In a potential breakthrough in treating Alzheimer's disease, scientists have uncovered a rare gene mutation that keeps plaque from forming in the brain and found that the disease may take hold 25 years before symptoms appear.
Two decades ago, researchers began discovering rare gene mutations that cause Alzheimer's disease in everyone who inherits them. Now, they have found the opposite: a mutation that prevents the devastating brain disorder. The protective mutation is also very rare -- it is not the reason most people do not develop Alzheimer's.
But what intrigues researchers is how it protects the brain. It does the reverse of what the mutations that cause Alzheimer's do. Those mutations lead to excessive amounts of a normal substance, beta amyloid, in the brain. The protective mutation slows beta amyloid production, so people make much less.
The discovery, published online Wednesday in the journal Nature, provides evidence that beta amyloid buildup is a driving force in the destructive brain disease. It also bolsters the hopes of drug companies that have developed drugs to reduce amyloid levels with the expectation that they might alter the course of the disease or even prevent it.
So far, the drugs have not succeeded, but companies and many researchers have argued that there are reasons for that and that it is too soon to give up.
If for no other reason, the discovery's implication for drug development "is hugely important," said Dr. David Altshuler, a genomics expert at Harvard Medical School and the Broad Institute of Harvard and MIT who was not involved with the research.
It indicates, he said, that drug companies' big bets on anti-amyloid treatments could pay off.
"This paper provides strong evidence that it would work in the general population if you did it right," Altshuler said.
Dr. Samuel Gandy, an Alzheimer's researcher who directs the Mount Sinai Center for Cognitive Health, had a similar response, calling the finding "extraordinarily important" -- the most significant in the field since researchers first reported a mutation that leads to the disease, 22 years ago.
As provocative as the protective gene mutation discovery is, the strategy of reducing amyloid levels -- the ultimate test of the amyloid hypothesis -- still must be evaluated in typical Alzheimer's disease.
The first few experimental drugs to reduce beta amyloid or to block the protein failed. Researchers and companies explain that away by saying they were not powerful enough and were studied in people who already had the disease and clear symptoms of mental decline.
By then, it might be too late to make any difference. When brain cells have died, nothing can bring them back.
The strategy now is to use new brain scans and other methods to find and treat people before they have symptoms of mental decline.
"The idea is that treatment has to start early to make a difference," said Ryan Watts, a neurodegeneration researcher at the drug company Genentech.
A second study, published in The New England Journal of Medicine, involved people with DNA that predisposed them to the disease before age 60. That research found changes in spinal fluid 25 years before symptoms began and brain volume differences 15 years earlier.
Together, the reports may lay groundwork letting scientists identify when it may be best to start treating patients and, perhaps, hold off the disease.
"These are steps on the pathway, really high-quality ones," said William Thies, chief medical officer for the Chicago-based Alzheimer's Association. Though the findings won't lead directly to drugs and diagnostics, they may provide a foundation for them, he said.
Some experts fear that if these latest efforts fail, drug companies may pull out of the field in frustration, leaving little hope for the millions of people with the disease.
More than 5 million Americans have Alzheimer's, which is the most common type of dementia, according to the Alzheimer's Association. Global dementia cases are expected to double within 20 years to as many as 65.7 million people.
This report includes material from The New York Times, Bloomberg News and The Associated Press.