Alzheimer's Researchers Go Back To Basics To Find The Best Way Forward

Jun 25, 2020
Originally published on June 25, 2020 9:28 am

Three research institutions in Seattle have joined forces to study how Alzheimer's disease takes root in the brain.

The consortium will create a new research center at the Allen Institute for Brain Science to study tissue from brains donated by people who died with Alzheimer's.

UW Medicine and the Kaiser Permanente Washington Health Research Group are also part of the effort, which will be funded by a five-year $40.5 million grant from the National Institute on Aging, a part of the National Institutes of Health.

The project, with its emphasis on basic research, represents part of a global do-over for the Alzheimer's field, which has weathered a series of failed attempts to develop a drug that could slow or stop the disease.

"The premise of this project here is that we need to take a step back," says Ed Lein, a senior scientist at the Allen Institute and the center's lead investigator.

That's a marked change from a decade ago, when there was great excitement about experimental drugs that could scrub away the sticky brain plaques thought to cause Alzheimer's.

Studies have shown that the drugs do their job, removing a toxic protein called amyloid-beta from the brain. But they don't help patients avoid memory loss or cognitive problems.

This image shows the buildup of toxic tau proteins in the medial temporal gyrus of a human brain. Though some drugs can now remove these proteins, that hasn't seemed to ease Alzheimer's symptoms. It's time to look more deeply into how the cells work, scientists say.
UW Medicine

As a result, pharmaceutical companies have been forced to abandon many clinical trials and have lost billions along the way.

That experience has a lesson, Lein says. Researchers have mistakenly been "trying to go right to the cure without really understanding the brain and what actually goes wrong that leads to dementias."

"We don't really understand what's happening at the very basic level of individual cells in the earliest stages of Alzheimer's disease," adds Dr. C. Dirk Keene, a neuropathologist with UW Medicine and a principal investigator at the new center.

So the consortium will focus on answering that question rather than developing treatments.

It will rely on technology pioneered by the Allen Institute that uses genetic information to classify brain cells.

"We have tools that let us understand all of the kinds of cells that make up parts of the brain," Lein says. "And we can now use these tools to understand what cell types are affected as the disease progresses."

One goal is to identify cells that become abnormal long before symptoms of Alzheimer's start to appear.

"If we can find the cells where something goes wrong, this would provide a new way to try to treat this disease," Lein says.

The project will look at neurons, which communicate using electrical signals, as well as glial cells, which are involved in immunity and functions like clearing away debris. There have been hints that glial cells play an important role in the development of Alzheimer's.

Another goal of the project is to look beyond the plaques and tangles in the brain that have been the focus of most treatment efforts.

"We need new targets," Lein says. We need new places to try to intervene in the disease at earlier stages ... before things have really gone haywire and the neurons themselves are actually dying."

Even though the focus is on basic science, it could lead to a treatment, Keene says.

"In the greatest scenario, I would love to find that cell that starts the process — where it is, when it happens and how to stop that from happening," he says.

But Alzheimer's is a complex disease, he notes, and probably won't be explained by a single abnormal cell.

"There's probably some cells in the brain that are causing problems and there's probably other cells in the brain that are trying to fix the problems," he says.

The consortium hopes to identify those and any others that are somehow involved in the process that leads to Alzheimer's. And, as with other projects at the Allen Institute, all the data will be freely available to the scientific community.

Copyright 2020 NPR. To see more, visit https://www.npr.org.

DAVID GREENE, HOST:

In Seattle today, three research institutions are unveiling a joint effort to learn precisely how Alzheimer's disease gets started in the brain. The project is part of a widespread do-over for the field of Alzheimer's research, which has endured the series of failed attempts to develop a treatment. Here's NPR's Jon Hamilton.

JON HAMILTON, BYLINE: A decade ago, there was a lot of excitement about experimental drugs that could scrub away the sticky brain plaques thought to cause Alzheimer's. The drugs did their job. But they didn't prevent the disease. And Ed Lein of the Allen Institute for Brain Science says that tells us something.

ED LEIN: We simply don't understand the system we're trying to treat very well. We're trying to go right to the cure without really understanding the brain and what actually goes wrong that leads to dementias.

HAMILTON: So the National Institute on Aging has awarded a $40 million grant to create a center run by the Allen Institute and two other Seattle institutions, UW Medicine and Kaiser Permanente. Lein is the center's lead investigator.

LEIN: The premise of this project here is that we need to take a step back.

HAMILTON: Lein says the idea is to use technology pioneered at the Allen Institute to study brains donated by people who died with Alzheimer's disease.

LEIN: We have tools that let us understand all of the kinds of cells that make up parts of the brain. And we can now use these tools to understand what sorts of cell types are affected as the disease progresses.

HAMILTON: Lein says one goal is to identify cells that become abnormal long before symptoms of Alzheimer's start to appear.

LEIN: And if we can find the cells where something goes wrong early in the disease, this would provide a new way to try to treat this disease.

HAMILTON: Lein says the project will look at neurons, which send electrical signals, as well as other brain cells involved in immunity and clearing away debris. Another goal of the project is to look beyond the plaques and tangles in the brain that have been the focus of most treatment efforts.

LEIN: We need new targets. We need new places to try to intervene in the disease at earlier stages in the disease, before things have really gone haywire and the neurons themselves are actually dying.

HAMILTON: One of the principal investigators at the new center is Dr. C. Dirk Keene. He's a neuropathologist with the UW Medicine, which includes the University of Washington Medical School. Keene says even though the project is focusing on basic science, it could lead to a treatment.

C DIRK KEENE: In the greatest scenario, I would love to find that cell that starts the process - where it is, when it happens and how to stop that from happening.

HAMILTON: But Keene says Alzheimer's is likely to prove more complicated than that.

KEENE: There's probably some cells in the brain that are causing problems. And there's probably other cells in the brain that are trying to fix the problems.

HAMILTON: Keene says the project should help identify those cells and any others that are somehow involved in the process that leads to Alzheimer's. And all the data from the project will be available to any scientist who wants to use it. Jon Hamilton, NPR News.

(SOUNDBITE OF TOBACCO'S "SPIRITS OF PERVERSION") Transcript provided by NPR, Copyright NPR.