A case made for Alzheimer’s prevention
It did not take long to discover there was some hype behind the latest drug being touted as the great hope for Alzheimer's disease. This summer, the biotech giant Biogen staged a press conference extolling the merits of its experimental drug aducanumab. CNN reported that the drug might be “a game-changer”, while The Independent called it “a breakthrough” that left one scientist “trying not to get too excited”.
Other scientists were trying not to get too angry.
The headlines could raise false hopes for patients and their families, they said, since there is little evidence the drug can reverse dementia. But some saw a silver lining: even if the experimental drug is not a cure, there is 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 to avert what many experts see as an impending disaster: by 2050, there will be 32 million people over the age of 80 in the United States, 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 is 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 is some disagreement about the exact relationship between plaques and Alzheimer's disease. Lon Schneider, director of the California Alzheimer's Disease Centre 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 is possible that 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 because of chance variation among patients. “The drug did what it was supposed to do,” he said. “It knocked down amyloid plaques in a 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 is not too early to start treatment.
There are a few significant obstacles 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 is the challenge of finding a drug safe enough to give to millions of healthy people.
In the Biogen trial, patients got different doses. Only the highest dose had any hint of an effect on the actual dementia, and at that dose, some patients developed dangerous brain swelling.
That risk looked to be confined to 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, will not help if the deposits turn out to be a symptom of the disease rather than a cause. But Tanzi said experiments that 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 do not 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.
•Faye Flam is a Bloomberg View columnist