At OHSU, researchers are testing a promising drug for Alzheimer’s — and searching for a cause

Drugs to treat Alzheimer’s disease have been in development for decades. But almost every clinical trial ended in disappointment.

One theory is that we treat people too late and not long enough.

Now Oregon Health & Science University is participating in one of the first studies to try to intervene earlier, with healthy 55- to 80-year-olds at risk for developing Alzheimer’s disease as they age.

It’s an international clinical trial called the AHEAD study, funded by the National Institutes of Health and the pharmaceutical company Eisai.

While clinical trials are happening all the time, this one comes at a time when the scientists focused on Alzheimer’s research are wondering whether the dominant theory about the cause of the disease, known as the amyloid hypothesis, might be wrong.

The AHEAD study is both a test of a single promising drug and an attempt to find more evidence about how Alzheimer’s disease begins.

The main focus of the study is a drug called lecanemab. It just received accelerated approval from the FDA for use in patients with early or mild Alzheimer’s. And it’s the first drug backed by reliable data showing it can slow the progression of Alzheimer’s disease — not by much, but a little.

It is called an anti-amyloid antibody. Some scientists believe that lecanemab and other anti-amyloids in development will work better if they are given to people before they start showing typical Alzheimer’s symptoms, such as memory loss.

Vancouver resident Barbara Klausman and Dr. Aimee Pierce are preparing for Klausman to receive an IV in November 2022.  Klausman volunteered for the AHEAD study to learn more about her personal risk for Alzheimer's disease, which runs in her family.

Vancouver resident Barbara Klausman and Dr. Aimee Pierce are preparing for Klausman to receive an IV in November 2022. Klausman volunteered for the AHEAD study to learn more about her personal risk for Alzheimer’s disease, which runs in her family.

Amelia Templeton/OPB

Barbara Klausman is exactly the kind of person the AHEAD researchers are looking for to participate in their research. Klausman lives in Vancouver. She’s 76. But on a November day last fall, wearing jeans and stylish dark green tennis shoes to match her sweater, she looked a lot younger.

“I look forward to waking up every day because there is always something to do,” Klausman said that day, as he sat in a small medical office at OHSU preparing for an IV drip of what could have been lecanemab. It could also just be saline, a placebo, she knew.

She has a very personal reason for volunteering to get these infusions.

“It was in 1989, my brother was in the army as a dentist in Europe and I wrote him letters saying, ‘There’s something wrong with Mom,'” Klausman said.

Klausman watched her mother’s Alzheimer’s slowly become more and more preoccupied. Klausman did what she could to be there for her mother. If she had a fit of excitement in the middle of the night, her father would call.

“And I would just pick her up and take her for a coffee, and then she would forget she was upset and I would take her home,” Klausman said.

In most cases, the disease progresses slowly. As neurons in the brain die, patients experience memory loss, then dementia, and finally death. Alzheimer’s is one of the leading causes of death for people age 65 and older.

Klausman’s mother died in 2003. But she felt she had lost her mother years before.

“It’s just hard to see someone you love going through that,” Klausman said last fall, nearly 20 years after her mother’s death. “Probably wasn’t her for the last eight years. But she still needed to be loved.

Klausman’s aunt also had Alzheimer’s disease and possibly her grandfather as well. Klausman wondered if her family history put her at risk as she got older. That question led her to the team of researchers at OHSU who were part of the AHEAD study.

“It is very likely that with Alzheimer’s disease, as with other diseases, we have a better chance of fighting it if we can detect and treat it early,” said Dr. Aimee Pierce, a geriatric neurologist and the study leader at OHSU.

Pierce and her team use brain imaging to look for two different markers of the disease: amyloid plaques and tau tangles.

We’ll come back to tau later. First amyloid.

Beta-amyloid plaques, shown in brown, and tau tangles, in blue, are thought to be key brain markers of Alzheimer's disease.

No one knows for sure what causes Alzheimer’s disease, but scientists have long thought that a protein fragment called amyloid beta looks suspicious. It forms unusual plaques in patients’ brains. And there is some genetic evidence from families with early-onset familial Alzheimer’s and people with Down syndrome pointing to this particular protein.

Anti-amyloid antibodies, such as lecanemab, can clear the plaques from patients’ brains. But in clinical trials, those drugs didn’t slow the progression of patients’ dementia much, if at all.

That’s why they try to give them to people many years earlier, when the plaques are just starting to develop.

“We know that these plaques are found in patients with Alzheimer’s disease,” Pierce said. “But we think they form many, many years before Alzheimer’s symptoms develop.”

At this point, Klausman has no symptoms of Alzheimer’s disease, no unusual memory loss, or anything else that would make most general practitioners suspicious. But brain scans confirmed that she has already developed amyloid plaques in her brain and may be at risk for the disease.

The AHEAD study provides a wealth of data on the two protein fragments that could cause Alzheimer's disease, amyloid beta and tau.  It takes four binders to hold the data Barbara Klausman collected during her first year in the process.

The AHEAD study provides a wealth of data on the two protein fragments that could cause Alzheimer’s disease, amyloid beta and tau. It takes four binders to hold the data Barbara Klausman collected during her first year in the process.

Amelia Templeton/OPB

Important caveat here: Not everyone with the plaques will develop Alzheimer’s disease; it’s just a risk factor.

As a study participant, Klausman will receive infusions at OHSU at least once a month.

“It’s never that bad. It’s never that bad,” she reassured the therapist as she placed the IV in her arm in October last year.

“Well, that’s good,” he joked. “If you show up with needles, you don’t want people to hate you.”

This approach – testing a preventive treatment in a long trial with an intravenous drug that can have very serious side effects – puts a lot of strain on the study participants.

Klausman joined this process a year ago. She has three more years of IVs ahead of her.

She also periodically visits for two different types of brain scans. And to help the scientists see if getting lecanemab protects against memory loss, Klausman has to undergo a lot of cognitive tests.

“It’s not my favorite thing,” she said of the tests. “I like to pass a test.”

And to protect the reliability of the research data, she doesn’t know what the tests found. The study is supposedly double-blind and placebo-controlled. That means half of the participants will receive a placebo, not the real drug. To avoid any bias, neither Klausman nor the researchers know which group she is in. She won’t find out until the study is over.

“You know the choices, between what will be revealed — one could be a real downer,” she said.

This is science in progress, so there’s no guarantee that even if Klausman gets lecanemab, it will work.

Here’s a big reason for skepticism: amyloid plaques, the thing lecanamab removes from the brain, may not be the underlying cause of Alzheimer’s after all. They’ve been the focus of most research, but some scientists think the plaques are a red herring, or even part of the body’s effort to protect brain cells from damage. Essentially, the plaques may not be the wound, but the bandage.

Scientists are beginning to wonder if amyloid plaques, pictured left, cause Alzheimer's or if something else like tau tangles are the culprit.

So some scientists think the real culprit is something else. It may be tau. That is the other protein fragment that is characteristic of this disease. In the brains of Alzheimer’s patients, tau appears as tangles of neurons. Until recently, they were difficult to see on brain scans of living patients.

For a long time, the prevailing theory has been that the buildup of amyloid somehow causes the harmful tau tangles. But because anti-amyloid treatments haven’t worked, scientists have increasingly questioned that theory, Pierce said.

She said the question now is, “Is the amyloid plaque really ceasing before the tau tangles develop? And that’s actually surprisingly hard to determine,” she said. “It takes quite a long-term study.”

The AHEAD study is one of the first to capture images of both amyloid and tau in the brain scans of more than a thousand older adults.

Pierce and the rest of the team will be able to compare those images to how the participants perform on their cognitive tests. And that could help unravel the central mystery of how Alzheimer’s disease begins.

For Klausman, the reason for participating is very clear. She can play a role in finding a cure for the illness that claimed her mother. She also has two daughters, so when she thinks about her family history and risk of the disease, she thinks about them too.

It would be nice if a cure became available during her lifetime, but she is not counting on that.

“By having studies like this, by the time they have to worry about it, which would be about 20 years from now, they won’t be worried or there will be treatment,” Klausman said of her daughters. “So yes, I’m doing this for them and for future generations.”

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