Dennis J. Selkoe, MD
Alzheimer's disease is a very complex disorder of the most human aspect of biology, of the thinking part of the brain. Patients lose their memory and other aspects of cognitive function gradually, over the course of five, ten, fifteen or twenty years. We've been asking why that is. What causes people to lose memory? It seems to be due to the buildup of a protein in the brain referred to as the amyloid protein or amyloid beta protein.
Many years before a person becomes forgetful, before she forgets where she parked her car or the names of some of her grandchildren, she will build up plaques in the brain composed of this amyloid protein. They're round plaques that can only be seen microscopically. Shortly after that buildup, tangles also will build up in the brain, made up of a different protein that has the Greek letter tau. The plaques and tangles together mount up over time, over decades we think, and lead to short circuiting of nerve cells. In essence, Alzheimer's is a failure of the systems in the brain that allow one nerve cell to communicate information to the next.
In 1992, my colleagues and I here at Brigham Women's Hospital discovered something very surprising - that this amyloid beta protein, that we think causes Alzheimer's disease, is made by everyone throughout life. This was a surprise when we had only seen this protein by isolating the amyloid plaques from people who had died of Alzheimer's disease.
Why doesn't everyone get Alzheimer's disease? We figured out, in the subsequent years after our 1992 discovery, that there are certain genetic risk factors and environmental factors that make people handle the amyloid protein poorly. Those are the folks who then get amyloid buildup and eventually get Alzheimer's disease.
Over the years we’ve been pushing ahead to understand enough about the starting point of Alzheimer’s disease to try to imagine treatments. I have written a lot of both scientific data and opinion articles, about why companies should focus on amyloid protein. And now, a number of them have.
Recently, there was what I would consider a true breakthrough in a therapeutic trial. Biogen has an antibody that they created in their laboratories that binds to and neutralizes the amyloid protein. They showed that the number of amyloid plaques in the patient's brain went down dramatically, particularly in the highest dose of their antibody, after just a year. Indeed, even after six months there was a lowering. This was something we never really expected in Alzheimer’s. Then, they coupled that lowering in amyloid plaques, which they could image with a PET scan, to a stabilization of memory. So people did not continue to decline and they were about where they were at the beginning of the 12 month trial.
And I should say that the antibody that Biogen is using in their trials is not the only one. The theory we put forward has led many companies to try to find anti-amyloid agents and there are other antibodies from other companies. It's a wonderful worldwide race, which is just what our patients would want.
We have evidence from the trial that Biogen did, or a trial that Eli Lilly did, or that Merck is doing now, that they are moving the needle. They are slowing down the amyloid buildup. They're even clearing the amyloid to some extent from the patient's brain and that's associated with cognitive stability.
The A4 trial was developed by my close colleague and friend, Dr. Reisa Sperling, here at Brigham and Women’s Hospital, and it involves many physicians and scientists around the world.
A4 stands for Anti-Amyloid in Asymptomatic Alzheimer’s. We usually don’t think of Alzheimer’s as being asymptomatic. We think of it as being very symptomatic - you can’t remember things, you get confused about your grandchildren. But here we’re asking people to enroll in the trial that are okay now, they might have a family history of Alzheimer’s or they certainly will have an abnormal PET scan or spinal fluid exam. If we enroll them, they’ll get a drug that we think will make it less likely they’ll go to the symptomatic phase of Alzheimer’s disease, they’ll stay asymptomatic, i.e. before symptoms.
We can't say that physical and mental exercise completely take away the amyloid protein or they dramatically lower its production in the brain. We can't say that. But it looks like physical and mental exercise beef up your brain in some ways, just like they would help your muscles, and give you better reserve in your brain. So if the Alzheimer process starts, you have more of what we call cognitive reserve. And that's why we think that people with more complicated professions, with higher levels of educational attainment, have less Alzheimer's than others.
The question I'm always asked is when is this treatment arriving? We can't get it soon enough. We have loved ones, we have relatives that have this. The answer is - in a few years; so not a decade and probably not half a decade, because the clinical trials are going very well.
In the meantime, people who are concerned about Alzheimer's or have it in their family can volunteer patients to come to our trials. We will assess them, diagnose them and see if they are eligible. And so, since there are no drugs that we can just write a prescription for today, the way to get at possible disease modifying treatments for Alzheimer's is to come into a trial. We think that's terribly important. Here at Brigham Women's Hospital and many other medical centers around the country, we're encouraging families and patients to come forward and volunteer for trials.
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