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In 1906, Dr. Alois Alzheimer worked with a patient named August D., a woman with extreme memory loss and paranoia. After she died, Alzheimer looked at her brain in autopsy. He found it had shrunk, and that there were unusual buildups in and around her nerve cells.

The main component of those buildups wasn’t identified until 1984 — it’s a protein called beta amyloid. Clumps of it in the brain are now considered hallmarks of Alzheimer’s disease.

Alzheimer’s disease currently poses a huge threat to our health and our economy — more than 5 million Americans are estimated to currently have the disease. But it has been as good at evading treatment as just about any disease out there.


The last Alzheimer’s drug approved was in December 2014, and it was a combination of two existing drugs. Before that, a new medicine for Alzheimer’s hadn’t entered the market since 2003. Of the six drugs ever approved to treat Alzheimer’s, none slow its progression.

But that hasn’t stopped drug makers from trying. For the better part of three decades, scientists’ efforts have been focused on beta amyloid — those buildups Dr. Alzheimer saw in his patient’s brain.


The theory that beta amyloid is a key part of what causes Alzheimer’s is known as “the amyloid hypothesis.” It says that targeting amyloid should improve the memory loss and other cognitive changes seen in Alzheimer’s.

Drug developers have tried to do this in a lot of different ways — some by removing it from the brain or bloodstream, others by preventing the plaque’s formation, and still others by training the body’s own immune system against it.

The industry as a whole has so far struck out. Out of 244 drugs tested between 2002 and 2012, only one successfully got to market.

But biotech company Biogen has confidence — or at least high hopes — in the prospects of one of its newest drugs, called aducanumab. It’s moved the medicine directly to Phase 3 trials and invested more than $2 billion in the program.

Listen to the last episode of the podcast: How biotech went from a risky investment to a booming business

However, not everyone in the field agrees that beta amyloid is even the right place to focus.

“Amyloid’s in the brain, we know that — but what role it has in the etiology of Alzheimer’s is unproven,” says Jeff Jonas, CEO of Sage Therapeutics, a biotech company in Boston. He’s in a camp along with many others in the field who think beta amyloid may be a dead end.

“The long string of clinical failures for this approach does not augur well for this approach to be a breakthrough therapeutic intervention for Alzheimer’s disease.”

Inside a healthy brain, proteins called beta amyloids are destroyed; in the brains of people with Alzheimer's disease, they are not and accumulate to form sticky plaques. Dom Smith/STAT

More recently however, scientists have discovered a possible genetic link to Alzheimer’s through a mutation in something called the amyloid precursor protein — a gene that appears to be linked to a person’s risk for getting Alzheimer’s disease. The finding boosted the efforts of companies like Eli Lilly, which will publish results of its Phase 3 study later this year.

But will it be enough to quiet skeptics of the amyloid hypothesis?

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The Signal podcast is produced by Katie Hiler.

Correction: An earlier version of this story misidentified a company engaged in a Phase 3 study of an Alzheimer’s drug. The company is Eli Lilly.