为何我们仍未攻克阿尔茨海默症？

你还记得我的名字吗？

Do you remember my name?

不记得。

No.

这段2018年《60分钟》节目中的女性，正遭受着老年最棘手的疾病之一——阿尔茨海默症的困扰。

In this twenty eighteen clip from sixty Minutes, a woman is dealing with one of the most troubling diseases of old age, Alzheimer's.

这个叫什么？

What's this called?

我手腕上戴的这个。

What I'm wearing on my wrist.

那个叫什么名字？

What's the name of that?

我不知道。

I don't know.

这是块手表。

It's a wristwatch.

对。

Yeah.

听起来熟悉吗？

Does that sound familiar?

嗯。

Yeah.

阿尔茨海默症是最常见的痴呆症类型。

Alzheimer's disease is the most common form of dementia.

记忆一点一滴地消逝，抹去我们所知的一切，包括对自我身份的认知。

Memory by memory, it erases everything we know, including our sense of who we are.

最终，它会剥夺我们行走、交谈和自理的能力。

Eventually, it can rob us of our ability to walk, talk, and care for ourselves.

数据揭示了一个残酷的现实。

The numbers tell a grim story.

每年，有超过50万美国人被诊断出患有痴呆症。

Every year, over half a million Americans are diagnosed with dementia.

其中大部分是阿尔茨海默病例。

Most will be Alzheimer's cases.

每年有超过十万美国人死于阿尔茨海默病，这使其成为美国第七大死因。

And over one hundred thousand Americans die of Alzheimer's each year, which makes it the seventh leading cause of death in The United States.

而这场危机只会愈演愈烈。

And the crisis is only going to get worse.

随着越来越多的人活到70岁及以上，阿尔茨海默病患者群体将持续扩大。

As more people live into their 70s and beyond, the population of people with Alzheimer's will grow.

因此科学家们长期疯狂寻找治愈方法也就不足为奇了。

So it's no surprise that scientists are furiously searching for a cure, and have been for a long time.

仅过去三十年间，制药公司和美国政府就已在阿尔茨海默研究上投入了数百亿美元。

Between drug companies and the US government, billions of dollars have been spent on Alzheimer's research in just the last thirty years.

但尽管投入了如此多的时间与金钱，我们仍未能找到可靠的治疗方法，更不用说治愈方案。

But despite all that time and money, we still don't have a reliable treatment for the disease, let alone a cure.

为何我们对这个已知一个多世纪的疾病仍未能取得更大进展？

Why haven't we made more progress against a disease we've known about for more than a century?

我们真的了解它的运作原理吗？

And do we even understand how it works?

还是说我们从一开始就走错了方向？

Or have we been heading down the wrong path since the very beginning?

我是卡尔·齐默，在本期《你所知道的世界·老龄化未来》节目中，我们将探讨阿尔茨海默病研究的现状：我们当前的位置、如何走到今天，以及未来的方向。

I'm Carl Zimmer, and in this episode of The World As You'll Know It, The Future of Aging, we're looking at the state of Alzheimer's research: where we are, how we got here, and where we go now.

要理解为何我们仍在寻找阿尔茨海默病的治愈方法，必须回溯到最初。

In order to understand why we're still searching for an Alzheimer's cure, you have to go back to the beginning.

而最适合带我们回到起点的人选之一是

And one of the best people to take us there is Doctor.

匹兹堡大学的神经生物学家卡尔·哈罗普博士。

Carl Harrop, a neurobiologist at the University of Pittsburgh.

几年前，他出版了一本名为《如何不研究：阿尔茨海默病的故事》的著作。

A few years ago, he published a book called How Not to Study a The Story of Alzheimer's.

让我们回到1906年。

So let's go back to 1906.

德国新兴精神病学家路易斯·阿尔茨海默痴迷于一个观点：大脑结构决定其功能。

Lois Alzheimer, an up and coming psychiatrist in Germany, is fascinated with the idea that the structure of the brain dictates its function.

这个观点在当时极具前瞻性。

And that was a very forward looking idea for its time.

阿尔茨海默博士

Doctor.

在法兰克福精神病院工作时，接诊了一位名叫奥古斯特·迪特的女性患者。

Alzheimer was working at the Frankfurt Psychiatric Hospital when a woman named Auguste Dieter was admitted.

她50岁了，变得偏执多疑。

She was 50 years old, and she had become paranoid.

她指控丈夫有外遇。

She accused her husband of adultery.

她坚信有人要谋害她。

She was convinced that someone was trying to kill her.

她会毫无理由地强迫性移动家中物品并藏起来。

She would compulsively move things around the house and hide them for no reason.

最终，奥古斯特的家人无法再照料她。

Eventually, Auguste's family could no longer care for her.

他们将她送进法兰克福医院，五年后她在那里去世。

They moved her to the Frankfurt Hospital, and after five years, she died there.

医生。

Doctor.

阿尔茨海默被奥古斯特的病例深深震撼，因此保存了她的大脑。

Alzheimer was so struck by Auguste's case that he had her brain preserved.

他认为如果研究她的大脑，或许能找到病因。

He thought if he could study her brain, he might find the source of her illness.

所以当他通过显微镜观察时，带我们看看他当时看到了什么。

So when he looked through the microscope, take us through what he was seeing at the time.

我们称之为沉积物，但实际上就是大脑里的一堆粘稠物。

I mean, we call them deposits, but they're just piles of goo in the brain.

此外还有这些死亡神经元的残骸，他称之为粟粒状缠结，因为它们看起来就像扭曲的金属丝。

And then in addition, these ghosts of dead neurons, which he described as miliary tangles because they looked like just twisted strands of wire.

医生。

Doctor.

阿尔茨海默发表了一篇关于他在奥古斯特大脑中观察到的现象的论文。

Alzheimer wrote a paper about what he saw in Auguste's brain.

他说，我通常看不到这些。

And he said, I don't see these normally.

它们是异常的。

They are abnormal.

奥古斯特的行为是异常的。

Auguste's behavior was abnormal.

因此，那些斑块和缠结一定导致了这种行为。

Therefore, those plaques and tangles must have caused the behavior.

这是一个相当合理的假设。

Now, that's a perfectly good hypothesis.

但从阿尔茨海默当时掌握的数据来看，同样合理的假设是：不，不，不，不，不，不。

But an equally valid hypothesis from the data that Alzheimer had would be to say, no, no, no, no, no, no.

疾病、痴呆、行为本身才是导致这些沉积物的原因。

The disease, the dementia, the behavior itself was what led to the deposits.

它们是症状而非病因。

They were symptoms rather than causes.

根据阿尔茨海默当时的数据，根本无法厘清这两者的关系。

And there's no way to untangle that given the data that Alzheimer had.

但他完全有理由——事实上这是一篇具有前瞻性的论文——提出斑块和缠结导致痴呆的观点。

But he was perfectly entitled, in fact, it was a forward looking paper, to put out this idea that the plaques and tangles cause the dementia.

论文发表后不久，奥古斯特·迪特的病症有了名称：阿尔茨海默病。

Soon after the paper was published, Auguste Dieter's condition got a name: Alzheimer's disease.

数十年来，医生们认为这是一种由中年人大脑中的斑块和缠结引起的特殊早发性痴呆症。

For decades, doctors believed it was a peculiar form of early dementia caused by plaques and tangles in the brains of middle aged people.

但到了1960年代，病理学家开始在许多患有痴呆症的老年人脑中发现这些斑块和缠结。

But by the 1960s, pathologists started finding those plaques and tangles in a lot of old people with dementia.

这使得阿尔茨海默病从一种罕见病症转变为普遍威胁。

This transformed Alzheimer's from a niche disease to a widespread threat.

因此阿尔茨海默病从像奥古斯特·迪特这样五十多岁患者所得的罕见病症，转变为65岁以上人群也普遍罹患的疾病。

So Alzheimer's goes from being this very rare condition that someone like Auguste Deter gets when she's in her fifties to something that a substantial number of people are getting who are 65 in addition.

确实如此。

That's correct.

1974年，美国政府成立了新的研究机构——国家老龄化研究所。

In 1974, the US government set up a new research center, the National Institute on Aging.

它派遣了大批科学家运用最新技术来解析阿尔茨海默病。

It deployed an army of scientists to use the latest technologies to make sense of Alzheimer's.

据哈罗普所说，新一代阿尔茨海默病研究者做了一些为未来六十年奠定基础的工作。

And according to Harrop, this new generation of Alzheimer's researchers did something that would set the stage for the next sixty years.

他们采纳了阿尔茨海默医生

They took Doctor.

最初的假说作为事实。

Alzheimer's original hypothesis as fact.

他们基本认定：既然在迟发性痴呆中也观察到斑块和缠结，那么所有这类痴呆必然具有相同病因。

What they basically decided was that we see plaques and tangles in dementia even if it occurs later, therefore all of this dementia must have the same cause.

他们付诸实践并取得了巨大成功。

And they ran with it and were hugely successful.

从20世纪80年代开始，研究人员在理解阿尔茨海默病方面取得了重大进展。

Starting in the 1980s, researchers made significant progress in understanding Alzheimer's.

其中一项发现是，他们搞清了斑块的组成成分。

For one thing, they discovered what plaques are made of.

脑细胞有时会排出一个有缺陷的蛋白质片段。

Brain cells sometimes expel a defective fragment of a protein.

这个片段被称为β淀粉样蛋白。

That fragment is called amyloid beta.

β淀粉样蛋白会相互粘连，在脑细胞之间形成团块。

Amyloid beta sticks together, forming clumps between brain cells.

这就是阿尔茨海默医生...

That's what Doctor.

最初观察到的现象，也就是我们现在所知的斑块。

Alzheimer first saw, what we now know as a plaque.

这些发现让科学家得以在分子层面建立关于阿尔茨海默病成因的理论。

These discoveries allowed scientists to develop theories about the cause of Alzheimer's on a molecular level.

到20世纪90年代，β淀粉样蛋白成为主要嫌疑对象，关于其如何造成损害的一种解释开始主导该领域。

By the 1990s, amyloid beta emerged as the prime suspect, and one explanation for how it wreaked its damage began to dominate the field.

据说阿尔茨海默病始于β淀粉样蛋白开始聚集成斑块时。

It's said that Alzheimer's starts when amyloid beta begins clump into those plaques.

这会引发包括神经元死亡在内的各种变化。

That triggers all sorts of changes, including the death of neurons.

根据这一解释，β淀粉样蛋白会逐渐破坏大脑，导致阿尔茨海默病那些毁灭性的行为症状。

Gradually, according to this explanation, beta destroys the brain, causing the devastating behavioral symptoms of Alzheimer's.

科学家们将这一解释称为淀粉样蛋白级联假说。

Scientists call this explanation the amyloid cascade hypothesis.

完全合理的假说。

Perfectly plausible hypothesis.

它符合所有事实。

It fit all the facts.

我想如果淀粉样蛋白是痴呆症的病因，那么这就为治愈阿尔茨海默病提供了明确靶点。

And I guess if amyloid was the cause of dementia, then that gave you a very clear target to cure Alzheimer's.

确实如此。

That is correct.

在淀粉样蛋白成为阿尔茨海默病研究核心靶点的时期，哈罗普刚进入这一领域。

At the time that amyloid was becoming a central target of Alzheimer's research, Harrop was just entering the field.

但当他审视淀粉样蛋白级联假说时，持怀疑态度。

But when he looked at the amyloid cascade hypothesis, he was skeptical.

如果淀粉样蛋白是阿尔茨海默病的关键，那么你会预期所有大脑中有淀粉样蛋白堆积的人都应该患病，对吧？

If amyloid was the key to Alzheimer's, then you'd expect that everyone with amyloid buildup in their brains would have Alzheimer's, right?

事实证明并非如此。

Turns out, that's not the case.

如果你观察健康人群（即没有认知缺陷、毫无症状的老年人）的大脑，其中30%的人会有可被诊断为阿尔茨海默病的淀粉样蛋白沉积。

If you look in the brains of healthy people, that is to say elderly people with no cognitive deficits, no symptoms at all, thirty percent of them, they'll have deposits of amyloid that could be diagnosed as Alzheimer's disease.

哈罗普向共事的阿尔茨海默病专家们提出了他的担忧。

Hair brought his concerns to the Alzheimer's experts he was working with.

他告诉他们，他想研究这种疾病的其他潜在病因。

He told them he wanted to study other potential causes of the disease.

当时的回应是，他们挺起胸膛，咂着舌头说：'孩子，如果你不研究淀粉样蛋白，那你就不算在研究阿尔茨海默病。'

The response at that time was to kind of puff up their chest, cluck their tongue and say, Son, if you're not studying amyloid, you're not studying Alzheimer's disease.

哇。

Wow.

他们真的对你这么说了。

They actually said that to you.

哦，是啊。

Oh, yeah.

那是一次我永远难忘的会议。

It was a meeting I will never forget.

所以你可以想象，当整个领域正兴奋地认为我们几乎已经破解了这种疾病，并将在几年内治愈它时，我作为持怀疑态度并提出质疑的异类有多格格不入。

So you can imagine what an outlier I was in being skeptical and questioning of a field that was just getting excited about how we had pretty much figured out this disease and would cure it within just a few years.

有几年时间，情况确实看起来很乐观。

And for a few years, things did look promising.

90年代末，一家名为Elan制药公司的研究人员通过基因工程让小鼠大脑中产生淀粉样斑块。

In the late 90s, researchers at a company called Elan Pharmaceuticals engineered mice to make amyloid plaques in their brains.

果然不出所料，这些斑块损害了它们的脑细胞，完全符合淀粉样蛋白级联假说的预期。

And lo and behold, the plaques damaged their brain cells, just what you'd expect from the amyloid cascade hypothesis.

随后Elan的科学家们采取了下一步行动。

Then the scientists at Elan took the next step.

他们给小鼠注射了一种疫苗，训练其免疫系统攻击淀粉样蛋白，结果成功了。

They gave the mice a vaccine that trained their immune system to attack amyloid, and it worked.

如果小鼠在幼年时接种疫苗，它就不会形成斑块。

If a mouse got the vaccine when it was young, it didn't go on to develop plaques.

如果科学家给已经形成斑块的老年小鼠接种疫苗，它们的免疫系统会攻击这些斑块。

If the scientists gave the vaccine to old mice that already had plaques, their immune system attacked them.

小鼠大脑中的斑块消失了，行为异常也随之消失。

The plaques in the mouse brain disappeared and so did the behavioral abnormalities.

即便是我这样的怀疑论者当时也说，如果不将这项研究推进到人体试验看看是否具有同样效果，几乎是不负责任的。

And even I as a skeptic was saying at the time, it would be almost irresponsible not to take this into people and see if it had the same effect.

于是伊兰制药公司启动了人体研究，但人毕竟不是小鼠。

So Elan Pharmaceuticals launched a study on people, But people are not mice.

人体临床试验开展后几乎立即被迫中止，因为事实证明当人体产生针对淀粉样蛋白的抗体时，会诱发脑炎。

Human clinical trials were done and almost immediately had to be halted because it turns out when you make antibodies against amyloid, you induce an encephalitis.

脑炎是大脑及其脑膜的急性炎症。

Encephalitis is an acute inflammation of the brain and its membranes.

所有出现脑炎的志愿者都康复了，但该疫苗对患者而言风险显然过高。

All the volunteers who developed encephalitis got better, but the vaccine was clearly too risky to use on patients.

研究人员也无法确定疫苗是否延缓了阿尔茨海默症患者的记忆衰退和其他症状。

And the researchers couldn't be sure whether the vaccine slowed down the memory loss and other symptoms of Alzheimer's.

伊兰公司在2002年放弃了疫苗试验。

Lan abandoned the vaccine trial in 2002.

这对淀粉样蛋白假说的支持者而言是个极其艰难的局面。

This was a very, very difficult state of affairs for the proponents of the amyloid hypothesis.

他们感到灰心丧气。

They felt discouraged.

该领域的许多人开始思考，我们是否在这里押错了宝？

Many people in the field were starting to think, have we bet on the wrong idea here?

我是查尔斯·皮勒，《科学》杂志的调查记者，也是关于阿尔茨海默病研究的新书《篡改》的作者。

My name is Charles Pillar, and I'm an investigative journalist with Science Magazine and the author of Doctored, a new book about Alzheimer's research.

查尔斯·皮勒的职业生涯一直在调查科技与科学领域的公共安全问题。

Charles Piller has spent his career investigating public safety issues in tech and science.

2021年，他将目光转向了阿尔茨海默病。

In 2021, he turned his eye towards Alzheimer's.

皮勒开始调查一篇在淀粉样蛋白级联假说遭遇困境时期发表的重要论文。

Pillars started investigating a prominent paper that came out right during that tough time for the amyloid cascade hypothesis.

2006年发生了一件深刻影响该领域的事件。

Something happened in 2006 that profoundly affected the field.

这是一项来自明尼苏达大学两位科学家凯伦·阿什和西尔万·莱斯内的杰出实验。

And this was a brilliant experiment coming from two scientists primarily at the University of Minnesota, Karen Asch and Sylvain Lesney.

这两位科学家做了件非常聪明的事。

These two scientists did something very clever.

他们成功从基因改造小鼠大脑中分离出一种特殊淀粉样蛋白，这种蛋白有个巧妙的名字——淀粉样β星56，非常朗朗上口。

They were able to isolate from the brains of genetically altered mice a particular kind of amyloid protein that had the clever name amyloid beta star 56, very catchy name.

他们提取这种星56蛋白进行纯化后注射到大鼠体内。

And they took this star 56 protein and purified it and then injected into rats.

这些大鼠随后表现出阿尔茨海默病的症状，比如记忆丧失。

And the rats then seemed to exhibit the symptoms of Alzheimer's disease, such as memory loss.

星56看起来可能就是阿尔茨海默病的核心物质。

It looked like star fifty six might be the very essence of Alzheimer's.

正是这种特定类型的淀粉样蛋白引发了症状，即便他将它从小鼠大脑转移到大鼠大脑。

This specific kind of amyloid was all it took to trigger symptoms, even if he moved it from the brain of a mouse to the brain of a rat.

这一领域注意到了这项发现。

The field took notice.

该领域多位顶尖专家认为，这项研究从根本上支持了他们关于淀粉样蛋白假说重要性的观点。

It was described by many of the top names in the field as fundamentally supporting their own ideas about the importance of the amyloid hypothesis.

因此，它成为几十年来阿尔茨海默病基础研究中最常被引用的论文之一。

And consequently, it had become one of the most cited basic research studies on Alzheimer's in decades.

当Ash和Lesney发表研究成果时，制药公司正在基于淀粉样蛋白级联假说寻找治疗阿尔茨海默病的新方法，试图避免引发脑肿胀。

While Ash and Lesney were publishing their results, drug developers were searching for new ways to treat Alzheimer's based on the amyloid cascade hypothesis, ones that wouldn't cause brain swelling.

多家公司研制出了抗淀粉样蛋白抗体。

A number of companies created antibodies against amyloids.

为测试效果，他们将抗体注射到阿尔茨海默病患者体内，认为抗体会精准定位斑块并促使免疫系统清除它们，从而改善症状。

To test them, they injected the antibodies into people with Alzheimer's, believing that the antibodies would zero in on plaques and prompt the immune system to wipe them out, leading to an improvement in symptoms.

至少，这是他们的期望。

At least, that was the hope.

现实却复杂得多。

The reality proved a lot messier.

临床试验持续了数年之久。

The trials dragged on for years.

2021年，FDA终于批准了首个抗体药物Aducanumab。

In 2021, the FDA finally approved the first antibody drug, aducanumab.

该药上市后，年治疗费用高达5.6万美元。

It was put on the market with a prescription costing a whopping $56,000 per year.

但这项批准并非没有争议。

But the approval was not without controversy.

参与评审该药物的FDA顾问中，没有一人建议批准它。

Not a single one of the FDA advisers who reviewed the drug recommended it for approval.

他们表示临床试验未能证明对患者有明显益处，且试验结果自相矛盾。

They said that the clinical trials hadn't demonstrated any significant benefit to the patients, and that the results of the trials were contradictory.

FDA无视这些建议，仍然批准了该药物。

The FDA ignored their advice and approved it anyway.

数名参与该药物试验的顾问以辞职表示抗议。

Several of the advisors for the drug trial resigned in protest.

那是在2021年6月。

That was in June 2021.

不久后，查尔斯·皮勒揭露了另一桩丑闻——不仅是关于疗效的争议，更是阿尔茨海默病研究领域内彻底曝光的学术丑闻。

It wouldn't be long before Charles Pillar uncovered a different controversy not just a disagreement regarding efficacy, but a full blown scandal inside the field of Alzheimer's research.

近年来，独立监督机构开始发现医学多个分支领域的科学论文存在不当行为。

In recent years, independent watchdogs have begun to find misconduct in scientific papers from many different branches of medicine.

有些科学家伪造数据、篡改图像，使研究结果看起来更具说服力。

Some scientists have fabricated data and doctored images to make their results look more impressive.

从癌症到心脏病学再到心理学，各领域已有数千篇论文被期刊撤稿。

In fields ranging from cancer to cardiology to psychology, journalists have retracted thousands of papers.

2021年底，皮勒收到关于其中一桩学术不端案件的线索。

In late twenty twenty one, Piller got a tip about one of these misconduct cases.

他了解到其中一位监督者——范德比尔特大学的神经科学家，名为博士。

He learned that one of these watchdogs, a neuroscientist at Vanderbilt University named Doctor.

马修·施拉格一直在调查一家名为Cassava Sciences的公司研发的一种新型阿尔茨海默病药物。

Matthew Schrag, had been investigating a new Alzheimer's drug from a company called Cassava Sciences.

针对他们工作的指控涉及在其研发药物simufilam的基础科学数据中伪造图像，该药物曾被描述为治疗甚至可能治愈阿尔茨海默病的疗法。

The allegations made about their work involved the falsification of images in their basic science behind a drug they developed called simufilam, was described as being a remedy, perhaps even a cure, for Alzheimer's disease.

施拉格注意到支持药物作用机制的部分图像存在异常。

Schrag noticed irregularities in some of the images supporting how the drug was supposed to work.

本质上，这些图像看起来像是经过Photoshop处理的。

Essentially, they looked photoshopped.

这些图像展示了药物中特定分子如何影响大脑不同区域。

The images showed how certain molecules in the drug affected different parts of the brain.

对于治疗脑部疾病而言，这相当重要。

Pretty important for a treatment for a brain disease.

当施拉格发现这些欺诈迹象时，该药物已进入临床试验阶段。

The drug was already in clinical trials when Schrag discovered these signs of fraud.

他撰写了一份报告并联系美国国立卫生研究院，警告他们Cassava公司可能基于伪造数据在人体上测试药物。

He wrote up a report and contacted the National Institutes of Health, alerting them that cassava was testing a drug on humans based on potentially fabricated data.

施拉格已尽己所能，现在可以让有关部门接手处理。

Schrag had done his part, and now he could let the authorities take it from there.

故事结束。

End of story.

事实上，这只是个开始。

Actually, this was just the beginning.

在调查Cassava Sciences期间，施拉格开始测试一些用于发现和检测可能被篡改图像的新技术。

While investigating cassava sciences, Schrag began testing some new techniques for finding and examining potentially manipulated images.

他想用一些新鲜的例子来尝试，与木薯无关的东西。

He wanted to try them on some fresh examples, something unrelated to cassava.

于是他拿起莱斯尼·阿施的研究，聚焦于56号恒星。

So he picked up the Lesney Asch study, zeroing in on star 56.

他审查了2006年发表在《自然》上的这项开创性研究——该研究在领域内极为重要——却惊讶地发现，那些验证研究基本前提的关键图像本身显然基于被篡改过的图片。

He examined this study from 2006 in nature, this seminal study that had been so important in the field and found to his surprise that some of the most important images that proved out the basic premise of the study were themselves apparently based on manipulated altered images.

皮勒与其他多位专家核实了SRAG的发现。

Pillar checked SRAG's findings with a number of other experts.

他们独立证实了这些图像曾被修改。

They independently confirmed that the images had been altered.

2022年，皮勒公开了这项发现：这篇极具影响力的论文似乎基于伪造数据。

And in the 2022, Pillar went public with the findings that this influential paper seemed to be based on doctor data.

真相曝光后发生了什么？

What happened once that came out?

产生了什么影响？

What was the impact?

这一事件对整个领域造成巨大冲击。

The story hit the field very hard.

它立即成为全球新闻头条，遍及欧洲、亚洲、南美洲和美国。

It was immediately the subject of global news headlines, including in Europe, Asia, South America, The United States.

我认为在领域内，这引发了真正的认知震动。

And I think in the field, it caused a real shutter of recognition.

莱斯尼·阿施的论文可能是阿尔茨海默病研究中最著名的图像造假案例，但绝非孤例。

The Lesne Asch paper might have been the most prominent Alzheimer's study marred by image fraud, but it was far from the only one.

施拉格发现，就连他自己的本科导师也曾为数十篇论文篡改过图像，其中包括他与施拉格共同发表的论文。

Schrag learned that even his own undergraduate advisor had manipulated images for dozens of papers, including ones that he and Schrag had published together.

施拉格随后撤回了其中数篇论文。

Schrag has since retracted several of those papers.

这些调查引发的余波持续了多年。

The fallout from these investigations has continued for years.

以卡萨瓦科学公司的药物为例。

Take the Cassava Sciences drug.

主导该药物大部分研究工作的科学家因伪造图像而被指控欺诈。

The scientist who led much of the work on the drug has been indicted for fraud for doctoring images.

卡萨瓦科学公司的CEO及其首席科学家被迫离职，并被处以数万美元罚款。

The CEO of Cassava Sciences and its head scientists were forced out of the company, and were fined tens of thousands of dollars.

2024年，该公司在临床试验失败后完全停止了阿尔茨海默病药物的研发。

And in 2024, the company discontinued development of its Alzheimer's drug entirely after it failed in clinical trials.

还有卡伦·阿什和西尔万·莱斯内发表的STAR 56论文。

And then there is the STAR 56 paper from Karen Ashe and Sylvain Lesnay.

阿什和大多数合著者认定存在图像篡改行为，并于2024年撤回了该论文。

Ashe and most of her co authors concluded that image doctoring had occurred, and retracted the paper in 2024.

但莱斯内坚持认为论文没有问题。

But Lesney stood by the paper.

由于皮勒和施拉格的工作，莱斯内和阿什曾任职的明尼苏达大学对莱斯内进行了两年半的调查。

As a result of Pillar and Schrag's work, the University of Minnesota, where Lesney and Ashe had done their research, investigated Lesney for two and a half years.

校方要求撤回他的另外四篇论文。

The university asked for four of his other papers to be retracted.

2025年初，莱斯尼辞去了他的职位。

And in early twenty twenty five, Lesney resigned from his position.

在调查了所有这些关于阿尔茨海默症的不同案例后，我是说，你对人们为何会这样做有什么见解吗？

After looking into all these different cases around Alzheimer's, I mean, you have any insight into why people would do this?

我的意思是，在任何科学领域伪造结果都已经够糟糕了，但这可是阿尔茨海默症研究。

I mean, fabricating results in any kind of science is bad enough, but this is Alzheimer's.

这些研究本可能开发出药物——无论是否有效——来帮助那些承受巨大痛苦的家庭。

These are studies that could lead to drugs that might or might not work to help families in incredible pain and suffering.

人们为什么要这么做？

Why do people do this?

当某个主导观点在领域内扎根后，撰写论文和持续强化该观点就会变得更容易，因为它已成为传统认知。

When a single dominant idea takes hold in the field, it becomes easier to write papers and to continue to reinforce that idea because it becomes the conventional wisdom.

我们在阿尔茨海默病研究中看到的——我在《篡改》调查工作中也发现——大量其他相关研究都曾被篡改。

And what we've seen in Alzheimer's disease, and I have found in my work for DOCTORED, is that a huge number of other Alzheimer's studies have been altered.

图像被篡改后扭曲了整个领域的研究思路。

The images have been altered and has skewed research thinking in the field.

其中多数与β淀粉样蛋白假说相关，部分原因是期刊、同行评审及该领域其他科学家普遍存在自满情绪。

And most of them have been associated with the amyloid hypothesis, in part because there's a lot of complacency among journals, among peer reviewers and other scientists in the field.

当某个观点获得普遍认同时，编造支持它的虚假论据就会变得更容易。

If something supports an idea that everyone believes, it become easier to create ideas that support it that are indeed false.

我请卡尔·哈罗普谈谈他对这些揭露事件的看法。

I asked Carl Harrop for his take on these revelations.

过去几年该领域陆续曝出多起丑闻，我想听听您对事件成因的看法，以及您认为这对领域会产生什么影响。

There have been a series of reports in the past couple years about some scandals in the field, and I just wanted to get your view on how this all happened and what you think the effect on the field is.

这可能会让人震惊，但科学家也是人，我们也有自尊心，有些人甚至毫无根据地确信自己了解疾病的运作机制。

This may come as a shock, but we scientists are human beings and we have egos and some of us have an unjustified certainty that we know how a disease works.

如果这种傲慢足够强烈，你会自信到当看到与理论不符的蛋白质印迹或显微镜载片图像时，就认定一定是载片出了问题。

And if that arrogance is sufficiently great, you are so confident that when you look at a Western blot or a image of a microscope slide that doesn't fit your theory, well, the slide must be wrong.

所以，我用Photoshop稍微修改一下，让它看起来符合我认为的正确答案也无妨吧。

So, it's okay if I do a little Photoshop work and make it look like what I know is the right answer.

这个问题当然不只存在于阿尔茨海默病领域，但不知为何，我们这个领域似乎特别容易吸引这类过度膨胀的自我。

It's a problem that's certainly not unique to Alzheimer's disease, but somehow our field seems to have attracted our fair share of those oversized egos.

阿尔茨海默病领域正在采取措施防止学术不端。

The Alzheimer's field is taking steps to prevent misconduct.

期刊编辑正在使用新工具来识别伪造图像。

Journal editors are using new tools to discover fabricated images.

科学家现在必须永久存档数据以供后续审查。

Scientists now have to permanently archive their data so that it can be reviewed later.

但即使这些丑闻结束，关于现有阿尔茨海默病药物的争议还远未平息。

But even if these scandals end, the controversy over current Alzheimer's drugs is far from over.

自2021年FDA批准阿杜那单抗以来，又有两种清除淀粉样蛋白的药物获批。

Since the FDA approved aducanumab in 2021, two additional amyloid clearing drugs have also been approved.

它们的工作原理基本相同，都是使用攻击淀粉样蛋白的抗体。

They work in much the same way, using antibodies that attack amyloid.

和阿杜那单抗一样，这些药物背后的假设是：只要能清除淀粉样蛋白，就能阻止阿尔茨海默病。

And like aducanumab, the assumption behind them is that if you can get rid of the amyloid, you can stop Alzheimer's disease.

但阿杜那单抗、仑卡奈单抗和多奈单抗这三种淀粉样蛋白清除药物，每年的费用都高达数万美元。

But all three amyloid clearing drugs aducanumab, lecanumab, and donanemab cost tens of thousands of dollars a year.

如果政府要为每位阿尔茨海默病患者支付治疗费用，他们的医疗预算将化为乌有。

If governments have to pay for everyone with Alzheimer's to receive them, their health budgets will go up in smoke.

更糟的是，这三种药物在临床试验中都与少量死亡病例有关联。

Making matters worse, all three drugs have been linked to a small number of deaths in clinical trials.

这些死亡案例直到药物获批后才被曝光，而且仅因调查报道和独立审查才得以揭露，并非制药公司主动披露。

Those deaths were not reported until after the drugs were approved, and even then only because of investigative reporting and independent reviews, not because the drugmakers disclosed them.

2024年，阿杜卡努单抗被生产商撤市，该公司声称此举与安全性和有效性无关。

In 2024, aducanumab was pulled from the market by its manufacturer, a move the company claims was not related to safety or efficacy.

关于疗效的争论仍在持续。

The debate about efficacy continues.

哈罗普等批评者指出，新药无法帮助患者好转，只能略微延缓病情恶化速度。

Critics like Harrop argue that the new drugs don't help patients improve, they only help them decline a little more slowly.

临床试验中所有参与者——无论是使用抗体药物还是安慰剂的患者——在18个月的试验期间病情都恶化了。

Everyone in the clinical trial, both people on antibody and people on placebo, got worse during the eighteen months of the trial.

无论是否接受治疗，没有一个人的病情出现好转。

No one got better, treatment or no treatment.

我审视这些数据后认为它通不过'祖母测试'：我会愿意让祖母的大脑承受这种治疗吗？

I look at that data and I say that doesn't pass the grandmother test, which is, would I want my grandmother to have this happen to her brain?

考虑到微乎其微的疗效，我的答案是否定的。

I say no, given the very small benefit.

即便我们承认存在疗效——对此我仍不完全确定——相对于提供的微小益处，风险实在太大。

Even if we accept that there is a benefit, and I'm still not entirely sure that there is, the risks are too substantial for the tiny benefit that is offered.

但其他阿尔茨海默病专家持不同看法。

But other Alzheimer's experts have a different take.

这两种药物的疗效大约能减缓21%的病情恶化速度。

With both drugs, the benefit was around twenty one percent slowing of decline.

当我们外推这些数据时，这可能意味着患者能多在家中生活三年，并保持相对良好的生活质量。

When we extrapolate out this data, this could be three years of living in their own home and having a reasonable quality of life.

我认为这对患者意义重大。

And I think that means a lot to patients.

是的。

Yes.

我是唐娜·威尔科克斯。

So my name is Donna Wilcox.

我是印第安纳大学医学院的神经学教授。

I am a professor of neurology at Indiana University School of Medicine.

同时我还领导着神经退行性疾病研究中心。

I also lead the Center for Neurodegenerative Disorders.

唐娜·威尔科克斯自1990年代起就开始研究阿尔茨海默病和其他形式的痴呆症。

Donna Wilcox has been studying Alzheimer's disease and other forms of dementia since the 1990s.

她同时担任《阿尔茨海默病与痴呆症》的主编，这是阿尔茨海默病协会的官方期刊。

She is also the editor in chief of Alzheimer's and Dementia, which is the official journal of the Alzheimer's Association.

她认为这些新药是一个充满希望的开端。

And she thinks the new drugs are a promising start.

试验数据表明，这些药物能让患者更容易维持科学家所称的日常生活活动能力。

Data from trials suggest that the drugs make it easier for people to sustain what scientists call activities of daily living.

我们谈论的是日常事务：刷牙、洗澡、穿衣、记得服药、吃早午晚餐。

We're talking about things we do every day: brushing our teeth, bathing, clothing, remembering to take medications, eating breakfast, lunch, and dinner.

这些都是日常生活活动。

These are all activities of daily living.

而在衡量日常生活活动的量表上，其效果更接近于减缓了35%的衰退速度。

And the benefit on a scale measuring activities of daily living was closer to a 35% slowing of decline.

认知能力至关重要。

Cognition matters.

显然，记忆力对人们很重要。

Obviously, memory matters to people.

但对于生活质量而言，我认为人们真正关心的是日常生活活动。

But for quality of life, I think activities of daily living are what people really care about.

那么在治疗阿尔茨海默病的研究中，淀粉样蛋白究竟扮演着怎样的角色？

So how much of a role does amyloid play in your work in terms of trying to cure Alzheimer's?

当我们思考淀粉样蛋白在阿尔茨海默病中的作用时，我认为我们的观点和假设已经发生了变化。

So when we think about the role of amyloid in Alzheimer's, I think our ideas and our hypotheses have evolved.

当我进入这个领域时——难以置信这已经是二十五年前的事了——我们当时主要研究一个非常基础的淀粉样蛋白假说，即淀粉样蛋白是引发因素，随后会驱动神经纤维缠结的形成。

When I came into the field, which shockingly is twenty five years ago now, we were working very much on a very basic amyloid hypothesis, which was that amyloid was the initiating factor that would then drive the formation of tangles.

这些缠结会导致神经元死亡，而正是神经元的死亡导致了认知障碍。

The tangles would cause the neurons to die, and it's the neurons dying that causes the cognitive impairment.

如果你当时问很多科学家说：

If you'd have approached a lot of scientists and said, hey.

我们有一种药物能完全清除大脑中的淀粉样蛋白。

We have a drug that completely clears the amyloid from the brain.

我想很多人会认为这就是治愈方法。

I think a lot would have thought that would be the cure.

随着时间推移和科学进步，特别是过去十年间，我们见证了科技爆炸式发展，使我们能够以不同方式研究事物。

As time has gone on and as our science has progressed and especially in the last ten years, we've had an explosion of science, technology that's allowed us to study things in different ways.

我们已经了解到淀粉样蛋白无疑是疾病最早发生的事件之一，但从淀粉样蛋白开始的病变过程要复杂得多。

We've learned that amyloid is certainly one of the earliest events that happens in the disease, but the progression from amyloid is a lot more nuanced.

因此我仍然相信淀粉样蛋白假说是正确的，只是与二十五年前相比已进行了诸多修正。

And so I do still believe that the amyloid hypothesis is correct with many, many modifications from where it was twenty five years ago.

对威尔科克斯而言，淀粉样蛋白是大脑长达数十年病变过程中的一个环节。

To Wilcox, amyloid is one step in a transformation of the brain that takes decades.

从一些出色的研究中我们得知，每个人——甚至我十几岁的孩子们——大脑都在产生β淀粉样蛋白。

We know from some beautiful studies that have been done that everybody, even my kids who are teenagers, everybody is making beta amyloid in their brain.

我们尚不清楚原因。

We don't know why.

我们不知道是何种正常生物过程导致这种现象，但所有人都会产生它。

We don't know what process, what normal biological process is causing this to happen, but we all make it.

关键在于我们都能有效清除这些蛋白。

The the thing is we all also clear it effectively.

通常通过血液或脑脊液排出。

Usually either into our blood or into our spinal fluid.

我们会将其清除。

We get rid of it.

大脑拥有处理这些废物的垃圾清理系统。

The brain has a garbage disposal system that gets rid of all this junk.

这个垃圾清理系统包括大脑中被称为小胶质细胞的特殊免疫细胞。

That garbage disposal system includes special immune cells in the brain called microglia.

小胶质细胞可能开始无法履行职责，导致β淀粉样蛋白在大脑中堆积。

It's possible that microglia start to fail at their job, and as a result, amyloid beta builds up in the brain.

威尔科克斯表示，慢性炎症可能导致小胶质细胞功能失常。

Wilcox says that chronic inflammation could drive microglia to fail.

这种炎症可能发生在身体其他部位，比如关节处的关节炎。

That inflammation might happen somewhere else in the body, like arthritis in the joints.

尽管这些炎症症状是全身性的，比如关节疼痛、肠道功能障碍。

Even though the symptoms of those inflammatory conditions are systemic, you know, joint pain, gut dysfunction.

炎症产生的蛋白质也会进入大脑，可能改变小胶质细胞功能，影响我们清除脑部废物的效率。

Those proteins that are made by the inflammation also get to the brain and probably modify the microglia and and probably modify how effectively we can get rid of the junk from our brain.

我们已有回顾性流行病学研究证实这点。

We have epidemiology studies that have looked at this retrospectively.

他们长期观察服用类风湿性关节炎药物的人群，发现这类药物似乎具有某种保护作用。

So they've looked at people who have been on drugs for rheumatoid arthritis for a long period of time, and it appears like there is some protection from that.

遗憾的是，免疫系统极其复杂。

Unfortunately, the immune system is incredibly complex.

非常复杂。

Complex.

免疫学家恐怕能把我所在的整个房间都写满各种免疫通路示意图。

You know, I mean, immunologists could probably take up this whole room that I'm sitting in writing out all the different immune pathways that exist.

威尔科克斯指出斑块堆积与阿尔茨海默病开始杀死神经元的过程有关。

Wilcox says that the buildup of plaques has something to do with how Alzheimer's disease starts to kill neurons.

一种可能是它促进了神经元内部缠结物的形成。

One possibility is that it spurs the formation of the tangles inside neurons.

但一旦神经纤维缠结开始形成，清除斑块可能无法阻止阿尔茨海默病，有时淀粉样蛋白的积累根本不会导致阿尔茨海默病。

But once tangles start to form, getting rid of plaques may not stop Alzheimer's, and sometimes the buildup of amyloid doesn't lead to Alzheimer's at all.

当怀疑论者指出那些大脑中有淀粉样蛋白却未表现出阿尔茨海默症状的人时，该怎么解释？

What about when skeptics will point to people who have amyloid in the brain and don't show symptoms of Alzheimer's.

相当一部分人，甚至六十多岁时，大脑中存在淀粉样蛋白，但他们并未表现出阿尔茨海默病的诊断特征，行为举止也完全正常。

A substantial fraction of people, even in their 60s, have amyloid in their brain, and they don't show the diagnosis of Alzheimer's and how they're acting and so on.

因此，这引发了关于淀粉样蛋白对阿尔茨海默病重要性的质疑。

So, that's led to questions about how important amyloid is to Alzheimer's.

是的，这是反对淀粉样蛋白假说的常见论据。

Yeah, and it's a common argument that is used against the amyloid hypothesis.

你说得非常对。

You're very correct.

有些人在尸检时被发现含有大量淀粉样蛋白，但生前认知功能完全正常。

There are people that come to autopsy that we look at that have a lot of amyloid and died perfectly cognitively normal.

说实话，我认为我们目前对此的真正解释仍是未知的。

You know, the true explanation for that, I think, we don't know is is the answer.

但我们对此现象有很多假设性解释。

But we have a lot of hypotheses as to why that would be.

而且想

And want

你有特别倾向的假设吗？

Do you have a favorite one?

我有个偏爱的解释，那就是认知韧性。

I have a favorite one, and that is resilience.

威尔科克斯表示，有些人或许能够弥补由炎症、淀粉样蛋白或缠结造成的损伤。

Wilcox says that some people may be able to compensate for the damage caused by inflammation or amyloid or tangles.

也许他们很幸运，遗传了保护大脑的基因。

Maybe they are lucky and inherited genes that protect their brains.

又或许他们早年的经历赋予了他们抵御阿尔茨海默病的能力。

Or maybe their experiences earlier in life gave them defenses to withstand Alzheimer's.

如果这是真的，那么我们都可以在年轻时采取措施，延缓晚年阿尔茨海默病的发展。

If that's true, then we can all take steps when we are younger to slow the progression of Alzheimer's later in life.

一些研究表明，教育、锻炼和健康饮食可能有助于抑制炎症和其他引发阿尔茨海默病的诱因。

Some studies suggest that education, exercise, and a healthy diet may help tamp down inflammation and other triggers for Alzheimer's.

生活方式的改变或许能在几十年后降低阿尔茨海默病的发病率，但阿尔茨海默病的危机已经迫在眉睫。

Lifestyle changes might reduce the rates of Alzheimer's disease decades from now, but the Alzheimer's crisis is already here.

如果我们不在阿尔茨海默病研究上取得重大进展，将会发生什么？

What's gonna happen if we don't make some big strides on Alzheimer's?

你知道，这会让许多家庭破产。

You know, it's gonna bankrupt families.

这将拖垮医疗保健体系。

It's gonna bankrupt health care systems.

数百万人将不得不入住养老院。

Millions of people are gonna be in nursing homes.

我们将有数百万正处于人生黄金期的患者。

We're gonna have millions and millions of individuals who are at the prime of their life.

像我这样四五十岁的人，会因为负担不起养老院费用而辞职照顾父母。

People my age, people forties, fifties, who are quitting work to look after their parent because they can't afford nursing home care.

如果因为员工需要照顾年迈父母而导致劳动力流失，我认为这是另一个被低估的经济影响。

And if we lose a workforce because they're caring for elderly parents, that's another economic impact that I think is underestimated.

我的意思是，过去这对我来说似乎还很遥远，但现在却迫在眉睫。

I mean, this used to seem like a long way off to me, and now it's imminent.

对吧？

Right?

我们不能再花25年时间才能让一种新药进入临床。

We can't have another twenty five years to get one more drug to the clinic.

我们必须尽快推进。

We have to be having a push as quickly as we can.

威尔科克斯乐观地认为她和其他人能应对这一挑战。

Wilcox is optimistic that she and others can meet that challenge.

一些研究人员正在调整淀粉样蛋白抗体药物，以降低其损伤血管和引发出血的风险。

Some researchers are tailoring amyloid antibody drugs so that they are less likely to damage blood vessels and cause bleeding.

与此同时，其他研究人员正在研发针对神经元内部缠结的药物。

Meanwhile, other researchers are working on drugs that attack the tangles inside of neurons.

甚至还有类似Ozempic的药物试验，可能有助于减轻大脑炎症。

And there are even trials of drugs similar to Ozempic that might reduce inflammation in the brain.

威尔科克斯承认过去对淀粉样蛋白级联假说存在过度关注，但她指出对阿尔茨海默症研究的长期支持让科学家得以探索不同的治疗途径。

Wilcox acknowledges there has been a hyperfocus on the amyloid cascade hypothesis, But she argues that long term support for Alzheimer's research has allowed scientists to pursue different avenues for a cure.

随着资金投入增加、研究深入和技术进步，我们现在对这种疾病有了更多理解。

With increased funding, with increased research, and increased technology, we understand so much more about this disease now.

我们知道淀粉样蛋白不会是唯一的治疗靶点。

We know that amyloid is not gonna be the only target.

临床试验的资金，甚至当你查看不同制药公司的投资组合时，会发现

And the funding for trials and even when you look at the portfolios for the different drug companies, there's

没有

not

太多β淀粉样蛋白的存在了。

a lot of amyloid in there anymore.

对吧？

Right?

我们正在研究其他方向，主要是因为我们已经可以将β淀粉样蛋白从清单上划掉了。

We're looking at other things, and mostly because we've been able to check amyloid off the list.

我很好奇，当你二十五年前刚进入阿尔茨海默症领域时，你认为未来会是怎样的？

I'm curious, when you started in the Alzheimer's field, over a quarter of a century ago, what did the future look like to you?

那时候，我认为整个领域包括我自己，都觉得这是个更简单的问题——只要能清除那些β淀粉样蛋白，我们就能高枕无忧了。

At that time, I think we, as a field and myself, thought it was a simpler problem and that if we could get rid of that amyloid, man, we'd be made in the shade.

我记得大概是2000年参加某个会议时，有人被问到：你觉得我们什么时候能有治疗方法？

And I remember it was probably the year 2000 going to a conference, and someone was asked, you know, when do you think we'll have a treatment?