‘A Time of Hope’: Experts on Alzheimer’s Drug Breakthroughs

It’s an exciting time for Alzheimer’s research, according to Madhav Thambisetty, senior investigator at the National Institute on Aging. “We’ve known for years that the brains of patients with Alzheimer’s disease have build up of abnormal proteins in them. We’ve been able to study these for decades,” said Thambisetty. “But this is the very first time that we now have drugs that we can use to try and clear these proteins from the brain. From a scientific perspective, I really think this is a landmark.” 

Scientists gathered at the American Association for the Advancement of Science’s Annual Meeting in Denver, Colorado last month. The meeting theme, Toward Science Without Walls, explored interdisciplinary science and the consequences of barriers that fragment the scientific community. Regina Barber, co-host and scientist in residence for National Public Radio’s science podcast “Short Wave” sat down with Thambisetty.

“We are now presumably on the threshold of drugs that we hope, and I use the word “hope,” might actually change the course of the disease itself,” Thambisetty said of Alzheimer’s drug lecanemab and the progression of other anti-amyloid drugs. “It’s clearly a time of hope. It’s also a hope that’s tempered with a little bit of caution, but it reinforces the importance of having patients participate in clinical trials and be enthusiastic in the promise of research.”

Below, some highlights from an interview between Barner and Thambisetty about the breakthrough research of anti-amyloid drugs, what Thambisetty thinks about prescribing them to patients, and his hopes for upcoming interdisciplinary research.

Regina Barber: Where are we seeing this drug or this combination of treatments actually clearing out [amyloid plaque from the brains of people in early stages of Alzheimer’s]? What kind of studies are doing that?

Madhav Thambisetty: The slide that I have behind you is the seminal publication in the New England Journal of Medicine, and that came out in January of last year, and it reports the results from a large phase three clinical study of a drug called lecanemab. This is an antibody that binds to one of these abnormal proteins called beta amyloid in the brain. It clears the brain of beta amyloid in patients who take the drug. This was a trial that recruited nearly 1,800 patients in the early stages of Alzheimer’s disease, randomized them to either the drug or placebo over 18 months, and it showed for the very first time that patients who took the drug actually seemed to decline slowly compared to patients who took the placebo. This is a landmark study and it led to the FDA giving the drug full approval for treating patients in the early stages of Alzheimer’s disease.

We’re just a year out from the approval. Again, this is a clear example of how research could potentially translate into effective treatments. 

Barber: Would you say in the last decade or even in the last five years is when we’ve had these massive advances?

Thambisetty: The last symptomatic treatment for Alzheimer’s disease was approved by the FDA in 2003. I was still doing my clinical training. These are symptomatic treatments, which means that they don’t really alter the course of the disease. The disease continues to progress, but they might slow the symptoms a little bit. But we are now presumably on the threshold of drugs that we hope, and I use the word “hope,” might actually change the course of the disease itself, because they’re able to alter fundamental biological aspects of the disease by removing some of these toxic proteins from the brain. That’s the hope.

Barber: When you say “clear out the proteins,” I’m imagining a buildup, and then actually reversing that buildup and taking it away. Is that what you’re saying?

Thambisetty: That’s exactly correct. For example, in the trial that we were just talking about, when you do PET scans, these are specialized scans of the brain that can measure this amyloid protein, patients who got the drug virtually dropped their levels of protein almost down to zero. These drugs seem to do a fantastic job of doing what they were supposed to do, which is to clear the brain of these presumably toxic proteins. 

“It’s clearly a time of hope. It’s also a hope that’s
tempered with a little bit of caution, but it reinforces
the importance of having patients participate in clinical
trials and be enthusiastic in the promise of research.” 

But these drugs also come with a risk of side effects. There is the risk of brain swelling, brain bleeding, and loss of brain volume which is shrinkage of the brain. As a practicing physician, I need to balance those risks versus benefits when I talk to my patients about these drugs. 

What we want to do is to be able to make sure that the patients have all the information that they need, and empower them and their families to make the right decision about whether this drug is right for them or not. We want to present the relatively small benefits in terms of disease slowing, versus real risks of brain swelling, brain bleeding and brain shrinkage. We’ve made a tremendous scientific advance, but it remains to be seen if that really translates into safe, effective, meaningful and accessible treatments for everyone.

Barber: What is your hope then, for the future? Do you hope to have another drug that doesn’t have these side effects or are you hoping to do a clinical trial on people who are further along in Alzheimer’s and see if that can be reversed?

Thambisetty: I think there are lots of avenues to explore in terms of research. I think as a field, we recognize that these are advances in treating Alzheimer’s disease. But there are likely to be many more approaches that we need to explore – not just clearing amyloid, not just clearing one or two of the toxic proteins in the brain, but perhaps to deal with inflammation in the brain and perhaps to deal with other processes in the brain like cell death. We are now at the point where we recognize that we might need multiple approaches to truly make an impact in altering the disease course.

“We’ve made a tremendous scientific advance,
but it remains to be seen if that really translates
into safe, effective, meaningful and
accessible treatments for everyone.” 

Barber: As a medical doctor, when you talk to patients and people in these clinical trials, do you feel that this is the first time in decades where you can give them some amount of hope?

Thambisetty: I definitely think so. It’s clearly a time of hope. It’s also a hope that’s tempered with a little bit of caution, but it reinforces the importance of having patients participate in clinical trials and be enthusiastic in the promise of research.

“We are now at the point where we recognize
that we might need multiple approaches to truly
make an impact in altering the disease course.”

A lot of my patients sign up to participate in clinical trials knowing fully well that they might not themselves directly benefit from the studies, but what they learn from the trials might help a generation down the line. So I think it’s really critically important to get patients enthusiastic about participating in these research studies.