Former Israeli Prime Minister Yitzhak Shamir who died of Alzheimer’s disease on June 30. (AFP)
July 12: A study of a rare gene mutation that protects people against Alzheimer’s disease provides the strongest evidence yet that excessive levels of a normal brain substance, beta amyloid, are a driving force in the disease — bolstering hopes that anti-amyloid drugs already under development might alter the disease’s course or even prevent it.
So far, the drugs have not succeeded. But scientists not connected with the new study said it suggested that the drug companies’ big bets on anti-amyloid treatments could yet pay off.
The implication for drug development “is hugely important”, said Dr David Altshuler, a genomics expert at the Harvard Medical School, the Broad Institute of Harvard and MIT.
Dr Samuel Gandy, an Alzheimer’s researcher who directs the Mount Sinai Center for Cognitive Health, called the finding the most significant in the field in two decades, since researchers first reported a mutation that leads to the disease.
The protective mutation, whose discovery was reported online yesterday in the journal Nature, is highly uncommon — it is not the reason most people do not develop Alzheimer’s. But what intrigues researchers is how it protects the brain.
Mutations that cause Alzheimer’s lead to excessive amounts of beta amyloid in the brain; by contrast, the protective mutation slows beta amyloid production, so people make much less. “This paper provides strong evidence that it would work in the general population if you did it right,” Dr Altshuler said.
Scientists at the drug companies agreed. “We are thrilled,” said Ryan Watts, one of the authors of the new paper and head of the neurodegeneration labs at Genentech, which is developing two drugs to reduce brain amyloid levels.
Dr Richard Mohs, leader of neuroscience early clinical development at Eli Lilly, said the company was “very encouraged by these study results”. They show, he said, that despite an initial failure, the strategy of focusing on drugs to reduce beta amyloid levels is “a logical path for the development of effective therapies that may slow disease progression”.
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.
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 who had been given an Alzheimer’s diagnosis, and a group of people 85 and older. 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, 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 per cent 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 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 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 meant that a buildup of amyloid was sufficient to cause the disease.