- In 2022, news broke that a critical, groundbreaking Alzheimer's research paper had allegedly been a fraud.

The paper, which found that a specific protein built up in the brain and caused Alzheimer's disease included manipulated data, and the media began to speculate on how many billions of dollars and thousands of hours of scientists' time had been wasted.

But then nothing.

The news article stopped, and the research continued, and now there are two potentially helpful Alzheimer's disease drugs on the market.

Since then, the evidence for fraud in that paper has piled up.

But so has evidence for protein buildup in the brain causing Alzheimer's.

Did fabricated scientific results accidentally set us on the right path towards a breakthrough?

Also, spoiler alert, we still don't really know what Alzheimer's is, so we need to talk about that too.

I'll come back to that at the end when I'm warm.

Alzheimer's disease is tricky because while we know a lot of the signs, symptoms, and pathologies associated with it, there's not one clear path from a single genetic mutation or environmental exposure that results in disease.

In other words, we don't 100% know what causes it, and we don't 100% know how each of the different things involved affects progression.

Behaviorally, the disease results in cognitive decline, memory loss, and personality change, which can have devastating effects on both those with the disease and loved ones around them.

Genetically, we can see an association between versions of a gene called APOE, which makes a protein that helps carry fats and cholesterol through the blood and an increased incidence of disease.

And the cellular level is seemingly both the most clear and the most complicated when it comes to knowing what's actually going on.

Cell death in the brain is tied to symptom onset.

That much is clear.

And if you look closely at the brain of a patient with Alzheimer's disease, you'll likely notice two main things at a cellular level.

The first are clumps of plaques of a peptide known as amyloid beta.

They were one of the first things that Alois Alzheimer noted when he described the disease back in 1906.

And yes, they are so visible that you could see them with 1906 technology.

While we don't actually know the normal function of amyloid beta, we do know that when amyloid beta precursor protein is cleaved into 40 or 42 amino acid long hydrophobic strings, they can aggregate into plaques outside of cells in the brain.

So basically, the proteins that normally make up amyloid beta get sliced at a specific place and form blobs that can't dissolve in water.

And these plaques typically start to show up about five to 10 years before behavioral symptoms.

But unfortunately, imaging techniques that detect these plaques can be expensive, uncomfortable, and invasive.

So they usually go undetected until symptoms start.

The second thing you might notice looking closely at the brain of someone with Alzheimer's disease are flame-shaped tangles of a protein called tau.

They really do look like a flame.

This time the tangles happen inside the cells of the brain rather than outside, like the amyloid beta plaques.

My hairbrush, no.

So to cure Alzheimer's, we just need to get rid of these plaques and tangles, right?

Easy, we solved it.

Nobel Prize here we come.

This is in fact one of the leading strategies that people are trying to solve Alzheimer's.

It is the amyloid beta hypothesis, the idea that these plaques are the primary drivers of disease, and that if we can get rid of them, we can cure it.

It is been one of the leading hypotheses for decades, but it is still just a hypothesis.

There is some evidence to support it, but no one has definitively shown that these plaques cause Alzheimer's or that removing them relieves symptoms, until.

One of the ways that people try to study both the causes and effects of these plaques is through mouse models, meaning that they genetically engineer mice to approximate Alzheimer's in humans.

One of these mouse models, given the super easy to remember name, Tg2576, produces way too much of the human version of the amyloid precursor protein that forms plaques, and also includes a mutation that leads to familial Alzheimer's, a rare form of the disease.

These mice wind up with some memory function impairment, much like what you would see in Alzheimer's disease.

And then an Earth-shattering study in 2006 found that these mice produced a very specific type of amyloid beta that had never been seen before called amyloid beta*56.

When they isolated that peptide and they injected it into rats, the rats developed memory issues.

Cause, effect.

The paper was incredibly highly-cited and at the time seemed like it might have finally proven the amyloid beta hypothesis.

We'll get back to that.

The paper found amyloid beta*56 using a lab technique called a Western blot, which looks something like this.

Do you see this band here?

That's amyloid beta*56, allegedly.

I really wanted to run a western blot to show you how this works, and I have run them before, and they are a nightmare and expensive, and I don't want to go back to that deep, dark place in grad school.

So instead, I found a friend.

- A lot of our animal models.

- [Narrator] This is Claire.

- Only recapitulate certain aspects of the disease.

So they either focus on the amyloid beta plaque pathology or they focus on the telepathy.

- [Narrator] Claire Butler is a postdoc in part of a consortium called Model AD that helps generate most models for studying late onset Alzheimer's.

- So we are really generating models that have both of those pathologies, plus other pathogenesis and other pathways.

- [Narrator] Claire very kindly, let me follow her around with the camera while she's set up a Western blot.

Basically, you take a sample that you want to look at proteins from, homogenize it and mix it all up and then put it into a gel that separates out the components by size.

- Put the electrodes in and then, so I've already set up the conditions there, 125 volts for an hour and 45 minutes.

Oh yeah.

- [Narrator] Sorry, the glare was- - [Claire] Yeah, probably too much.

And you just press "run".

And so to know if it's actually going properly, you'll see these little bubbles here.

So this means that you're actually getting an electrical current through the gel.

- [Narrator] Amazing.

But you can't see them in the clear gel, so you have to transfer the proteins from the gel to a membrane using electricity, and then use antibodies that bind to the proteins that you want to see to make them show up when you run it through this very, very fancy scanner.

- [Claire] Let me just press "start".

(machine whirring) I was going to say, it's going to take like- This is good because this is starting to look overexposed.

Whereas here you can see some of those red bands here.

- [Narrator] Yeah, a little bit, - [Claire] Not too strong.

The whole thing takes around two days, and at the end you get a picture like this.

On the left is a ladder, essentially a ruler of known protein sizes.

So for each sample in a vertical column or lane, you can judge what size your protein of interest is.

And so there is amyloid beta*56, right there at the 56 kilodaltons spot.

And you can see that, allegedly, it becomes more abundant as the mice get older.

But if we zoom in a bit and computer enhance, you'll notice this supposed amyloid beta*56 line looks strikingly similar to this other line from another part of the Western blot.

Look at all the other lines in this image.

Each one is a unique shape of proteins and antibodies come together at one point in the gel.

But this one, one of the most cited Western blots in the history of Alzheimer's disease, is not unique.

And there were lots of problems like this across multiple Western blots in this paper.

After years of considering this, nature just retracted that original paper in June of 2024, because they agree, there were problems here.

But by the time that paper was retracted, billions of dollars had already been spent chasing down this amyloid beta hypothesis.

And now, one of the most convincing pieces of evidence supporting it turned out to be MS Paint.

But research kept moving.

I remember reading this expose of this fraud two years ago while I was traveling in an airport and thinking, everything's going change, and then nothing changed.

Did I imagine all that?

Have I been Mandela affected?

I emailed a number of Alzheimer's research to ask if maybe I was missing something, but they all agreed that while the paper was highly-cited and influential, the field was already well on the path of investing in research on the amyloid beta hypothesis before this ever came out.

This paper added fuel to the fire, but it didn't radically change the path that researchers were already on.

Scientists still strongly believe that amyloid beta is important for disease development, just not amyloid beta*56.

In spite of this glaring, ugly, and honestly kind of sloppy fraud, amyloid beta is still one of the most likely culprits or signs or co-occurrences.

So with how complicated what we do know about this disease is, how do we treat it?

Ideally, you want to treat someone before disease symptoms start, because currently our best treatments can lessen disease progression, but not reverse it.

There are two on the market right now, both attempting to clear amyloid beta plaques out of the brain using antibodies.

If this all sounds a little shaky based on our lack of clear understanding in the relationship between amyloid beta and Alzheimer's, you're not wrong.

But these two drugs targeting amyloid beta both seem to at least slow cognitive decline over an 18-month period.

Unfortunately, both come with low to moderate risks of brain swelling or bleeding, and neither reverses the progression of disease.

But with no better options at the moment, it is worth patients and families considering those trade-offs.

Interestingly, we're not quite sure yet why they work.

Researchers have some hypotheses based on how your brain processes clotting, but again, we're still a little bit in the dark here.

So did alleged fraud throw us down a path towards wasting millions of dollars?

No.

Did it leave us right to a cure for the disease?

Also, no.

It did lend some support towards the therapies that are currently our best bet.

But not only is that not good justification for manipulating data, but the picture is still very complicated, and it's not like our current best bet therapies are home runs either, but we are getting there through the good, honest, hard work of lots of people, including people like my new friend Claire.