Two decades ago, researchers began discovering rare gene mutations that cause Alzheimer's disease in all who inherit them. Now, they have found the opposite: a mutation that prevents the devastating brain disorder.
The protective mutation also is very rare; it is not the reason most people do not develop Alzheimer's disease. 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 strong evidence that beta amyloid buildup is a driving force in this destructive brain disease.
It also bolsters the hopes of drug companies that have zealously 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 on them.
If for no other reason, the discovery's implication for drug development "is hugely important," said 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," Dr. Altshuler said.
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 field's most significant since 22 years ago, when researchers first reported a mutation that leads to the disease.
Discovery of the protective gene mutation, a result of the revolution that has occurred in genetics, arose when researchers scanned the entire DNA of 1,795 Icelanders. About 1 in 100 had a mutation in the gene for a large protein that is sliced to form beta amyloid.
Then the investigators studied people ages 85 and older and people who had been given an Alzheimer's diagnosis. Those with the mutation seemed protected from Alzheimer's disease.
The investigators, led by Kari Stefansson, chief executive at DeCode Genetics, an Icelandic company, then looked at genomes of North Americans and found the gene mutation in only about 1 in 10,000 people. That indicates, Dr. Stefansson said, that the mutation arose relatively recently in Scandinavia.
The protective gene even appears to override a very strong risk factor for Alzheimer's disease in old age -- two copies of a gene known as ApoE4. Ninety percent of people with two ApoE4 genes get Alzheimer's by age 80. But Dr. Stefansson says there are 25 people in his study with two copies of ApoE4. None has Alzheimer's disease.
The research "is obviously right," said John Hardy, an Alzheimer's researcher at University College London and a discoverer of the first gene mutation found to cause the disease. "The statistics and the finding are pretty secure."
The discovery is part of a continuing story that implicates beta amyloid as a central and crucial player in this destructive brain disease. The idea began two decades ago with discovery of very rare gene mutations that always cause Alzheimer's in those who inherit them, usually by middle age. The mutations were different in different families, but all had the same effect: They increased the amount of beta amyloid in the brain. That meant that a buildup of amyloid was enough to cause the disease.
Elderly people with Alzheimer's -- who typically did not have these gene mutations -- also had excess amyloid in the brain. So, researchers reasoned, that might mean that excess amyloid was causing the disease in them, too.
Additional evidence of the role of beta amyloid was reported Wednesday in The New England Journal of Medicine. Using spinal taps and brain scans to track the protein, investigators found that people with one of the Alzheimer's-causing mutations start making too much beta amyloid as long as 20 years before they have symptoms of the disease.
Researchers and drug companies have focused on the amyloid hypothesis to the extent that almost every experimental drug being tested to slow or halt Alzheimer's disease aims to reduce amyloid in the brain.
But a crucial question remained. Was amyloid really causing Alzheimer's in elderly people? Might the protein instead be a bystander, accumulating, for example, as part of the brain's response to damage?
The discovery of the protective gene mutation provides strong clues. People with the mutation make substantially less beta amyloid, but other than that they are no different from anyone else. And they do not get Alzheimer's.
Many questions remain, of course. Most people do not have the protective gene mutation, but as common as Alzheimer's is, most people do not get it. It is not clear why.
And most who develop Alzheimer's do not have one of the rare gene mutations that cause it. The reasons for their disease are unclear.