Jason and Karin Marder of New York. Jason Marder, who turned 70 on Tuesday, July 10, 2012, was diagnosed with Alzheimer's more than eight years ago. In the roughly five years that her husband has taken Gammagard, "there has been decline" in his health but it is very minimal and the kind of slowing down you might expect from ordinary aging, she said. "He travels the subways, he does things that you and I do. And our quality of life together is what's most important."

Seth Wenig, Associated Press - Ap

Mutation found that prevents Alzheimer's

  • Article by: GINA KOLATA
  • New York Times
  • July 12, 2012 - 5:45 AM


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 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 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 Alz-heimer'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.

'Findings are pretty secure'

The discovery of the protective gene mutation, a product of the revolution that has taken place 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 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, he 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 Stefansson says 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 Alz-heimer'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 the 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 meant that a buildup of amyloid was sufficient to cause the disease.

Seniors with Alzheimer's -- who typically did not have these 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.

Is it more than a hypothesis?

Researchers and drug companies focused on the amyloid hypothesis to the extent that almost every experimental drug being tested to slow or halt Alz- heimer'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 seniors? 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 Alz-heimer'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.

People could be tested to see if they have the protective mutation, Stefansson said, but he added, "The benefits of doing so are not obvious to me." He explained that since the gene is so rare, chances that a person being tested would have it -- especially if that person is not Scandinavian -- are extremely low.

As provocative as the discovery 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.

Researchers and companies explain away the failure of the first few experimental drugs to reduce beta amyloid levels or to block the protein 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 researcher at the drug company Genentech.

Of course, people with the newly discovered mutation have lower levels of beta amyloid for their entire lives. Watts said, "You couldn't start earlier than that."

© 2018 Star Tribune