Part One of our 5-part series "Desperate for a Cure: The Search for New Alzheimer's Treatments."
Harvard-Mass General researcher Dr. Rob Moir has a hypothesis about a small protein, or peptide, that the body makes called amyloid-beta, or Abeta. This is the stuff that's known to clog the brains of Alzheimer's patients with the disease's telltale plaques. But Moir's hypothesis is that Abeta may actually be part of our immune system.
"My take on it revolves around a central an idea that I was asking for a number of years that I never really had an answer for," he said. "And that is, 'What does a-beta do.' Right? And I went around and I asked all the old guys in the field and most of them said 'It’s rubbish! It’s an accidental catabolic product! It does nothing. Go away.'”
But Moir came across striking similarities between chemical Abeta and a group of other peptides, known to be part of our innate immune system, as opposed to our more sophisticated adaptive immune system.
"Now adaptive immunity is very sexy—antibodies, t-cells," he said. "But, on a day-to-day basis, that ain’t what’s keeping you alive. It’s the innate immune system. Because without it, you’re going to get an infection on your lungs, in your mouth, on your skin, you’re going to die real quick. "
Focusing on Abeta
The innate immune systems uses peptides to quickly attack pathogens that enter the body. And Moir thinks that the plaques typically seen in Alzheimer's could be the innate immune system at work, with the brain making Abeta peptides in response to an infection. The Abeta plaques could actually be prisons for pathogens.
"We’ve been proposing that these deposits that you see in the brain and possibly other amyloid disease are actually extra-cellular traps," he said. "And the way they work is very simple, they physically constrain the bug so they can’t get around and infect other cells, can’t eat."
Moir is thinking about Abeta in a new way. And if he's right, it could open up a whole new world of treatment options. Maybe a vaccine could prevent the infection, or a drug could kill it so Abeta doesn't have to.
In any case, Abeta has been the focus of most Alzheimer's drug discovery programs for the past two decades. Today, the Food and Drug Administration and the field at large are testing drugs that regulate Abeta like cholesterol, turning its production down to what could be a safe level. The idea is to get these drugs into people early, before symptoms appear.
"The newspaper's will lead to you to believe that we're all lost at sea," said Harvard-Mass General Alzheimer's researcher Rudy Tanzi, a prominent figure in the world of Alzheimer's, largely because of his role in co-discovering key genes related to the disease.
"We're not lost at sea," he said. "We know an incredible amount about this disease, especially from genetics. We have a pretty good idea of what triggers it, what the pathway is, and then we can think about therapies to intervene. We are not knowledge constrained, we are budget constrained."
Looking for Targets
Across the country, relatively small groups of science investigators are working to stop Alzheimer's disease. They're looking at the pathology of the disease -- how it develops and how it progresses in the body. They know Abeta builds up over the course of years before Alzheimer's symptoms appear with memory lapses and personality changes. And they know more about the cascade of the disease from there than ever before.
"It kills me when I read in big newspapers that the Alzheimer's researchers are running around scratching their heads having no idea what causes this disease," Tanzi said. "Genetics has taught us what causes this disease. It's incontrovertible evidence. You just have to take that information, look at the big picture, and say, "Here are my choke points, here is where I can intervene." And then you need as much money as possible, as many labs as possible, to come up with the targets for drug discovery. "
Alzheimer's is always fatal, and there are only a handful of drugs on the market to treat it, and none of them help for very long. One recent analysis by the pharmaceutical industry found that since 1998, more than 100 Alzheimer's drugs failed in clinical testing. They either were unsafe, or they just didn't work, probably because they weren't very potent. One drug showed some modest success for people with mild Alzheimer's, but a followup study showed no improvement for people with later stages of the disease.
"We're hoping that pharmaceutical companies are not scared away, that some are already pulling out of Alzheimer's out of frustration," Tanzi said. "And I'd say to be frustrated now with the failures of the past doesn't make sense. Because yeah, they were shots on goal but in some cases it was a 5th grader shooting the ball from the midline of the soccer field. Don't give up just because these were the first shots on goal. We're getting closer and closer down to a good shot, and nows the time to actually pour it on, not back out."
The Tau Hypothesis
Still, some Alzheimer's specialists disagree on using Abeta as the drug target.
Alzheimer's researcher Dr. David Schubert of the Salk Institute in La Jolla, California said there's been too much time spent focusing on Abeta, which appears to build up over about 15 years before people even experience symptoms.
"So this is where we have this disagreement with people focusing on one target, one pathway, I just don't think that that's going to work in the long run," he said.
The Alzheimer's field has a long-standing debate over Abeta and the plaques it causes. Some researchers say a better drug target could be a different protein called tau, which breaks down and forms tangles in the brains of people with Alzheimer's.
Schubert suggests that perhaps a variety of accumulated proteins should be cleared out of the brain. In any case, while many researchers say a preventative for Alzheimer's could be available in the next five or 10 years, Schubert said he's not optimistic.
"Where the research is at the present time?" he asked. "It's basically got big problems because all of the drugs that have been tested in the clinic have failed to date. So there's really nothing out there that looks promising in the near future. There's a lot of stuff in the pipeline. But at the present time there's nothing that looks promising."
Most researchers agree that successful treatment of Alzheimer's would likely include a cocktail of drugs. One could regulate amyloid, perhaps another could clear it from the brain. A third might deal with brain inflammation or with Tau tangles.
Several of the nation's top researchers say things appear to be falling into place -- there's better testing for the disease; better animals to test drugs in; and new thinking about when to try drugs in humans. Some of the longest, most expensive and complex drug trials are either just underway or about to begin. And with 16 million people expected to suffer from Alzheimer's by 2050, researchers say the stakes are too high to fail.