Drugs to treat Alzheimer’s disease have been in development for decades. But almost every clinical trial has ended in disappointment.
One theory is that we’re treating people too late and not long enough.
Now, Oregon Health & Science University is participating in one of the first studies that tries to intervene earlier, with healthy 55- to 80-year-olds who are 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 happen all the time, this one comes at a moment when the scientists focused on Alzheimer’s research are questioning whether the dominant theory of what causes the disease, known as the amyloid hypothesis, might be wrong.
The AHEAD study is both a test of a single promising drug and an effort to uncover more evidence about how Alzheimer’s starts.
The main focus of the study is a drug called lecanemab. It’s just been given accelerated approval by the FDA for use in patients with early or mild Alzheimer’s. And it’s the first drug backed by reliable data that shows it may slow down the progression of Alzheimer’s disease — not a lot, just a little.
It’s called an anti-amyloid antibody. Some scientists think lecanemab and other anti-amyloids under development will work better if they are given to people before they begin to display typical Alzheimer’s symptoms, like memory loss.
Barbara Klausman is just the kind of person the AHEAD researchers are looking for to participate in their study. Klausman lives in Vancouver. She’s 76. But on a November day last fall, wearing jeans and stylish dark green tennis shoes that matched her sweater, she looked a lot younger.
“I look forward to waking up every day because there’s always something to do,” Klausman said that day, sitting in a small medical office at OHSU and getting ready for an infusion of what might have been lecanemab. It also, she knew, might just be saline solution — a placebo.
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 as Alzheimer’s disease slowly took more and more of her mother’s mind. Klausman did what she could to be there for her mom. If she was having an episode of agitation in the middle of the night, her dad would call.
“And I’d just go pick her up and take her for a cup of coffee, and then she’d forget she was upset and I’d take her home,” Klausman said.
The disease progresses slowly for most. As neurons in the brain die, patients experience memory loss, then dementia and ultimately death. Alzheimer’s is one of the leading causes of death for people 65 and older.
Klausman’s mom died in 2003. But she felt she’d lost her mom years earlier.
“It’s just difficult to see somebody you love going through that,” Klausman said last fall, nearly 20 years after her mother’s death. “Probably the last eight years it wasn’t her anymore. But she still needed to be loved.”
Klausman’s aunt also had Alzheimer’s and possibly her grandfather too. Klausman wondered if her family history put her at risk as she aged. That question led her to the team of researchers at OHSU who were part of the AHEAD study.
“It’s most likely the case that with Alzheimer’s, as with other diseases, that if we can detect it early and treat it early, we’ll have a better chance of fighting it,” said Dr. Aimee Pierce, a geriatric neurologist and the study lead at OHSU.
Pierce and her team are using brain imaging to look for two distinct markers of the disease: amyloid plaques and tau tangles.
We’ll come back to tau later. First, amyloid.
No one knows for sure what causes Alzheimer’s disease, but for a long time scientists have thought a protein fragment called amyloid beta looks suspicious. It forms unusual plaques in the brains of patients. And there’s some genetic evidence from families with early-onset familial Alzheimer’s and people with Down syndrome that points to this particular protein.
Anti-amyloid antibodies, like lecanemab, can clear the plaques from patients’ brains. But in clinical trials, those drugs haven’t slowed down the progression of patients’ dementia much, if at all.
That’s why they’re trying 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 that they form many, many years before the symptoms of Alzheimer’s develop.”
Right now, Klausman doesn’t have symptoms of Alzheimer’s, no unusual memory loss or anything else that would make most general practitioners suspicious. But brain scans confirmed she has amyloid plaques already developing in her brain and could be at risk for the disease.
Important caveat here: Not everyone with the plaques will develop Alzheimer’s; it’s just a risk factor.
As a participant in the study, Klausman has been getting infusions at least once a month at OHSU.
“It’s never that bad. It’s never that bad,” she reassured the therapist setting the IV in her arm last October.
“Well that’s good,” he quipped. “When you show up with needles, you don’t want people to hate you.”
This approach — testing a preventative treatment in a long trial with a drug that needs to be given through an IV and can have very serious side effects — it’s a lot to ask of study participants.
Klausman joined this trial a year ago. She’s got three more years of infusions ahead of her.
She also comes in periodically for two different types of brain scans. And, to help the scientists see if getting lecanemab protects against memory loss, Klausman has to take a lot of cognitive tests.
“It’s not my favorite thing,” she said of the tests. “I like to ace a test.”
And, to protect the reliability of the research data, she doesn’t know what the tests have found. The study is what’s called double-blinded and placebo-controlled. That means half the participants are getting a placebo, not the real drug. To avoid any bias, neither Klausman nor the researchers know what group she’s 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 is getting lecanemab that it will work.
Here’s one big reason for skepticism: Amyloid plaques, the thing lecanamab clears from the brain, might 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 are even a part of the body’s effort to protect brain cells from damage. Essentially, the plaques may not be the wound, but the bandage.
So some scientists think the real culprit is something else. Possibly, it’s tau. That’s the other protein fragment that’s a signature of this disease. In the brains of Alzheimer’s patients, tau shows up as tangles inside neurons. They have been hard to see on brain imaging scans of living patients until relatively recently.
For a long time, the prevailing theory has been that the buildup of amyloid somehow triggers the damaging tau tangles. But as anti-amyloid treatments have failed to work, scientists have increasingly questioned that theory, Pierce said.
She said the question now is: “Does the amyloid plaque truly accumulate before the tau tangles develop? And that is 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 are performing on their cognitive tests. And that might help crack the central mystery of how Alzheimer’s starts.
For Klausman, the reason for participating is very clear. She can play a part in finding a cure for the disease that claimed her mother. She also has two daughters, so when she thinks about her family history and the risk of the disease, she’s also thinking of them.
It would be nice if a cure became available in her lifetime, but she’s not counting on it.
“By having studies like this one, by the time they have to worry about it, which would be about 20 years from now, there won’t be a worry anymore or there will be a treatment,” Klausman said of her daughters. “So yes, I am doing this for them and for future generations.”