Part 5 of our 5-part series "Desperate for a Cure: The Search for New Alzheimer's Treatments."
BOSTON -- One of the longest and most anticipated Alzheimer drug studies in history is about to begin, and Dr. Reisa Sperling is wondering if people will come. It's called the A4 study, and Sperling is the project leader.
"I sometimes get very worried," she said, "who will we find that wants to come into a 3-year trial on the chance that they might develop Alzheimer's disease dementia?
"It's a very large study, so we're looking for 1000 individuals who meet the criteria to come into the study, that is, people who have amyloid building up in their brain, but don't have any clear symptoms of Alzheimer's disease."
The full name is a mouthful, but it says a lot: It's the "Anti-Amyloid Treatment in A-Symptomatic Alzheimer's Disease Study." They're going to treat people with an experimental drug - one designed to cut down on a protein called AmyloidBeta, which forms sticky plaques in the brains of Alzheimer's patients. The people they're going to give the drug to don't have any noticeable symptoms of the disease. In fact some of them would likely never even develop it.
"So to find those 1,000 individuals to come into the A4 study," Sperling said, "we anticipate that we'll have to screen about 5000 individuals at 60 sites around the United States and Canada, and we're also talking to Australia about a central site there."
The trial will cost well more than $100 million, and the first candidates should start coming in for screenings by year's end. Volunteers don't need to have a history of Alzheimer's in the family or even concerns about their memory. But it's okay if they do. They must be 65 or older; willing to take the drug or a placebo; willing to get a genetics test, and to have their brains scanned once or twice a year. They also must be open to answering all sorts of questions about how they live their lives.
"The important things are, these are people who are normal who can make their own decision about whether they want to contribute or not," Sperling said. "But I think it is time that we must begin these trials. And it seems to me unethical to not begin them when we have a generation facing Alzheimer's disease."
Across the Alzheimer's field, researchers are paying close to the A4 study as a test of the increasingly-popular hypothesis that the way to stop Alzheimer's is to put it off. Delay it, slow it down to prevent it. The drug used in A4 works by binding to amyloid of a certain size and clearing it out of the body before it turns toxic. The medicine was tested before, and while safe, it didn't really help people in later stages of the disease. But for people with mild symptoms, the disease seemed to slow down.
"We ended up choosing it even though it showed only minor lowering of Amyloid plaques. It was the only one that had a clinical signal," Sperling said. "So although the overall study was negative, when they looked at the mild patients, those who had the mildest dementia, those subset of patients benefited in both of the phase 3 trial."
In Alzheimer's disease, the AmyloidBeta protein builds up. It turns toxic, and little pieces start killing brain cells and forming sticky plaques. Then another protein called Tau stops operating the way it should, folding into what are called tangles inside the cells. The idea is to prevent the disease by cutting back on the bad AmyloidBeta in the body with the drug.
"I have to admit," Sperling said, "that sometimes I feel a little bit guilty, because I am a clinician and a neurologist. I take care of people who are already suffering from alzheimer's dementia, and it really breaks my heart to say to them, I don't have something to offer them. And that the best time for treatment would have been 5 years or 10 years earlier. So I don't want to abandon the idea that we will look for successful treatments for people who already have dementia. And I think combination therapy will be very helpful."
By combination therapy, Sperling's talking about something like a cocktail of drugs, similar to how HIV is treated. And at Mount Sinai Hospital in New York City, Dr. Samuel Gandy is working on a drug that could be part of the Alzheimer's cocktail.
"We think," Gandy said, "we might need a drug to prevent amyloid buildup or help amyloid break down; to reduce the buildup of tangles, or to help tangles break down - 'and/or' drugs like this one that will generate new nerve cells in critical parts of the brain like the hippocampus."
Gandy's team started working with this compound because it controls how nerve cells release amyloid when they're communicating. They tested the medicine in animals and found it reduced amyloid. Then he discovered a pharmaceutical company in California also was working with the compound.
"They were interested in it not because of amyloid, but because it stimulated the birth of new nerve cells in the hippocampus," he said. "So we did the experiment again and looked not only at the amyloid levels, but this time looked at the birth of nerve cells in the hippocampus. And there was enormously robust birth of new nerve cells in the mice with the Alzheimer's gene that had gotten this drug."
Gandy still has safety work to do before the drug can be tested in humans -- something he hopes can happen next year. Meanwhile, his lab is studying stem cells. There's also genetic work, because some genes increase risk, while others protect us from the disease. Gandy references one particular group of people in Iceland.
"They have a genetic mutation in the amyloid that causes them to have, from the moment of conception, only half as much amyloid as the rest of us," he said. "And they never ever get Alz disease, even if they have other high risk genes. That's sufficient to protect them. Now we have mutations in the amyloid gene that either causes the disease or protects the disease, so it seems all the more important to focus on that molecule."
Sperling's A4 project will do more than test the hypothesis that anti-amyloid is the key to stopping or delaying the disease. Thanks to the regular brain scans and surveys, researchers will watch the disease develop in some brains and not in others. It's a good opportunity to pick up on new hints of when the disease is present. New biomarkers. And perhaps the volunteers could be followed beyond the 3 years, giving researchers more data as they search for the drugs to delay Alzheimer's, prevent it, and also to cure it.
Note: To learn more about volunteering for the A4 drug trial, contact the Center for Alzheimer's Research and Treatment at Brigham and Women's Hospital in Boston.