Rapamycin for Alzheimer's Disease: Overcoming Barriers to a Promising Treatment

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• Alzheimer's Research Failure on Aging Biology
• Rapamycin Clinical Trial Urgency
• Generic Drug Funding Challenge
• Rapamycin Reputational Problem
• Side Effects Misconceptions Clarified
• Changing Clinical Perceptions
• Full Transcript

Alzheimer's Research Failure on Aging Biology

Dr. Matt Kaeberlein, MD, PhD, identifies a fundamental failure in Alzheimer's disease research. He states that biological aging is the single greatest risk factor for developing Alzheimer's. Despite this clear connection, the research community has largely ignored this critical link. Dr. Kaeberlein calls this oversight "embarrassing" during his discussion with Dr. Anton Titov, MD.

More than half of the National Institute on Aging budget specifically targets Alzheimer's disease research. However, only a small fraction addresses the underlying biology of aging. This misallocation of resources represents a significant strategic error according to Dr. Kaeberlein. The recent approval of an amyloid-beta targeting drug that doesn't help patients further demonstrates this flawed approach.

Rapamycin Clinical Trial Urgency

Dr. Matt Kaeberlein, MD, PhD, emphasizes that rapamycin clinical trials for Alzheimer's were needed fifteen years ago. He expresses deep frustration with the Alzheimer's research and clinical communities for their inaction. Dr. Matt Kaeberlein, MD, believes these communities should be "ashamed of themselves" for not testing rapamycin in dementia contexts.

During his conversation with Dr. Anton Titov, MD, Dr. Matt Kaeberlein, MD, highlights rapamycin's proven efficacy in mouse models of Alzheimer's disease. The medication shows significant promise in delaying or potentially preventing dementia progression. Despite overwhelming preclinical evidence, human trials remain conspicuously absent from the research landscape.

Generic Drug Funding Challenge

The generic status of rapamycin presents significant funding challenges for clinical trials. Dr. Matt Kaeberlein, MD, PhD, acknowledges that pharmaceutical companies lack financial incentive to develop generic drugs. This profit motive issue contributes to the slow pace of rapamycin research for Alzheimer's disease.

Dr. Anton Titov, MD, draws parallels with other generic preventive medications like aspirin. These drugs show significant health benefits but receive limited research funding due to their generic status. Governments worldwide bear substantial costs for Alzheimer's care, yet public health bodies haven't prioritized rapamycin trials despite potential long-term savings.

Rapamycin Reputational Problem

Dr. Matt Kaeberlein, MD, PhD, identifies reputation as the primary barrier to rapamycin research. The medication earned its reputation as an immunosuppressant in organ transplant patients. At high daily doses, rapamycin demonstrated various side effects in this vulnerable population.

This historical context created lasting negative perceptions among physicians. Many clinicians maintain outdated views about rapamycin's safety profile without considering newer dosing regimens. Dr. Matt Kaeberlein, MD, explains this reputational challenge during his interview with Dr. Anton Titov, MD.

Side Effects Misconceptions Clarified

Dr. Matt Kaeberlein, MD, PhD, clarifies significant misconceptions about rapamycin side effects. The data clearly show that low-dose, intermittent rapamycin use presents minimal risks. In healthy people taking weekly low doses, side effects are very small and often indistinguishable from placebo.

Dr. Matt Kaeberlein, MD, emphasizes that the transplant patient experience doesn't reflect rapamycin's safety in preventive contexts. Even if side effects were more significant, the potential benefit of delaying Alzheimer's by 10-15 years would justify the risk. This perspective remains largely absent from clinical discussions about rapamycin.

Changing Clinical Perceptions

Dr. Matt Kaeberlein, MD, PhD, expresses cautious optimism about changing clinical perceptions. He notes growing research interest in cellular senescence across various disease communities. This represents a gradual paradigm shift toward recognizing aging biology's role in age-related diseases.

Dr. Matt Kaeberlein, MD, acknowledges that changing medical perspectives requires substantial time and evidence. Dr. Kaeberlein describes his alternating frustration and optimism during his discussion with Dr. Anton Titov, MD. He believes momentum is building for proper evaluation of rapamycin's potential in Alzheimer's disease and other age-related conditions.

Full Transcript

Dr. Anton Titov, MD: So, for example, if we talk about Alzheimer's disease and billions were spent on failed medications, they could have been redirected to aging research, considering the dismal track record. And rapamycin is also, as you wrote in your peer-reviewed articles, connected to Alzheimer's disease. So is it time for a clinical trial of rapamycin in Alzheimer's disease?

Dr. Matt Kaeberlein, MD: Yeah, it was time for a clinical trial for rapamycin and Alzheimer's disease fifteen years ago when I first started proposing it. I mean, to say I'm not frustrated by the lack of the Alzheimer's disease community paying attention, first of all, to the biology of aging, but second to rapamycin specifically, would be an understatement. I think they should be ashamed of themselves.

There's no excuse that rapamycin hasn't been tested in the context of Alzheimer's disease and other dementias right now. It's a failure of the Alzheimer's research community. It's a failure of the Alzheimer's clinical community, in my view.

So yes, I think there's a lot of promise there. I think, though, again, taking a step back, the bigger problem is—and this isn't unique to the Alzheimer's research community, but I think it's particularly relevant in that context—we know that biological aging is the greatest risk factor for Alzheimer's disease. That is crystal clear.

The fact that the Alzheimer's disease research community has not paid attention to that link is embarrassing, in my view. It's still the case that more than half of the National Institute on Aging budget goes specifically to study Alzheimer's disease without taking into consideration the role of biological aging in Alzheimer's disease.

A much smaller fraction of the budget goes to understanding the biology of aging. So I think that's a mistake. I think it should be clear to anyone paying attention that that's been a mistake.

And I think the fact that we now have a drug approved that targets amyloid beta but doesn't help patients should also make it clear to people that it's been a huge mistake to focus all of our efforts on studying amyloid-beta instead of studying what is creating permissive physiology for Alzheimer's disease, which is the biological aging process.

So I would certainly hope that will change. It takes a long time in biomedicine for paradigms to shift. I feel like that's starting to happen.

I feel like people are starting to understand the connection between the biological mechanisms of aging and Alzheimer's disease and other age-related diseases. I think the growth of research on, for example, senescent cells in the Alzheimer's research community, the obesity community, cancer community, is an indication that finally, finally, the biomedical community is starting to pay attention to what we've been telling them for many years now.

Which is that these hallmarks of biological aging certainly create a permissive environment for age-related disease and potentially play a causal role in age-related disease. But to some extent, that doesn't matter if we can understand that biology. We can intervene before people get sick and keep them from developing Alzheimer's disease or age-related cancers, kidney disease, heart disease, or immune senescence.

Right, all of this collection of diseases where biological age is the greatest risk factor. So yeah, I mean, frustrating, yes. Optimistic that things are changing, yes. So I hope that will continue.

Dr. Anton Titov, MD: Do you think that it's a bit controversial? I spoke in London to a very renowned mathematician who played a critical role in determining, for example, the preventive effect of tamoxifen on breast cancer, Dr. Jack Cuzick, and he said that aspirin is the number two cancer prevention step one can take after quitting smoking. And obviously, there's a lot of research going on, but aspirin is generic, so that's partly why the pharmaceutical industry cannot make billions and billions on widely available generic drugs.

So there is less impetus to conduct very expensive clinical trials. Rapamycin is generic. Do you think that has something to do with the reluctance of major funding for clinical trials of Alzheimer's or other dementias and rapamycin, even though they are funded not necessarily by the pharmaceutical community but by public health bodies? After all, it's the governments around the world who bear a substantial cost of caring for people with Alzheimer's disease. It's not just about the pharmaceutical industry.

Dr. Matt Kaeberlein, MD: Yeah, so it's a good question. I think that's part of it. I don't think that's the primary challenge, but absolutely, I think the fact that there is not an incentive from a financial and profit perspective to develop rapamycin has contributed to the slow pace.

But actually, the bigger problem is reputational. And that stems from the fact that rapamycin was first used and FDA approved for use in organ transplant patients. So it got a reputation as an immunosuppressant that has a collection of not terrible, but not great side effects in that patient population.

At high doses given daily in organ transplant patients, there's a long list of side effects that have been at least somewhat associated with rapamycin. And so in the clinical community, because of the way it was developed and used, there is a perception among many physicians that rapamycin has bad side effects.

The data are clear in my mind. I think most people who have read the studies on once-weekly lower dose rapamycin use in healthy people will agree with this, that in that context, the side effects from rapamycin are very small. And in fact, in most cases, not different from a placebo.

But because the reputation is already there, it's difficult, I found, in the clinical community to overcome a reputation problem. So I think it's the combination of the lack of profit motive, and maybe even more so the reputation challenge that rapamycin has, as a barrier to getting clinical trials funded outside of the pharmaceutical community.

From my personal experience, I can tell you, because I've talked with people at the Alzheimer's Association and other potential groups that could fund these kinds of studies, you present them the data showing that in every mouse model of Alzheimer's disease and in normative aging in mice for dementia and Parkinson's disease, rapamycin works, and it works well.

They're enthusiastic about potentially doing a clinical trial. Then they talk to some physician who doesn't know anything about the data, probably has never used rapamycin, but is told it's got a lot of side effects. And their expert tells them, oh, yeah, rapamycin has a lot of side effects, and they become less interested in studying it for Alzheimer's disease.

So I think that's been a problem. I also don't quite understand why, even if rapamycin side effects were comparable to what's seen in organ transplant patients in this context, if I had somebody I loved who had Alzheimer's disease, I'm pretty sure that they and I would be willing to tolerate that level of side effects if you could delay Alzheimer's disease by ten years, or fifteen years, or maybe prevent it altogether.

So I still don't even quite understand the side effect concern. But it's also not real. And I think it's unfortunate. Gradually, that's changing again.

I go between being frustrated at how long this has taken to optimism that finally, I feel like there is some momentum where people are starting to actually collect data on side effects and risk and slowly changing the perception in the clinical world about rapamycin. Still, it's going to be a long road, but I think that's been one of the main things that have prevented these types of clinical trials for something like Alzheimer's disease.