Drugs Can't Cure Alzheimer's. Could They Prevent It?
It didn’t take long to discover there was some hype behind the latest drug being touted as the great hope for Alzheimer’s disease. Earlier this summer, the journal Nature
Other scientists were trying not to get too angry. The headlines could raise false hopes for patients and their families, they said, since there’s little evidence the drug can reverse dementia. But some saw a silver lining: Even if the experimental drug isn’t a cure, there’s reason to believe something like it might ward off Alzheimer’s disease in healthy people, sort of the way statins are thought to prevent heart attacks. And preventive therapy for the brain could help avert what many experts see as an impending disaster: By 2050, there will be 32 million people over the age of 80 in the U.S., and unless something big changes, about 16 million will have Alzheimer’s disease.
Those experts are excited not about the drug itself but about a proof of principle that came out of the its most recent clinical trial, in which 165 participants were given varying doses of the drug or a placebo. Brain scans revealed that those taking the drug had a marked reduction in amyloid plaque -– a deposit associated with Alzheimer’s disease. There were some hints that the drug may slow down the progress of cognitive decline, but that was less convincing to researchers not involved with the study.
How could aducanumab have a big effect on the plaques and not on the dementia? It could be that by the time even mild symptoms appear, it’s too late, said Rudolph Tanzi, an Alzheimer’s researcher at Massachusetts General Hospital in Boston. “It’s like having someone with congestive heart failure going to a cardiologist and getting Lipitor,” he said.
There’s some disagreement about the exact relationship between plaques and Alzheimer’s disease. Lon Schneider, director of the California Alzheimer’s Disease Center at the USC School of Medicine, says some people die with full cognition and memory and upon autopsy are discovered to be as full of plaques as those of Alzheimer’s patients. The plaques, he said, are a risk factor for future cognitive and memory impairment and clinical Alzheimer’s. It’s possible reducing plaques at some early stage will prevent the disease, but he considers this still a hypothesis that needs to be tested.
The Biogen study was never intended to find signs of cognitive improvement, he said. The sample size was too small. Differences in cognitive test results could be due to chance variation among patients. “The drug did what it was supposed to do,” he said. “It knocked down amyloid plaques in dose-dependent and predictable way. The rest, about marked clinical effects, was hype and noise.”
Other trials are recruiting people who are “cognitively intact” –- people with no signs of decline, but with plaques that show up in brain scans. The hope is that treating even earlier with anti-amyloid drugs might prevent or postpone the onset of dementia. “Some people say the plaques are there 25 years before symptoms appear,” Schneider said. “Should we treat people 25 years before symptoms?”
Mass General researcher Tanzi estimates 15 years can pass between the time the plaques appear and the symptoms do. And yes, he says, that’s not too early to start treatment.
There are a few major obstacles to to cross before prevention is possible, however. First, detecting the signs of amyloid plaque now requires a rather involved procedure called a PET scan. Eventually, Tanzi said, blood tests for plaque formation could become a reality. Another problem is with the drug itself, which has to be administered once a month directly into the vein. Other experimental drugs aimed at preventing amyloid plaques are more easily formulated into a pill, making them more practical for widespread use.
Then there’s the challenge of finding a drug safe enough to give to millions of healthy people. In the Biogen trial, patients got different doses. The highest dose showed the most promising hint of an effect on the actual dementia, and at that dose, some patients developed dangerous brain swelling. That risk was worse for people with a particular genetic risk factor -- a gene called APOE4 -- but those people make up a significant fraction of Alzheimer’s patients.
Fighting plaque, no matter how early, won’t help if the deposits turn out to be a symptom of the disease rather than a cause. But Tanzi said experiments he published in 2014 using human brain cells add strong evidence to the view that plaques are a cause of the disease, along with inflammation. A few people can get plaques and stay healthy because they don’t get the inflammation, he said.
One side benefit of early tests for Alzheimer’s plaques could be the ability to better test the possible beneficial effects of lifestyle changes. Some people can lower their cholesterol by changing their diets, losing excess weight and exercising more, after all. Tanzi says you can improve your odds of avoiding Alzheimer’s at least a little by eating a healthy diet (he goes with a Mediterranean diet), getting enough sleep and managing stress.
The stress part is tricky, however, given that massive deploying of tests for Alzheimer’s risk could really stress people out -- especially if this happens before there are reliable prevention measures. One thing that’s bad for your brain, he said, is worrying about your brain.
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