In Preventing Alzheimer’s, Mutation May Aid Drug Quest
老年痴呆病因新证
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.
20年前，研究人员第一次发现罕见的基因突变导致了老年痴呆症（阿尔兹海默病）。而如今，他们发现，有一种基因突变能够防止这种毁灭性的大脑功能紊乱。这种防护性突变也很罕见，因而并非大多数人不患老年痴呆症的原因。但是让研究人员感兴趣的是它保护大脑的方式。那些致病的基因突变导致脑中的正常元素乙型淀粉样蛋白过量从而引发了老年痴呆症。与此相反，防护性基因突变会减缓淀粉样蛋白的生成，因而减少其总量。
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.
这项发现于周三被发表在《自然》(Nature)的网络版上，它为证明淀粉样蛋白过多是导致这种破坏性脑部疾病的主因提供了有力证据。这也为那些积极研发降低乙型淀粉样蛋白含量药物的制药公司带来了希望，他们期待自己的药物能够改变发病过程，甚至是防止疾病的发生。到目前为止，这类药物还没有获得成功，但是制药公司和许多研究人员辩称，这其中有着很多原因，因而不能轻言放弃。
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.
即便没有其他原因，这项发现对于药物开发“意义巨大”，戴维·阿特舒勒(David Altshuler) 博士称。他是哈弗大学医学院(Harvard Medical School)及布洛德 研究所(the Broad Institute of Harvard and M.I.T.)的基因组学专家，但并未参与这项研究。
It indicates, he said, that drug companies’ big bets on anti-amyloid treatments could pay off.
他表示，制药公司在抗淀粉蛋白的治疗药物上下了巨大赌注，而这项研究结果表明，他们很可能会有所收获。
“This paper provides strong evidence that it would work in the general population if you did it right,” Dr. Altshuler said.
“这份研究结果提供了强有力的证据，证明了如果操作正确，这种药物可以适用于普通人群，”阿特舒勒博士说。
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.
主管西奈山医学院认知健康中心（Mount Sinai Center for Cognitive Health）的塞缪尔·甘迪(SamuelGandy)博士的研究领域也是老年痴呆症。他给出了类似的回应，称这项研究结果“极为重要”,是22年前研究人员首次发现基因突变导致老年痴呆症以来该领域的最显著研究成果。
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.
研究人员在扫描检查1795个冰岛人的全部DNA时发现了这个防护性基因突变。这也是基因学领域的变革所带来的成果。大约每一百个人中，有一个人体内负责将大型蛋白质分化为乙型淀粉样蛋白的基因发生突变。之后，研究人员对年满85岁的人群与老年痴呆症患者进行研究。他们发现身体存在这种突变的人似乎因此受到保护而不患老年痴呆症。由冰岛基因解码公司(DeCode Genetics)首席执行官卡里·斯蒂芬森(KariStefansson)博士带领的研究团队随后研究了北美洲人群的基因组，他们发现一万人当中只有一个人有这种基因突变。斯蒂芬森博士表示，研究结果说明这种基因突变发生在在斯堪的纳维亚，而且时间较晚。
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.
这种防护性基因甚至似乎能够压制导致老年人患老年痴呆症高风险基因，即ApoE4基因的两个变体。90%拥有这两种ApoE4基因的人会在80岁之前患上老年痴呆症。斯蒂芬森博士说，研究人群中的25人拥有这两种ApoE4基因变体，但他们并未患上老年痴呆症。
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.”
作为第一例致病基因突变的发现者，英国伦敦大学学院(University College London)的老年痴呆症专家约翰·哈迪(JohnHardy)表示，这项研究“显然是正确的，其数据与结果都相当可靠。”
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.
发现淀粉样蛋白在这种破坏性脑部疾病中扮演关键角色是一个漫长的研究过程，而这项研究结果只是其中一部分。这方面的研究开始于20年前。当时，研究人员发现，有一种人必定会患上老年痴呆症，而这些人都继承了一种非常罕见的突变基因，他们往往是人到中年就已发病。这种突变在不同的家族中表现不一，但是他们都有相同的结果，即增加了脑部乙型淀粉样蛋白的含量。这意味着脑部淀粉样蛋白的积累足以致病。
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.
那些患老年痴呆症的年长人士通常没有突变基因，但他们的脑部都含有过量的淀粉样蛋白。所以，研究人员分析，这可能意味着他们患病也是由淀粉样蛋白过量引起的。
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.
研究人员和制药公司将大量精力集中在淀粉样蛋白假说上，这导致几乎所有用来减缓或防止老年痴呆症的实验性药物都是通过减少脑部淀粉样蛋白来发挥作用的。
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.
虽然发现防护性基因突变令人激动，降低淀粉样蛋白水平的策略——淀粉样蛋白假说的最终考验——仍然必须在典型的老年痴呆症患者身上进行评估。比如，也许只有从出生起就具有较低水平的淀粉样蛋白才能最终免于患上老年痴呆症。
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.
研究人员和制药公司解释称，最初的几种实验性药物之所以未能成功地降低脑部淀粉蛋白水平和限制蛋白质的产生，是因为药性不够强，而且药物是在那些已经患有老年痴呆症，智力明显下降的人群中试用的。在那一阶段，药物可能已经无法引起改变。脑细胞的死亡是不可逆转的。
The strategy now is to use new brain scans and other methods to find and treat people before they have symptoms of mental decline.
现在的新策略是，研究人员通过新的脑部扫描和其他方法锁定相关人群，并在他们的智力开始下降之前对其展开治疗。
“The idea is that treatment has to start early to make a difference,” said Ryan Watts, a neurodegeneration researcher at the drug company Genentech.
“现在的想法是。病人必须及早治疗， 这样才会有效果，”制药公司基因泰克(Genentech)的神经性退变研究人员瑞安·沃茨(RyanWatts)说。
来源：好英语网
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