What causes Alzheimer’s?

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More than than 6 million Americans are currently living with Alzheimer's disease.

It's a terrible neurodegenerative form of dementia that destroys the memory and physically deforms the brain.

As the population ages, this 6 million number will only increase.

So scientists have been searching for an Alzheimer's cure for decades, but they haven't had much luck.

You know, my father died of dementia, and it's really hard, but I also, I expect for science to be having a hard time with this.

This is Alexis Pedrick.

She's the host of the science history podcast, Distillations.

You know, the brain is complex, and if all these researchers are going back and forth over different theories, that makes sense to me.

That's what Alexis told her producer, Rigo Hernandez, when he pitched her a story on Alzheimer's.

And Rigo sort of stopped me and said, well, but we're not going back and forth over all these different theories.

We've been pursuing one theory, the same theory, for about 30 years.

And that kind of stopped us in our tracks.

I mean, it blew our minds, this idea that we've kind of been excluding all other sort of research and ideas and treating science like it's this zero-sum game.

I'm Noam Hassenfeld, and this week on Unexplainable, How We Got Stuck in This Zero-Sum Game, which has led to an even trickier question.

What does that mean for a disease like Alzheimer's?

So Alexis, before we get into the different hypotheses of what might be causing Alzheimer's, Do we have any understanding of how it actually works in the brain?

A little bit.

I mean, we don't know a lot.

So back in 1906, there was this guy, Dr.

Aloise Alzheimer, and he observed this patient of his that had delusions and memory loss.

And after he did this autopsy, he stained the tissues of her brain and he found all these sticky plaques and tangles.

And that's kind of what we consider to be the hallmark of the disease now.

So, you know, we know what it looks like.

We know what it does.

but we don't know exactly what causes it.

Okay, so this is, I assume, where we get to the different theories, right?

Right, exactly.

So what's the one hypothesis that's been dominating Alzheimer's research?

So it's called the amyloid hypothesis because it focuses on this type of brain trash called the beta amyloid.

Brain trash?

Yeah.

Okay.

It's a technical term, brain trash.

Sure, yeah, it sounds technical.

So basically, your brain's a really busy place.

It's got neurons that are constantly firing off and doing things.

And these neurons and all the other cells in there, they produce trash, like the beta amyloid protein.

So in a normal brain, all that gets flushed out.

It's fine, no problem.

But the amyloid hypothesis says that when the beta amyloid doesn't get flushed out, you get these sticky plaques that Aloise Alzheimer observed.

And that's when you have the hallmarks of Alzheimer's.

The memory loss, the cognitive impairment, everything he was seeing that patient do.

So the idea in this hypothesis would be to just get rid of all the beta amyloid proteins, you know, the brain trash, and that would help Alzheimer's patients get better.

Yeah, if we can prevent it from building up and causing all these problems, all systems go.

This is still just a hypothesis, though, right?

How did it take over Alzheimer's research?

So we talked to this guy named John Hardy, who's a geneticist in the UK.

And he's out, he's doing his research in the early 1990s, and he found that plaques could form when there was a mutation in the protein that produces beta amyloids.

And that's what really kicked things into high gear.

Many, many other hypotheses have been suggested.

And when we found the mutation, I felt this was the referee.

And so the referee called it for the amyloid hypothesis.

That's how I felt it.

And I think that's how everybody else felt it.

The way he explained it made a lot of sense.

If you have this mutation that causes you to have a lot more beta amyloid, all that buildup reaches critical mass.

It causes inflammation.

It gives you these tangles.

The neurons start to die.

And then you've got Alzheimer's.

Okay, so it's not like an injury.

It's not an accident.

It's just something genetic.

It's just something genetic.

I mean, it's a mutation, according to his theory.

He describes this thinking.

He dashes off a letter to the journal Nature with his findings, you know, kind of explains all this evidence he's found and what he thought thought was compelling.

And when I wrote the article, which is called the amyloid cascade hypothesis, I wrote that over a weekend,

literally without thinking.

We just sent it in, and to my amazement, it was accepted immediately.

And were there other ideas besides the amyloid hypothesis floating around in the early 90s?

Yeah, so there's a couple.

One is that there's a virus, or you can think of it like an infectious agent that's actually causing Alzheimer's.

There's another one that says that there could be these misfolded brain proteins known as prions

or another brain protein called tau.

And like, that's what actually causes the sticky plaques and tangles.

And that's where Alzheimer's is coming from.

But the amyloid hypothesis blows up.

And the amyloid hypothesis is king, basically.

So how did the amyloid hypothesis win this zero-sum game and take over Alzheimer's research?

I'm going to say something that sounds a little bit flippant, but it's not flippant.

It blew up because we're human and we like easy answers.

Frankly, it was simple.

It was easy to write the arguments down in a convincing way.

And it was therefore easy to sell within pharma and within academia.

It was a clear narrative.

You know, it was a clear target, amyloids.

If we get to the amyloids, we can do something about this.

We can fix it.

And so we ran with that.

Is that a bad thing?

That, you know, it seems like scientists found what they think is the cause of the problem.

They pour lots of resources into it.

That seems like, you know, the beginning of a success story, right?

Yeah.

I mean, listen.

Bad is probably not a good descriptor.

You know, it's an understandable thing.

I'm human.

I like easy answers.

But there's two sort of big problems with this.

One is that we haven't been investing in other hypotheses.

And that might be fine if it weren't for problem number two, which is that it doesn't seem like this one completely works.

Between 1998 and 2014, 123 Alzheimer's drugs failed in clinical trials.

For 30 years, right, we've been developing and testing drugs all pegged to the amyloid hypothesis.

A promising experimental Alzheimer's drug.

An experimental Eli-Lee drug.

The drug developed by pharmaceutical giants Pfizer and Johnson Johnson.

Failed its first clinical trial.

Failing to meet end goals in a pivotal study.

We've had some drugs that do seem like they can target the plaques, but that doesn't really...

That doesn't really seem to move the needle in terms of the rest of the cognitive impairment and memory loss.

The drug did not prove effective at slowing memory loss.

Experts say this is a big blow to a theory about the cause of the disease that Alzheimer's is caused at least in part by brain plaque.

So it's not working as well as we would want it to work.

So scientists had this consensus that amyloid proteins were causing Alzheimer's and there were some drugs that actually did work on the amyloids

but that didn't actually help Alzheimer's patients get better.

So doesn't that mean that the amyloid hypothesis might be wrong?

Yeah, so back when we spoke with John Hardy, he didn't really think it was wrong.

I don't think it's wrong, but I think it is oversimplified.

Science is about evidence.

You know, if you're not worried about the results of the clinical trials, then you're not a scientist.

So of course I take these failures absolutely seriously.

And of course, they have made me change my views.

I mean, I think it's easy to get really caught up in whether or not this hypothesis is right.

But actually, the point is not whether or not it's right.

It's that we have put all our eggs in the basket of the amyloid hypothesis.

And that means we're not putting energy into looking at anything else.

And that means we could be missing something important.

But there are other ideas around there.

It's just

because amyloid made so much sense and we really want it to work, anything that doesn't fit into that has been sidelined.

So for these other hypotheses that aren't about amyloids, what does that sidelining actually look like?

So we talked to this neurobiologist named Ruth Izaki.

Professor Izaki and doctor if you prefer, or just Ruth, whichever suits you.

And she was working on one of the other Alzheimer's hypotheses, the one I told you about, the virus infection.

And basically, you get an infection, like say a common form of oral herpes, right?

The thing that gives you cold sores.

And that infection spreads to your central nervous system where it leads to inflammation and Alzheimer's and these sticky plaques.

So, Ruth is looking into this.

This is her theory.

And she said she would submit all these papers and she'd get rejection after rejection after rejection.

I can't remember how many journals we tried, but we certainly tried several, all of which refused it.

She would go to these conferences and they either wouldn't allow her to speak or, you know, they'd cut her time down.

You know, one conference she said she went to in 2004, she got squeezed into the schedule and she had like 10 minutes tops.

I was told that it was apparently a huge battle to let them agree even to my giving a talk for 10 minutes, which of course was one of many other 10 minute talks and therefore attended by relatively small number of people.

Mostly they would just relegate her to having a poster.

Which was generally ignored by the people who were, let's say, senior and influential.

So it's a vicious cycle.

You know, you don't get any attention, so you don't get published.

Your hypothesis doesn't get out there.

You don't get any money.

So then you have less money to explore why your hypothesis would work or not work, right?

And it just keeps going and going.

I mean, I was very upsetting all the time.

I was worried that my lab would just disappear, but the people who were working with me were all on short-term grants.

And if I didn't get money to continue, they'd obviously have to leave.

So that went on for years and years.

Do we know who was actually sidelining Ruth?

Like who was making the decisions here?

Oh man, that is a complicated question.

Okay.

So, you know,

you can say, yes, the conference organizers gave her less time, right?

But the conference organizers are also responding to a broader community of science.

And those people are responding to funding and to research and to publications, people who report on it and decide which stories are the most interesting stories, which ones have legs and the general public.

So if this were as easy as kind of saying this one person or these one group of people made a bad decision, it's kind of like when I say we, I really do mean we, like all of us.

What does Ruth feel like could have happened to the viral hypothesis that she was working on if she hadn't been sidelined?

I mean, for her, you know, if she had an opportunity to really explore this, we might find that maybe there's maybe Alzheimer's works in a way that we hadn't considered before.

Or we might find that, you know, she was completely wrong.

And it turns out, actually, it's not a virus infection.

The point is that, you know, science is about asking questions, right?

Yeah.

And I assume it's not just Ruth who's being sidelined, right?

I imagine, you know, you named a couple of hypotheses here from virus to tau to others.

I mean, could we have even other hypotheses if we hadn't been so singularly focused on the amyloid hypothesis?

Yeah, absolutely.

And I think, you know, on our podcast, we're looking at science that happened 100 years ago, 50 years ago, you know, 500 years ago.

And the one consistent truth is that we get to our best work by having lots of different hypotheses, hypotheses, lots of different ideas.

Even if that makes science really, really messy

and difficult to navigate, that's what we need.

So if we did not sort of sideline everything else before we had deeply explored them, we would be in a different place right now, I think.

After the break, what happens when scientific research is carried out as a a zero-sum game?

We'll take a look at the consequences of sidelining research for patients, their families, and the entire medical system.

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Unexplainable, we're back, and I'm here with Dylan Scott, healthcare reporter at Vox.

Hi.

In the first half of the show, we were talking about this single-minded focus on the amyloid hypothesis, which has sort of prevented these other ideas about how to treat Alzheimer's from taking hold.

So I guess when we're thinking about nowadays, what are the consequences of this type of attachment to a hypothesis that hasn't really made a lot of progress?

I mean, first and foremost, the record of Alzheimer's drug development over the past few decades has has been one of failure.

Between 1998 and 2014, about 130 drugs went through clinical trials trying to treat Alzheimer's disease, and almost all of them have failed.

But now we just got this brand new Alzheimer's drug approved, right?

First time in a while.

Yeah.

This summer, the FDA approved a drug, finally, the first drug in nearly 20 years for Alzheimer's disease called Aducanumab.

And it has been developed by Biogen, one of the major pharma manufacturers in the world.

And they really got started testing this drug back in 2015.

And what they found was there did seem to be an effect on the amyloid plaques, but in terms of cognitive functioning, patients did not really seem to be seeing a benefit.

So this drug has sort of just done what other amyloid drugs have done in the past, right?

It does what it's supposed to do.

It removes the amyloids, but patients aren't getting better.

Yeah.

It seems so clear that in March of 2019, Biogen announced like, this drug isn't working.

We're going to halt these trials.

You know, this was another dead end in the pursuit of an Alzheimer's treatment.

Okay, same story, same result, right?

Yeah.

But they came back in October of 2019 with a surprise.

They said that like after some of these patients had been allowed to finish the treatment, they went back in.

They had two trials going simultaneously, and they actually found that in one of those trials, according to their read of the data, there was a subset of patients who had actually seen a cognitive benefit from the disease.

Okay, okay, a subset of patients?

A subset of patients, exactly.

And they basically found like, well, if you look at these specific patients and if we throw out a few other patients who, it turned out had a very rapid progression of Alzheimer's disease.

In other words, if we trim the data a little bit to our liking, we can show a positive effect for some patients.

Would it be fair to say that that's sort of like shooting the arrow into the tree and then painting the target on afterwards?

I mean, yeah, it does seem like that kind of thing.

You know, to put it mildly, this is a really unconventional way for data to be analyzed, and it's certainly not typical for data that's going to be used as the foundation for the FDA to approve a drug.

So what happens then is Biogen says, well, we think we've shown some benefit and we're going to push ahead for FDA approval anyway.

And so, the FDA Advisory Committee for Neurological Therapies gets together and they all sit down and they look at the data, and they are almost unanimous in saying that the drug does not actually seem to be effective.

And so, you know, usually that would mean that the FDA would not approve this drug.

But then, this June, the FDA said that, in spite of this track record in the clinical trials, we are going to go ahead and approve this drug for use by patients in the U.S.

This is weird, right?

It's not normal.

This is not how things are usually done.

What could they have possibly been thinking?

I mean, like, what is...

You're outlining all the arguments against approving this drug.

Like,

why would they approve it?

Well, that's a good question.

And honestly, I don't think we have a very satisfying answer to that question.

You know, the FDA itself has asked an independent investigator to probe the approval of Adjucanumab and kind of figure out what happened, which I think speaks to how strange the circumstances of this drug's approval really were.

But I think there's at least three things that may have motivated the FDA's decision-making.

What kind of things?

First and foremost, like there clearly is a way to splice this data and show some positive effect for some patients.

Secondly, I think there is some optimism within the FDA and certainly in the Alzheimer's advocacy community that now that we've had one drug approved, the hope would be that this will lead to more drug development down the road.

But the third, and I think maybe the most persuasive argument in favor of the FDA approving this drug is on behalf of the patients.

You know, there are people out there who just want a chance to try this drug.

And, you know, we've seen the FDA do this with cancer drugs, where they've approved a new treatment that in the clinical trials only only shows a marginal benefit, not that different from what we're talking about with this Alzheimer's drug.

And I think the thinking behind those decisions is here are people who are facing a terminal illness.

What's the harm in letting them try something that might have a benefit for them?

Is it really as simple as that?

I mean, there must be downsides to just throwing spaghetti at the wall and seeing if it sticks, right?

Absolutely.

There are downsides to approving a drug in this way.

You know, I think for starters, the most important difference between adjucanumab and these cancer drugs we're talking about is that like with any given cancer, it's going to be a pretty small number of patients who actually qualify for this hypothetical drug that may or may not be effective.

But when we're talking about Alzheimer's disease and adjucanumab, there are 6 million people in the U.S.

right now who are diagnosed with Alzheimer's disease.

And we're expecting millions more people to be diagnosed in the coming years as our population is getting older.

Yeah.

And so this is a drug that's really expensive.

Biogenists set a list price of $56,000 a year.

And on its own, it could double Medicare's drug spending every year.

And this is all for a drug that we're not even sure whether or not it works.

So it's certainly possible that we're going to have this drug that overwhelms the U.S.

healthcare system because it costs so much.

And we're just going to be giving the patients who receive it false hope because it doesn't even work.

Yeah.

I mean, how do we weigh the potential benefit of hope against the potential downside of false hope to millions and millions of people?

Well, I think it's telling that the Alzheimer's community itself is divided on this question.

I've talked to people who work with patients, who work with caregivers, and what they've heard from those folks is maybe half of them are really excited.

You know, I was listening to an episode of Today Explained recently where a patient was participating in the Ajucanomab trial and seemed really exhilarated about it.

I am very sympathetic to the scientific method.

I am trained to believe in the science.

But I guess I wish the scientists could

understand

that this is the first ray of hope that those of us living with Alzheimer's have had.

And you've got other people who are actually really mad, who feel like Biogen and the drug industry are taking advantage of them and selling them false hope.

And one of the people that I spoke with was Randy Epstein, who's a medical reporter, but also somebody who has a very direct connection to Alzheimer's disease and knows the toll that it takes on people.

My dad's name was Robert V.P.

Hutter.

When she was young, her dad was really, really smart.

He was a doctor.

A brilliant pathologist, a world-renowned pathologist, a quiet person with a dry sense of humor.

He ended up up later in life being diagnosed with Alzheimer's disease, and he actually died a few years ago before this new drug was available to patients.

But Randy remembers her mom desperately searching for a cure or a treatment, anything that could potentially buy them more time.

I think it's really hard when you've been married to someone who's your equal or been with someone or partnered

and you see their decline.

How can you not try something?

But she also, you know, she's a reporter.

She's somebody who has a pretty astute sense of good practices in medicine.

And she doesn't buy the idea that any kind of hope is worthwhile.

Because to her, there is something predatory about putting a drug out on the market with limited evidence of its effectiveness and then expecting people who are desperate for hope to be able to make a rational decision about it.

I am actually so glad my father is not alive during this debate.

I'm glad that my family does not have to debate whether he should take this drug.

I can't imagine right now

someone who has a mother, a father, a partner with Alzheimer's.

Who do they look to for advice?

Right now, I'm not sure they can look to the FDA.

I'm not sure they can look to the Alzheimer's Association.

And not everyone can pick up the phone and like call the chair of neurology and have an in-depth discussion.

People are just,

I feel bad for that anxiety of what people are going through.

You know, I think it's easy to blame the FDA here.

And obviously there are good arguments for blaming them.

But it also seems like from talking to Alexis in the first half of the show, this is just a much bigger problem than just the FDA, right?

This seems like a problem.

that's been decades in the making that comes from the entire scientific community thinking that one hypothesis is the only way to treat Alzheimer's.

And then even after scientists get sign after sign that it's not working, they still stick with this original hypothesis.

I mean, that all just doesn't seem like the way science is supposed to work.

Well, right.

I mean, my understanding of science is that it's, it's a process of trial and error.

And yeah, you figure out what works and what doesn't, and then you update your assumptions accordingly.

And what's frustrating about what's been happening with Alzheimer's drug development and drug research is that we don't seem to be updating our assumptions, even as we get all of this evidence that a particular hypothesis isn't necessarily panning out.

And you know, when the conventional wisdom becomes calcified, when we become so stuck in our ways that we're not receptive to alternative explanations or other approaches, you end up in a situation like we have now, where we have a drug being approved with limited evidence, and all it may be offering to patients is a false sense of hope.

This episode was reported and produced by Rigo Hernandez, Dylan Scott, Alexis Pedrick, and me, Bird Pinkerton.

It was edited by Noam Hasenfeld and Brian Resnick with help from Meredith Hodnott and Manding Nguyen, who also did the fact-checking.

Noam wrote the music, Christian Ayala did the mixing and sound design, Lauren Katz wrote our newsletter, thank you Lauren, and Liz Kelly Nelson is the VP of Vox Audio.

We also wanted to shout out the amazing Sharon Begley who died earlier this year.

This episode draws on her award-winning reporting on Alzheimer's disease and the amyloid hypothesis and we really wish we could have had her on the show to talk about it.

Special thanks as well to the Science History Institute, to Russ Paulson and Rachel Sachs, and to Randy Epstein, who wrote a really great book called Aroused: the History of Hormones and How They Control Just About Everything.

If you want to hear more about Alzheimer's, the Distillations podcast actually did a two-part episode on the subject.

And their first part is all about the effects that Alzheimer's disease has on caregivers.

So it's really worth checking out.

We will link to that in our newsletter, which you can subscribe to at vox.com slash unexplainable.

It's very worth it.

If you have a minute to leave us a review or a rating, we'd really love that.

But we'd also love to hear from you.

So email us.

We're at unexplainable at vox.com.

Unexplainable is part of the Vox Media Podcast Network, and we'll be back in your feed next week.

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