NEW YORK — 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 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 there are reasons for that and 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 Dr. David Altshuler, a genomics expert at Harvard Medical School and the Broad Institute of MIT and Harvard. Altshuler was not involved with the research.
“This paper provides strong evidence that it would work in the general population if you did it right,” Altshuler said of anti-amyloid treatments.
‘This paper provides strong evidence that it would work in the general population if you did it right.’
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.
The discovery of the protective gene mutation, a product of the revolution that has taken place in genetics, arose when researchers scanned the 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 appeared to be protected from Alzheimer’s disease.
The investigators, led by Dr. 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, Stefansson said, 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 Stefansson said there are 25 people in his study with two copies of ApoE4. None have 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 the 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 buildup was sufficient 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 excess amyloid was causing the disease in them, too.
Researchers and drug companies focused on the amyloid hypothesis to the extent that almost every experimental drug being tested to slow or halt Alzheimer’s disease is designed to reduce the amount of 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.
As provocative as the discovery of the protective gene mutation is, Hardy noted, the strategy of reducing amyloid levels — the ultimate test of the amyloid hypothesis — still must be evaluated in typical Alzheimer’s disease. For example, perhaps people need to have lower levels of beta amyloid from birth to really be protected from Alzheimer’s disease.