After a great failure, scientists and patients are looking for a new type of drug for Alzheimer's disease

Scientists are defining a new path in their quest to treat Alzheimer's disease.

The shift comes from necessity. A series of expensive failures in experimental drugs targeting a toxic protein called amyloid beta has led to a shift in approach.

The latest disappointment came in March, when drug maker Biogen and partner Eisai announced the discontinuation of two large-scale clinical trials of an amyloid drug called aducanumab.

"It was as if I had been punched in the stomach," says Phil Gutis, 57, an Alzheimer's disease patient in one of the trials. . "Participating in this trial has given me hope for the future."

Gutis, who has already been a journalist for The New York Times and worked as a lawyer at the American Civil Liberties Union, had hoped that the experimental drug would preserve some of his remaining memories.

"I'm just being erased," he says.

The day before the end of the trial of the aducanumab, Gutis had flicked photos of his dog Abe, a Jack Russell terrier, who died last year. He was trying to remember the companion who had shared his life for 12 years.

"But there were no memories," he says. "And then, I talked to a friend about it and she said," You do not remember walking on the trail and how he used to stumble and d & # 39; to try to trip you? "And I'm like, no, I do not do it."

The failure of aducanumab has been a huge disappointment for patients and researchers alike.

Even though previous amyloid medications had failed, it had a remarkable ability to eliminate the toxic protein from the brain. And preliminary studies have suggested that this could also slow the progression of dementia.

The end of the aducanumab seems to mark the end of the era when pharmaceutical companies injected billions of dollars into amyloid drugs. Scientists have largely said, "OK, we give up," said Gutis.

Now the question is: what comes next? And scientists say that there is a wide range of potential responses.

Current strategies include everything from modulating the brain's immune system to looking for drugs that can protect healthy brain cells from toxins.

"Treating with amyloid is probably important, but it will not be enough," says Dr. Daniel Alkon, president and chief scientist of the biotechnology company Neurotropic.

Prior to joining Neurotope, Alkon worked for decades as a researcher at the National Institutes of Health, and then at the Blanchette Rockefeller Neuroscience Institute at West Virginia University. His research has focused on memory formation and cabling that allows brain cells to communicate.

And this led him to focus on an essential feature of Alzheimer's disease that did not concern amyloid.

"One of the first events of Alzheimer's disease is the loss of this wiring," Alkon said. "And as the loss of wiring progresses, the loss of cognitive function progresses."

Alkon and a team of scientists have therefore studied genetically modified mice to develop a state similar to Alzheimer's.

And he says that they have achieved something surprising.

"You saw this very important wiring loss and you could actually reverse it," he says. "You can regenerate the wiring."

The brain has achieved this by creating new connections between brain cells. And this process was controlled by a natural protein called PKC-epsilon.

Alkon's team thought that if they could find a way to refine PKC-epsilon, they could perhaps ask the brain to replace some of the wiring lost in Alzheimer's disease.

"We asked if there was a known drug in the world that could target PKC-epsilon safely, without harming a patient," Alkon said.

And they found one.

It's called bryostatin-1 and comes from a small marine animal often mistaken for an algae.

Decades ago, researchers at the National Cancer Institute studied bryostatin in the treatment of cancer. This effort did not work.

But Alkon thought that bryostatin might be beneficial for Alzheimer's disease because it was very effective in activating PKC-epsilon.

So his team tried it, first on animals, then on a small group of people, including one named Frank.

"He sat on a chair and stared at the ceiling," said Alkon. "A few weeks after treatment, he started swimming, playing pool, communicating, feeding himself."

Two preliminary studies have suggested that patients with advanced Alzheimer's disease could get better with bryostatin. And a more rigorous study of about 150 people suggested a modest benefit for some.

So now, Neurotrope is trying to confirm these results in another trial.

And of course, bryostatin is only a potential treatment, says Dr. Steven Arnold, professor of neurology at Harvard Medical School and Mbadachusetts General Hospital.

Several other experimental drugs target a toxic substance called tau that accumulates in the brain cells of patients with Alzheimer's disease, he says. And still others are targeting the inflammation or mechanisms of brain cells to eliminate toxins.

"These are all very powerful ways to possibly prevent, delay or even reverse Alzheimer's disease," says Arnold.

Some experimental drugs may have applications other than Alzheimer's disease. These drugs are designed to protect brain cells against various threats and help them function better.

"If we do this, we may discover that it is not only beneficial for Alzheimer's disease, but also for other degenerative conditions of the brain, such as Parkinson's disease." says Arnold.

Meanwhile, patients with Alzheimer's disease, such as Gutis, who currently defends the interests of the Alzheimer's Association, continue to research anything that could help them.

Gutis was wiped out when the drug trial in which he had been arrested was interrupted. But, asking him to sign up for another trial, he said, "I would do it in a moment."

AUDIE CORNISH, HOST:

Scientists are changing course in their quest to treat Alzheimer's disease. The new leadership follows a series of failures with drugs targeting a toxic protein called beta-amyloid. The researchers are now hoping that the drugs target other targets, and as NPR's Jon Hamilton reports, the patients are too.

JON HAMILTON, BYLINE: Phil Gutis was 54 years old when he was diagnosed with Alzheimer's disease; It was three years ago.

PHIL GUTIS: I'm being erased – all those memories, you know, the memory of my dog.

HAMILTON: His dog Abe, a Jack Russell died last year. A few weeks ago, Gutis was found leafing through Abe's photos and trying to remember the dog that had shared his life for 12 years.

GUTIS: But there were no memories. There were no memories of me and him. And then, I talked to a friend about it, and she said, you do not remember walking on the trail and how he used to trot in front and try to make you stumble and da-da-da (ph)? And I'm like, no, I do not do it.

HAMILTON: Until recently, Gutis thought he could keep at least some of his remaining memories. He had participated in the trial of an experimental drug called aducanumab.

GUTIS: Participating in this trial has given me hope in the future.

HAMILTON: The drug had elicited a lot of excitement because it was really effective at removing amyloid beta from the brain. But in March, researchers announced that this did not prevent dementia. Gutis said the news was a huge disappointment for patients and researchers.

GUTIS: I think scientists have largely said, "Okay, we give up because that is – I mean, a lot of drugs targeting this have now failed.

HAMILTON: So the scientists are trying to figure out what's coming next. They are studying various strategies, ranging from modulating the immune system of the brain to protecting healthy brain cells. Dr. Daniel Alkon is President and Scientific Director of a company called Neurotrope. He says the scientific community has learned something important from all these failures with amyloid drugs.

DANIEL ALKON: Dealing with amyloid is probably important, but that will not be enough.

HAMILTON: Alkon had suspected him for years. He had spent decades as a researcher studying memory and cabling for brain cells to communicate. And this led him to focus on a feature of Alzheimer's disease that did not concern amyloid.

ALKON: One of the first events of Alzheimer's disease is the loss of this wiring. And as the loss of wiring progresses, the loss of cognitive function progresses.

HAMILTON: So, Alkon and a team of researchers studied genetically modified mice to develop a disease similar to Alzheimer's disease. And he says that they have achieved something surprising.

ALKON: You've seen this very significant wiring loss and you can actually reverse it; you can regenerate the wiring.

HAMILTON: Creating new connections between brain cells. This process was controlled by a protein called PKC-epsilon. Alkon said that if the team could find a way to tweak PKC-epsilon, it might perhaps ask the brain to replace some of the lost wiring in Alzheimer's disease.

ALKON: We asked if there was a known drug in the world that could target PKC-epsilon safely, without hurting a patient?

HAMILTON: And they found one – it's called bryostatin-1 and comes from a marine animal often confused with an algae. Decades ago, researchers at the National Cancer Institute studied bryostatin-1 as a treatment for cancer; this effort did not work. But Alkon thought the drug could be effective against Alzheimer's because it had a dramatic effect on PKC-epsilon. So his team tried it, first on animals, then on a small group of people, including one named Frank.

ALKON: He was sitting on a chair, staring at the ceiling, hallucinating. A few weeks after our treatment, he started swimming, playing pool, communicating, eating.

HAMILTON: Two preliminary studies have suggested that patients with advanced Alzheimer's disease could improve with bryostatin-1, and a more rigorous study of about 150 people suggested a modest profit. So now, Neurotrope is trying to confirm these results. And of course, bryostatin-1 is only a potential treatment. Several others target a toxic substance called tau that accumulates in the brain cells of patients with Alzheimer's disease. And Dr. Steven Arnold, from Harvard Medical School, says other drugs target inflammation or how brain cells clear toxins.

STEVEN ARNOLD: These are all very powerful ways to possibly prevent, delay or even reverse Alzheimer's disease.

HAMILTON: Arnold says that there is a growing interest in drugs that can protect brain cells and help them function better.

ARNOLD: If we do this, we will discover that it is not only beneficial for Alzheimer's disease, but also for other degenerative conditions of the brain, such as Parkinson's disease.

HAMILTON: Meanwhile, patients with Alzheimer's disease like Phil Gutis continue to search for anything that could help. Gutis says that he was devastated when the drug trial in which he had been arrested was stopped, but he would welcome the opportunity to try again.

GUTIS: I mean, it will probably take at least a year before I can participate in another medical trial. But I would like – in a second.

HAMILTON: Jon Hamilton, NPR News. Transcription provided by NPR, Copyright NPR.