科学与数学statnews.com
阿尔茨海默病“小圈子”如何阻碍治愈研究
How an Alzheimer’s ‘cabal’ thwarted progress toward a cure
2019 — 2022，它一次次回到首页
黑点是上首页（≥ 50 分）的那次投稿，空心点是没冲上去的投稿，点越大分数越高。
导读
这篇 STAT News 报道梳理了阿尔茨海默病研究长期被“淀粉样蛋白假说”主导的局面，以及批评者所称的“小圈子”如何影响资金分配和论文发表，挤压了对其他假说的探索。文章同时指出，这个群体并非有组织的阴谋，很多人真诚相信自己的方向；问题在于把一种必要但不充分的机制当成唯一答案。
为什么经久不衰：它把科学共识如何固化成路径依赖、资助和评审机制如何压抑异见讲得具体可感，是理解科研激励扭曲的经典案例。
HN 评论精选
一线研究者亲述：主流框架束缚选题，资深评审维护毕生工作，大学还抽走一半经费。
这篇文章百分之百属实。十年前我大学毕业后的第一份工作在一个阿尔茨海默病研究实验室。我们的 PI 把写基金申请变成一门艺术：申请看起来符合主流理论，实际是想测试他真正认为值得测试的假说，只在结果里作为“有趣的旁注”呈现。他相信淀粉样蛋白理论已被明确证伪。他向我解释，像他这样的人工作几十年，半退休到接受基金申请的岗位，会有意无意地维护或验证自己毕生的工作。他的原话是：“科学就像天主教会，有很多美好的理念，但里面全是人。”我没有证据或例子，但我怀疑这种动态不限于阿尔茨海默病研究。文章没提到的另一个科研锚点是赞助大学从实验室拿走多少钱。为了给我们的研究盖上大学背书（这对可信度是必需的），大学拿走了我们基金的一半（一半！）。
cockatiel_day查看英文原文
This article is 100% true. My first job out of college 10 years ago was in a lab focused on Alzheimer’s research. Our Principle Investigator made an art of writing grant applications for studies that would appear to be in line with mainstream theory, but were really intended to test theories he actually thought were worth testing, presented in results as an “interesting” aside. He believed the amyloid theory had been conclusively disproven. He explained to me that people like him work for decades, quasi-retire into positions accepting grant applications, and have a conscious or unconscious agenda to preserve or validate their life’s work. His money quote was “science is like the Catholic Church, a lot of nice sentiments but full of people”. I don’t have any evidence or examples, but I suspect this dynamic is not limited to Alzheimer’s research. Another anchor to research not mentioned in the article is how much sponsoring universities take from research labs. To put a university endorsement on our research, which is needed to be credible, the university took half (half!) our grant money.
淀粉样蛋白是必要非充分条件；问题不是研究它，而是把它当成唯一故事。
这篇文章有些过时。Biogen 曾以缺乏疗效为由提前终止淀粉样蛋白抗体 Aducanumab 的 III 期试验，但细看数据后似乎不应终止，Biogen 现在正为 Aducanumab 申请 FDA 批准。总的来说，淀粉样蛋白无疑是阿尔茨海默病的关键部分。Alois Alzheimer 首次描述该病时就注意到淀粉样斑块是关键病理发现，确诊也要求存在斑块。许多早发型阿尔茨海默病变异由 APP（淀粉样蛋白前体）或与 APP 加工密切相关的基因（如 PSEN1、PSEN2）突变引起，这些突变常导致极高水平的淀粉样蛋白和斑块。淀粉样蛋白升高和斑块是必要条件是早发和晚发都必要，但显然不是充分条件：很多人脑内满是斑块和淀粉样蛋白，却几乎没有认知衰退。所以问题不在于承认淀粉样蛋白是故事的重要部分，而在于把它当成唯一部分和唯一可想到的解决方案。
zosima查看英文原文
The article is not quite updated. Biogen did end their phase 3 trial of the amyloid-beta antibody Aducanumab early, citing lack of efficacy. A closer look at the numbers however appeared to reveal that they shouldn't have. And Biogen is now filing Aducanumab for approval by FDA. [1] All in all, there is no question that amyloid-beta is a key part of Alzheimer. Already Alois Alzheimer, when first describing Alzheimer's disease, noted amyloid-beta plaques as a key pathological finding. Amyloid-beta plaques are a characteristic of the disease, and a proper Alzheimer diagnosis requires the presence of amyloid-beta plaques. Many variants of early-onset Alzheimer are caused by mutations either directly in APP (the precursor to amyloid-beta) or genes intimately involved with APP-processing (e.g. PSEN1 and PSEN2). These mutations often cause extreme levels of amyloid-beta and amyloid plaques. Raised levels of amyloid-beta and amyloid plaques is a necessary condition for Alzheimer's disease, both early- and late-onset. But it's clearly not a sufficient criteria: many people have brains full of plaques and amyloid-beta, but little or no cognitive decline. So the problem with Alzheimer's research is not so much the understanding that amyloid-beta is a significant part of the story, but rather focusing on it as the only part of the story and the only conceivable solution. [1] https://edition.cnn.com/2019/10/22/health/biogen-alzheimers-drug-fda/index.html
三十年反复靶向淀粉样蛋白无一成功，Derek Lowe 质问还要坚持多久。
相关：Derek Lowe 的《Had Enough, Eh? Come Back and Take What's Coming to You!》一文写道：“很难估计这个想法上花了多少时间、精力和金钱。这还只是抗体！还有其他针对淀粉样蛋白假说的尝试（分泌酶等），没有一个成功。记住，过去三十年还有大量临床前工作从未见天日（我自己参与过一些），你没听说过它们是因为它们也没用。什么都没用。一次都没有。淀粉样蛋白假说被从不同方向、用不同候选药物反复靶向，却从未有一次显示出真正帮助阿尔茨海默病患者。Biogen 的 Aduhelm 我也算在内。所以我再问：我们还要这样干多久？”
nabla9查看英文原文
Related: Derek Lowe: Had Enough, Eh? Come Back and Take What's Coming to You! https://www.science.org/content/blog-post/had-enough-eh >It is hard to even begin to estimate the amount of time, effort, and money that has been spent on this idea. And this is just the antibodies! There are plenty of other whacks that have been taken at the amyloid hypothesis (secretase enzymes and more), and none of them have ever worked. Keep in mind that there are plenty of preclinical efforts over the past thirty years that never even saw the light of day (I was on some of those myself), and the reason you never heard about any of them is because they didn't work, either. Nothing has worked. Not once. The amyloid hypothesis has been targeted again and again and again from different directions with different drug candidates, and never, ever even once has it shown signs of truly helping Alzheimer's patients. I very much include Biogen's Aduhelm in that assessment. So I ask again: how long are we going to keep doing this?
学术激励让作者在讨论部分自我否定以通过评审。
作为一名科学家，没有什么比推翻你领域里重要人物的成名发现更容易被拒之门外。一个副作用是“讨论与结果不符”的论文。读论文时讨论部分公然与论文自己的结果矛盾是常事。实际发生的是作者为了通过充满敌意的评审而否定自己的发现，赌的是敏锐的读者会注意到矛盾，忽略讨论，从结果中得出自己的结论。
georgewfraser查看英文原文
There is no better way to get shut out as a scientist than to disprove the career-making findings of the important people in your field. One of the side effects of this is the “discussion does not match the results” paper. It’s routine to read papers where the discussion blatantly contradicts the papers own results. What is happening is the authors are disclaiming their own findings in order to get past hostile reviewers, betting that astute readers will notice the contradiction, ignore the discussion and draw their own conclusions from the results.
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