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 on 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 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 Dr. David Altshuler, a genomics expert at Harvard Medical School and the Broad Institute of Harvard and M.I.T. who was not involved with the research.
即便沒有其他原因，這項發現對于藥物開發“意義巨大”，戴維·阿特舒勒(David Altshuler) 博士稱。他是哈弗大學醫學院(Harvard Medical School)及布洛德 研究所(the Broad Institute of Harvard and M.I.T.)的基因組學專家，但并未參與這項研究。
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.
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.
主管西奈山醫學院認知健康中心（Mount Sinai Center for Cognitive Health）的塞繆爾·甘迪(SamuelGandy)博士的研究領域也是老年癡呆癥。他給出了類似的回應，稱這項研究結果“極為重要”,是22年前研究人員首次發現基因突變導致老年癡呆癥以來該領域的最顯著研究成果。
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 one 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 one 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 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.”
作為第一例致病基因突變的發現者，英國倫敦大學學院(University College London)的老年癡呆癥專家約翰·哈迪(JohnHardy)表示，這項研究“顯然是正確的，其數據與結果都相當可靠。”
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.
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.
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 is designed to reduce the amount of amyloid in the brain.
As provocative as the discovery of the protective gene mutation is, 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 neurodegeneration researcher at the drug company Genentech.