an older person might take longer to learn the directions to a new location, or the story line of a new joke. But if a person does learn these things and learns them well, they are not going to forget them any more rapidly than someone many years younger than themselves.

We've also learned that at least some changes in memory are the result of changes in the brain. We're currently trying to understand what parts of the brain change with age, why they change in some people and not others, and if there is any way that we can prevent these changes from happening, or at least minimize them.

What is very clear is that the memory changes in normal aging are very different from those in Alzheimer's disease, even early in its course. A person with early Alzheimer's disease will not only have trouble learning something new, but, even if they manage to learn it, they will forget it much more rapidly than a normal older person.

That's why, for example, someone with early Alzheimer's disease will almost never be able to learn how to use a new piece of equipment around the house, such as a new microwave oven, or a new CD player, because the information is lost so rapidly. And one finds that these problems become gradually worse, so that they interfere more and more with a patient's daily life.

DR. POTTER: The central problem in Alzheimer's disease is that neurons in the brain die. This decay in an Alzheimer's brain is very clear; you can see it. You can see how fat and sassy a normal brain looks. In the brain of an Alzheimer's victim, the tissue areas are shrunken, and if you could count the cells, which Alzheimer did in 1907, you would find out that they were much fewer than normal.

Something is killing those cells. Accumulations of certain lesions in the brain - little "Brillo pad" aggregates of a protein called amyloid - occur by the thousands in Alzheimer's brains and seem to be associated with the death of neurons. We want to understand how these amyloid deposits, or "plaques," form and why they kill neurons.

The first step is to isolate the plaques and ask what are the components. In 1984, George Glenner found that one major component of the amyloid deposits is a tiny piece of the amyloid protein - the beta protein. Later, we and others found that two other components of these deposits are essential for their formation. Together, these data indicated a biochemical pathway, a series of steps that occur in the Alzheimer's brain and lead ultimately to the neuronal degeneration.

When you kill neurons, you're going to lose memories. You're going to lose your cognitive ability. You're going to change your personality and all the other features of Alzheimer's disease will begin to develop. This pathway occurs only in Alzheimer's disease, and it essentially leads to a catastrophe.

DR. ALBERT: Accurate diagnosis of Alzheimer's disease has historically been a very great problem, because the plaques and tangles - even though we have very powerful imaging tools - can't be seen by the typical kinds of scans that patients take. We have to have some brain tissue on a slide in order to see them. That can only be done either after an autopsy or with a brain biopsy, which is something that we don't typically recommend for most people.

Now, all major medical centers that see a lot of patients with Alzheimer's disease have a standard set of procedures that everyone goes through. We examine patients' medications and medical illnesses to see if any could be responsible for the mental decline. We order standard laboratory tests, including imaging procedures like a CAT scan, to see if illnesses exist that can be the cause of the problem. The patient has a careful neurologic exam, a psychiatric exam, neuropsychological testing, and we take a very careful history to see if the progression of symptoms is characteristic of Alzheimer's.

Using these procedures, major medical centers in the United States have achieved 90 percent accuracy in identifying Alzheimer's disease. But this accuracy only pertains to patients who have developed a considerable amount of mental difficulty. We want to be able to look at very early patients to see if they are going to develop problems.

Researchers are exploring all sorts of possibilities. For example, they're trying to develop a single medical test, perhaps measuring substances in the blood or brain fluid that change in an Alzheimer's patient. They want to know whether, if they see these changes in a questionable patient, it will predict that the patient will then develop the full-blown disease.

We are also looking at the memory problems that Alzheimer's patients have, to see if there is something characteristic about them. Then, perhaps, by extrapolation, see if questionable patients have the same characteristic problems and go on to develop the full-blown disease.

And we are using imaging. Although it can't be used to see plaques and tangles, our work with patients in the mild to moderate stages of Alzheimer's has indicated that certain kinds of measurements on MRI can tell you who has the disease and who doesn't.

The reason for this new emphasis on very early diagnosis is that workers in the field feel that, in the not-too-distant future, there will be effective treatments for Alzheimer's. And we want to be able to to intervene as early as possible with these treatments.

DR. POTTER: If we could prevent, for instance, clippage of the beta protein from its precursor, that might be a therapeutic approach. That's being tried in a number of laboratories. If we could also prevent the formation of the amyloid, keep the beta proteins from sticking to each other, then you could form beta protein and it wouldn't make any difference; you stop the disease at that point.

Other laboratories are trying to prevent the neuronal cell death by testing the beta protein amyloid filaments with neurons growing in culture. These culture cells are very important, because if we can reproduce the steps of Alzheimer's in the laboratory, then we can test potential therapies.

Most recently, mice have been developed that seem to get some characteristics of Alzheimer's disease. Those mice will be very important for testing potential therapeutic agents.

Once we have agents, of course, we have to be able to use them in patients just as early as possible, before too much neurodegeneration has occurred. Then the therapies would be more effective.

DR. POTTER: Apolipoprotein E (ApoE) and another protein called ACT are essential components of the amyloid deposits. They seem to help the beta protein form filaments. The beta protein will do it by itself, but much slower than if you add these other proteins.

In the Alzheimer's brain, for reasons we don't understand yet, an inflammation occurs and (apolipoprotein E and ACT) proteins are over-expressed. When they're over-expressed, they stick to the beta protein and help it form amyloid filaments. The risk factor in some patients who have ApoE4, a special kind of ApoE, is that the ApoE4 protein is a better promoter of amyloid formation than any other protein known. These patients get Alzheimer's disease more easily than the general population.

Q: Are there any studies that have been done on food, or components of food that influence that at all?

DR. ALBERT: Actually, some recent data suggest that vitamin E or vitamin C might retard the development of Alzheimer's disease. These data come from community studies in Boston and Iowa, and they are very suggestive. They are early, but on the basis of that, a number of people are planning to try to give large numbers of people these vitamins, to see if it reduces the development of Alzheimer's disease.

Q: Could you comment on the eye test?

DR. POTTER: The eye test is a curious phenomenon that we found in the literature on Down's Syndrome and then tried in Alzheimer's patients. A very common drug, totally harmless, dilates the pupils in the eye. Down's patients are hypersensitive to it, and every single Down's syndrome patient gets Alzheimer's disease.

When we tried the same drug in Alzheimer's patients, they also were hypersensitive to it. It's a scientific discovery, but it's not a test. It will be several years before it can be tested again, reproduced, extended and refined - before we can call it a test.