What exactly does this vaccine do?

Although we don’t know quite what causes Alzheimer’s disease, we do know that affected individuals end up with abnormal plaque lesions in their brain tissue. It turns out, and this was discovered in the ’80s, that the lesions are made up of something called beta-amyloid. This vaccine is a synthetic form of beta-amyloid that is mixed with an immune booster and shot into the arm. The idea is to stimulate the patient’s immune system to target the plaques in order to reduce and remove them. This is a very simplistic version of what happens.

How does the vaccine get rid of the plaques?

Beta-amyloid is a tiny protein fragment. Imagine that you have a lot of these that stick together like glue to form plaque…. When we create a vaccine with the synthetic form of beta-amyloid, the body makes antibodies to beta-amyloid which start circulating in the blood. A few of them make their way into the brain, where they physically bind to the plaque and act as flags for scavenger cells in the brain to digest plaque material and to clean it up.

Is beta-amyloid part of a healthy brain?

No. There are tiny soluble levels of it in us all the time, but it’s kind of like cholesterol. It’s okay if it’s floating around, but the moment it starts sticking to itself and forming insoluble aggregates, it’s bad news. The little bit that is there normally gets washed away. We think it’s a by-product of protein metabolism.

In cases where the plaque accumulates, do you know why the brain malfunctions?

There are ideas about it, and I could go into them at great length. But the bottom line is we don’t know. It’s genetic in part. If you have certain genes, you have a greater likelihood of getting Alzheimer’s disease and a greater likelihood of getting these plaques. And there are few very rare genes, where, if you have the defective gene, you will always get the disease. But they are very, very rare. In fact, we use these defective genes in mice. That’s where we discovered the vaccine was effective.

What did you find from testing mice?

For a few months after the mice are born, their brains are absolutely normal. But as they age, they get more and more lesions, so by the time they are one to two years old, their brain tissue looks very similar to what Alzheimer’s patients’ brain tissue looks like. We did two experiments with mice. In the first, we gave mice with defective genes the vaccine at six weeks of age, when they had no lesions, and continued giving it until they were a little over a year old, an age when their brains should have had a lot of lesions. It turned out–and this was the study we published in 1999 in the journal Nature–that when their brain tissue was examined, there were essentially no plaques. It was such an astounding result we thought that something must be wrong. It was truly remarkable. Of course, as astounded as we were, we made sure the results were real. Then we worked on a more difficult experiment. In this one, we didn’t start the immunization process until the animals were already one year old and went until they were about 18 months old.

They already had the lesions.

Yes. Between 12 and 18 months the number of plaques goes way up, it’s almost exponential. So we decided to see if the immunization could change the course of this process. The long and the short of it is that it radically changed the course. It prevented all accumulation or further increase in plaques; in fact, it reversed the numbers somewhat. It didn’t bring the numbers of plaques down to nothing, but it clearly reduced them. We’ve done more elegant studies recently where you can literally see the existing plaques go away as a result of the immunization or the antibody treatment.

Did you see any side effects in mice?

No. We wouldn’t be in clinical trials if we saw any problems. We looked extremely thoroughly and saw nothing. In fact we even looked inside the neurons to see if they were healthy. We found no evidence of toxicity. We also looked at other animals and didn’t find any evidence of toxicity.

What about potential side effects in people?

The thing that most scientists in the field said was, “What about an autoimmune response, because this is a fragment of a normal protein?” The bottom line is that we’ve never seen any evidence of it and we’ve looked extremely hard. There probably won’t be [an autoimmune response] and there are valid scientific arguments for that.

How did the vaccinated mice do as far as memory was concerned?

They did quite well in performance and cognitive tests.

Can you describe some of the tests?

Imagine there are spokes–or arms–going out from a swimming pool and the mouse can swim in one of six directions. Only one arm has a platform. The mouse doesn’t know where the platform is, but if it gets there, it can rest. If you plop a normal mouse in the pool, it will make fewer and fewer errors over time until it will eventually swim straight to the platform. A mouse that has the defective human genes in it, if it gets the pathology, never learns to find the platform. It doesn’t remember. If a mouse with the defective human gene is immunized, it performs very similarly to normal mice. [Still], it’s not quite the same as humans losing their keys and forgetting how to balance their checkbooks.

What clinical trials have been done so far in people?

Safety trials are always the first step. Usually there are a small number of patients because you don’t want to unnessessarily put people at risk. We’ve done two. In the United States, about 24 patients with mild to moderate Alzheimer’s disease were injected with a single dose of synthetic beta-amyloid…. It was a very conservative study, and it was found to be well-tolerated and safe. In the United Kingdom, we gave multiple doses to the same 75 or 80 people over time. We wanted to find out if the vaccine was safe and if it was generating an immune response. It was obviously very key to know whether or not the exact formulation we had chosen was effective. At any rate, it was safe and well-tolerated, which was good news, and it also generated an immune response in some patients.

So you found no ill effects?

Essentially. I can’t say there was no small reaction in somebody’s arm…

What do you hope to learn from phase II of these trials?

We’re going to test about 375 patients, in both the United States and Europe. It will be a two-year study. We want to see if the immunotherapy changes the course of decline these people usually endure. The main thing we’ll ask is, “Are the patients doing better cognitively as a result of the immunotherapy than they would have otherwise?”

If it does work, do you think the vaccine would be a one-shot deal?

We don’t know. It’s probably going to be multiple immunizations to elicit the kind of immune response we want to get. That’s going to be one of the questions we are going to examine.

You’ve said that when you gave the vaccine to the younger mice who hadn’t yet developed symptoms of disease, the disease never developed at all. Do you think that in the future we might get vaccinated for Alzheimer’s disease before we even have symptoms of the disease?

I think it’s conceivable. I think time will tell, and we’ll need clinical experience. It might be something in between, where we give it to individuals who have mild cognitive impairment–people who don’t have Alzheimer’s disease, but have memory complaints and cognitive complaints. That would be, I think, the group that is targeted next. Because a certain percentage of that group will go on to get Alzheimer’s disease.

Having developed the vaccine, what do you make of all this?

It’s exciting. Many of us who have worked on this for a number of years believe that beta-amyloid is the cause of Alzheimer’s disease. Well, if it is, then treating it this way should help. This is the first thing to be taken this far. And we’ve been working in this area for a decade. [If it works], it would be wonderful, primarily for the patients.

How has the idea of a vaccine been met within the scientific community?

Nature is probably one of the more highly regarded journals, and it was very well received there. You know, it’s such an odd thing. No one I know of has ever used an immunization procedure to treat any sort of CNS [central nervous system] disease, at least not purposefully.

Do you think it may start a trend, where people will look for vaccines for other CNS diseases?

I certainly hope so. I hope it will open up new avenues.

What other kinds of CNS diseases?

The most direct analogy, interestingly, would be Mad Cow disease, because it’s also an extra-cellular aggregate with an aggregating protein that occurs in the brain. There are a number of [CNS diseases] like this. There are some that have an aggregating protein within the brain but it’s inside of a neuron. In this case and in the case of Mad Cow disease, the proteins aggregate outside and in between the neurons. In Mad Cow disease, the protein starts out inside and ends up outside. So something like this might help to clean it up. At the scientific level, of course, there is a long discussion about all of this.

What are some of the plusses and minuses of this vaccine?

I don’t know of any particular minuses. The unknown here is that if you remove amyloid out of the brain and it becomes a healthier brain, how many of the neurons are going to come back and function normally? I think the ones that have died will not be able to. It’s my hope that the ones that are sick will be able to come back. So you can’t necessarily undo the damage. It’s a bit like stroke patients, sometimes they recover dramatically and sometimes don’t recover at all. I don’t know which this will be, or if it will be variable. Some work suggests there are stem cells in the brain, or progenitor cells, which might replace lost neurons. If [the vaccine] works, we enter a brave new world of neuroscience, and we’ll find some interesting questions.