Neurobiologist Karl Herrup shares his take on why the field of Alzheimer’s has struggled to find a cure, and what it would take to course-correct.
The lack of effective treatments for Alzheimer’s have spurred scientists to rethink the dominant approach to tackling the disease: the amyloid hypothesis. This hypothesis proposes that the accumulation of beta-amyloid proteins triggers the degenerative processes of Alzheimer’s. But some researchers say that the idea has not only crowded out research of alternative hypotheses, but it also falls short of capturing the complexity of the disease. Given the string of clinical trial failures, they believe it’s time that we reevaluate our concept of Alzheimer’s.
Karl Herrup, author of How Not to Study a Disease: The Story of Alzheimer’s (2021) joins Being Patient to speak about how the field of Alzheimer’s went down the wrong path in the search for a cure, the consequences of the Food and Drug Administration’s (FDA) approval of Aduhelm, and his vision for a new path in studying Alzheimer’s, aging and dementia.
Being Patient: What is your book about and what are its key messages?
Karl Herrup: It’s about my professional and personal reactions to how the field has been approaching the problem of how we find a cure for Alzheimer’s disease. After working in the field and coming to it not as a clinician but as a basic scientist, there are a few key messages that I want to get across in the book.
The first is that we have a very hard time defining Alzheimer’s disease. What is problematic about that is you can’t cure what you can’t define.
The other key message is that for reasons having to do with some initial enthusiasm, followed by stubbornness [and] followed by ego, ideas [aside from] the dominant thread of Alzheimer’s disease have been pushed out of the way. The field has tried to enforce uniformity of thinking about how Alzheimer’s disease works and it’s been unproductive.
The other point I’d like to bring out is that I try [to] end [the book] on a note of hope. I end with the idea that despite the missteps we have gone through in the last two or three decades, we’re in a position right now to correct those mistakes and to move forward. One of the reasons I wrote the book was to try [to] catalyze that change and make it happen more quickly.
“Despite the missteps we have gone through in the
last two or three decades, we’re in a position right
now to correct those mistakes and to move forward.”
Being Patient: In the 1980s and 1990s, there was great optimism and momentum in the field of Alzheimer’s. Can you tell us about the key discoveries that scientists made during that time and how we ended up heading towards the wrong direction?
Karl Herrup: What I tried to do in writing the book is I set myself a goal that there were no heroes and no villains in this story. A lot of very smart and very passionately devoted people all went at this problem with the same intensity.
What got us off track was, in many ways, we became a victim of our own success. There were fundamental discoveries that seemed to point to such an obvious conclusion that no one — and I include myself in that — could have been blamed for being just incredibly optimistic about rapidly finding a cure.
What were those discoveries? The first was the discovery of the small peptide that makes up what are known as amyloid plaques, which is one of the pathological deposits in the brain of someone with Alzheimer’s disease. The second major step was the [discovery of the] parent protein that generates that peptide. Then the third major step, and this is where a lot of the electricity came from, was the discovery that mutations in that protein were causative for genetic, rare but aggressive, familial forms of Alzheimer’s. That linkage between the genetics and what seemed to be the biochemistry of the disease was all almost too seductive to avoid.
The fourth discovery was equally electrifying. We could engineer the mouse genome in such a way that it reproduced those plaques in the mouse, an experimental model used by lots of neuroscientists both then and now. Even more importantly, by giving essentially a vaccine, we were able to remove the plaques, and the behavior of the mice changed in a way that suggested we were on the right track.
All of these things coming together made it almost irresistible to say, ‘Well, there’s nothing left to do but go to humans and pull amyloid out of the brain: problem solved.’ Sadly, that turned out not to work.
That initial enthusiasm solidified into a prejudice and hypothesis became dogma. That’s always dangerous in science and what I try [to] chronicle in the book is how past those initial exciting days, more and more data began to accumulate [showing] that the fundamental idea was wrong. That’s where we went astray, and that’s where we find ourselves today with very expensive clinical trials failing one after another. We just need to start listening to our own data.
Being Patient: The hypothesis you’re referring to is the amyloid hypothesis?
Karl Herrup: Exactly so.
Being Patient: There was one instance that really captures how the amyloid hypothesis has come to dominate the field of Alzheimer’s. As you chronicled in your book, a member of the external advisory board for the lab that you worked at told you, “Son, if you’re not studying amyloid, you’re not studying Alzheimer’s.” The hypothesis has been the mainstay of Alzheimer’s drug development, and when it comes to the pharmaceutical industry, you noted that greed, stubbornness and bad advice were ultimately the likely reasons that led drug companies down the wrong path. Tell us more about your thinking.
Karl Herrup: I want to preface my comments with an admission. Of all the topics I touch [on] in the book, the one that remains the most mysterious to me is why these for-profit companies that are hugely successful financially made what in the end, not in the beginning, such bad business decisions. To not have pursued the anti-amyloid therapies in the beginning would have been almost irresponsible, let alone not good business decisions.
But they kept at it, and to this day, keep at it. I’ve yet to get my head around [it]. No matter how greedy you are, no matter how stubborn you are and no matter how bad the advice you’re getting, at some point when you’re hemorrhaging billions of dollars, somebody somewhere in the company ought to be saying something like, ‘Whoa, whoa, whoa. I think we need to retreat here.’
The pharmaceutical industry is an interesting partner in the fight against any disease. They have their own agency. They’re partners, but their motivation is different from those of us in clinical and basic research who are actually looking for the biological basis in a cure for the disease. They are interested in making money and that has negative connotations, but honestly, we need them.
We can’t fight Alzheimer’s disease without them. We need the profit-driven infrastructure that can take a good scientific idea and reduce it to practice. Without that, a good idea is virtually worthless. They are tremendous at those final steps in the process, but they seem to have been bit by the same bug that rules the research community, and that is, if you aren’t studying amyloid, you aren’t studying Alzheimer’s. To paraphrase in the language of business, if you aren’t looking for drugs that reduce amyloid, you’re not in the Alzheimer’s business.
Being Patient: The FDA approved Aduhelm, the anti-amyloid drug, in June 2021. What are your thoughts about this decision then?
Karl Herrup: It was a horrible decision. The reason it’s a bad decision is not just [due to] the science, because even to this day, although I’m of course passionate about the lack of a role for amyloid, that’s not a settled discussion. We can still debate that back and forth. The destructiveness of the FDA decision was that it took the biomarker of amyloid deposition and made that the sine qua non of Alzheimer’s disease.
There was virtually no clinical benefit from either of the two major arms of the study that was done. By tweaking the statistics and doing a bunch of post-hoc analyses, one of the two [arms] looked like there might have been a small signal. But the signal was small, and cognition continued to decline. It wasn’t as though [Aduhelm] had stopped Alzheimer’s in its tracks, even for those people where it was most efficacious.
The problem with the FDA decision is that by using amyloid as a surrogate for the disease, they essentially said the amyloid cascade hypothesis is completely correct, and therefore, it is anticipated that by reducing amyloid, clinical benefit will follow. That really caused a firestorm in the field.
To take an uncertain marker like brain beta-amyloid or CSF (cerebrospinal fluid) beta-amyloid, and make that the basis of a billion-dollar health care decision, just struck everyone as reckless, even for people who work and believe in the eventual success of a therapy based on the amyloid cascade [hypothesis].
The FDA would now have virtually no basis in turning down a drug that removed tau fibrillary tangles, for example, even if once again there was no clinical benefit, because the logic would be exactly the same. There are now other anti-amyloid drugs in the pipeline. The FDA will have very little logical ground to stand on in turning down these applications, if it can be shown that there is a reduction in amyloid.
From my perspective, as a basic researcher, one of the other really chilling consequences is that it reinforces that very comment, which is if you aren’t studying amyloid, you aren’t studying Alzheimer’s disease.
Now, therapies [for] anti-inflammation, restoration of myelin integrity, DNA damage, roles of aging and mitochondria, you name it, are going to be muscled out even further. Worse, they will be judged on the basis of whether or not they reduce amyloid, independently of whether or not they help the clinical picture of dementia.
Being Patient: Looking forward, you propose a new model of Alzheimer’s, one that consists of neighborhoods with different cell types. These neighborhoods form cities and ultimately, a nation. Can you share with us about this concept of Alzheimer’s?
Karl Herrup: We call ourselves neuroscientists when we study the brain. That reflects a prejudice from years ago that the function of the brain depends first and foremost, and almost exclusively, on the function of one type of cell in the brain called the nerve cell or the neuron. What we’ve come to appreciate over time…is that no cell functions by itself in the brain.
That was where that concept of neighborhood came from. Even in the tiniest sliver of brain substance, yes you have neurons talking to each other using brain electricity, but there are astrocytes required to feed them the nutrients. There are blood vasculature cells, which are necessary to filter and nurture the astrocytes and other cells in the brain. There are microglial cells that help ward off disease and help keep synapses clean and tidy. Then, there are oligodendrocytes.
The point is it’s this neighborhood of different cell types that is the unit of the brain, and it’s only when the cells work together and interact effectively that you have normal brain function.
My proposal for Alzheimer’s disease is to think of it as a loss of these neighborhoods. Different neighborhoods interact differently. As you expand and start looking at what I call cities, which are groups of neighborhoods, and beyond that, nations, the interactions become more complex at each level, but so do the potential for disease. I try and demonstrate how the model can be used to explain Alzheimer’s in a different way. It doesn’t just depend on neurons and on amyloid.
Being Patient: You have also emphasized the importance of gaining a deeper understanding in the biology of aging. Why do we know so little about aging, and why is this area of research crucial for studying Alzheimer’s?
Karl Herrup: First of all, you can’t understand Alzheimer’s unless you understand aging. The simplest proof of that is young people don’t [often] get [Alzheimer’s]. It is extraordinarily rare below the age of 65.
The reason we don’t know a lot about the biology [of aging] is precisely because it takes a long time to study it. People look for quick experiments that will satisfy an NIH (National Institutes of Health) study section or get you a paper for promotion or tenure. That’s the simple answer.
But where my optimism runs highest is precisely in [this] area. I believe the biology of aging has finally captured the interest of biologists around the world, and we are making great strides in understanding what drives it and how it works to predispose us to a whole range of degenerative diseases.
The interview has been edited for length and clarity.
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