just asking questions

Is the New Alzheimer’s Drug a Serious Breakthrough?

The brain scan of a patient affected by Alzheimer’s disease. Photo: BSIP/Universal Images Group via Getty

Alzheimer’s disease is one of the most intractable problems in modern medicine; the last few decades have seen a steady drumbeat of seemingly promising treatments for the debilitating illness that eventually came to nothing. So when the FDA approved Lecanemab last week, it was major news — particularly because unlike its controversial predecessor Aduhelm, Lecanemab appears to yield real benefit in patients. But its relative efficacy may actually point to limitations in the way Alzheimer’s is treated going forward. I spoke with Nobel laureate Thomas C. Südhof, a professor of molecular and cellular physiology at Stanford, about what the new drug does and doesn’t do, and why he thinks we’re due for a rethinking of how Alzheimer’s works.

The FDA says Lecanemab offers modest improvement in patients with early-stage Alzheimer’s. This medication carries significant health risks, it’s very expensive, it involves intravenous infusions every two weeks, and its benefits may not even be noticeable to the patient or the people around the patient. Still, in the realm of Alzheimer’s research, this seems like a fairly big deal. But not all researchers are convinced about the drug’s benefits. What are your overall thoughts on Lecanemab and whether the FDA should have approved it?
It’s a very difficult question. My thoughts are that the clinical-trial results with this drug were amazingly positive, and this is truly an advance and a boost to the field, because it’s the first time any drug has had a convincing positive effect on the disease progression. Moreover, I think that they help the field understand better the disease itself.

Having said that, there’s a reason to be cautious. The trial results, although positive, showed only a 27 percent decrease in the rate of progression, which is depressingly low. In other words, patients’ suffering was not ameliorated significantly. Their disease was still getting worse with time, it was just getting worse a little slower.

Certainly, it differs from Aduhelm, the drug that the FDA infamously approved two years ago against the recommendation of one of its own councils and an independent panel. There was a congressional investigation into that approval process, which found that the drugmaker, Biogen, which also co-developed Lecanemab, was overly cozy with the FDA. Do you trust that the agency did the right thing this time?
I have no insight into the approval process and can’t really comment on that. Clearly, it was deeply concerning that the FDA approved Aduhelm. I think the criticisms that were voiced appear to be very much correct. I’m afraid that in recent years the FDA has become too sensitive, too responsive to patient concerns. I think that’s not good for patients because, in the end, it’s the patients who suffer when a drug turns out to be not as advertised.

In this case, with the second antibody from Biogen and Eisai, there seems to be a clear rationale for approval, and the FDA seems to have been more careful in the approval, which is great.

We spoke back in August about how a researcher may have falsified images in a highly influential paper from the mid-2000s. That paper helped solidify the approach to attacking Alzheimer’s that has been prevalent for decades, which is to target those plaques made up of beta-amyloid proteins, also known as Abeta plaques. So now we’ve got this data that really puts that approach to the test. And we’ve found that it doesn’t come close to solving the problem. Do you think this discovery will spur people to think about the entire macro picture of the disease in a different way? 
What this indicates to me is that, yes, Abeta plaques play a role in the disease, and we have to consider them in any kind of treatment. But clearly, they alone are not responsible for the progression of the disease, because if they were, this drug would have halted progression, which it didn’t. It halted it in a statistically significant way, but a 27 percent decrease in the rate of decline is not a major effect.

For me, my overall view of the disease changes quite a bit. I don’t know how much other people would agree with that. But for me, this clinical trial allows definitive conclusions, which is rare. I don’t want to call it the ultimate experiment, but it really provides tremendous progress in understanding the disease. To me, this means that we need to go back to the drawing board and really dig deeper into the disease and try to understand why these patients actually become sick. I want to note that there is one other additional approach that is being pursued, including by companies that I consult for, for the purposes of disclosure. That is to combat neuroinflammation in the brain, which I think is going to be a very important avenue to treatment. But that also may be just one feature. We don’t know whether either one of these by themselves is actually responsible for the disease.

Drug companies have seen that the current approach, targeting these proteins, has yielded FDA approval twice and could make them tons of money. Is there incentive to just keep going with that, or do you think that, because it looks like there are limits to its success, they’ll try something else?
I think certainly some companies will try something else. They employ a lot of really smart people and a lot of people who truly care for patients. It’s not that they only want to make money. They actually do want to help. I fear, however, that some companies, at least, will also be narrowly just trying to develop better Abeta antibodies thinking that maybe this just isn’t good enough. You could argue that, well, you cleared all the plaques, but there’s still a tiny bit left. I think that’s unlikely to succeed, but I can’t completely rule it out.

There’s another side to this that I also would like to mention, which is that based on our own research, Abeta may be biologically more complicated. It may not just be a bad thing — it may actually have an endogenous function of its own, and getting rid of all Abeta may be bad for people. It’s not a generally accepted conclusion, but we think it’s highly likely that Abeta is actually involved in a regulatory process in the brain that is important for how the brain processes information. In that case, getting rid of all Abeta may be just as bad as having too much of it.

If that’s true, would the effects show up down the road for people taking Lecanemab?
Yes. If you step back for a moment, you may recall that the most promising avenue to treatment was initially thought to be to inhibit the enzyme that produces Abeta, an enzyme called BACE. It was possible to do that with small molecules, which, unlike antibodies, can potentially be supplied lifelong, like a statin. Great drugs were developed that do this. The problem was that these drugs turned out to actually make people cognitively worse, not better. Not only were they ineffective, they were actually counter-effective.

Well, that seems like a problem.
That was a big surprise. But if you think about it, maybe it wasn’t so surprising, because maybe the cleavage product that results from BACE, in this case Abeta, may actually have a physiological role. We don’t actually know whether Abeta is all bad or whether there is a sweet spot, so to speak, in between. If you have too much of it, it destroys the brain or can be quite detrimental. If you have too little, it might also not be so good.

I guess this just all speaks to the brain’s incredible complexity and how little we still know about it.
Not only the brain — it’s biology. Just think of cancer. Cancer is not the brain, it’s just a cell that basically becomes abnormal and gets out of control. Nevertheless, it turns out to be insanely complex. Life is complex. It has to be, if you think about it. On a broader philosophical level, there’s only so many genes, and these genes must do many more things than there are numbers of genes, so you have to have complexity as a result of the need to evolve. That’s true even for bacteria, even for viruses. Just think of COVID-19 and how much it has surprised us.

Bottom line, this drug is an advance, but it’s not a slam dunk. And the only way, I believe, personally, that we can make progress is in a sort of two-step. First do more clinical trials, but those are extremely expensive. Second, do more biology, get more to the basics of what happens in the disease. What is the role of neuroinflammation? What is the role of Abeta? How do these pieces fit together? Why is aging so important in the disease process? Because Alzheimer’s disease is a disease of aging. Even if people have mutations and genes that cause Alzheimer’s disease 100 percent, they don’t get it until they’re in their 40s or 50s. Before then, they’re perfectly normal cognitively. Those are the questions that we need to address.

This interview has been edited for length and clarity. 

Is the New Alzheimer’s Drug a Serious Breakthrough?