Groupthink.

It's a popular concept, because it SEEMS to be everywhere.

Which is weird, because there's more than a little controvery in the Social Psychology literature about whether it's a thing.

Actually.

In large part, because it's hard to replicate.

However, the question of whether Groupthink is a thing, or not, is a topic for another time.

But, what I'll tell you, is that I've seen it in my own work, when it comes to baseball, and the word and concept came up, repeatedly, in my conversation with Alzheimer's Disease researcher Dr. Karl Herrup.

Herrup, Alzheimer's & NOT

In November 2021, I interviewed Alzheimer's researcher Dr. Karl Herrup. Topics we discussed included...

• Alzheimer's Disease
• Thomas Kuhn and Anomaly
• Groupthink

CHRIS OLEARY: My guest today is Dr. Karl Herrup. He's the author of, "How NOT to Study a Disease: the Story of Alzheimer's." Dr. Herrup is a professor of neurobiology and investigator in the Alzheimer's Disease Research Center at the University of Pittsburgh School of Medicine. I assume that's UPMC. He has his PhD from Stanford and did postdoc work at Harvard. So obviously he's a he's a serious person has has good credentials. This is not ivermectin, we're dealing with here. This is a serious person. Dr. Herrup, welcome.

DR. KARL HERRUP: Thank you. Nice to be here.

CHRIS O'LEARY: So this is, first and foremost, a podcast about Innovation. But I also talk about its evil twin Unnovation, which is why Innovation doesn't happen. And that's how I came across your book and your work and this general topic. About a year ago, I was looking for examples -- I'm a student of Thomas Kuhn, the paradigms guy -- and I was looking for examples of Kuhn's "crisis." Even disasters. Where science doesn't function well. And I was doing keyword searches looking for signs of Groupthink and dysfunction, looking for words like...

   - Shunned
   - Ridiculed
   - Rejected
   - Mocked

...and came across Sharon Begley's article -- the late Sharon Begley -- article in STAT...

- How an Alzheimer's cabal thwarted progress toward the cure

I tried to contact some of the people there. Dr. Ruth Itzhaki, who was my first interview did talk to me. But there are other people who DON'T want to talk to me. And then I came across your work in your book, "How NOT to Study a Disease," and thought that was just absolutely fascinating and absolutely dead on to what I'm interested in.

So I'd be interested if, kind of first off the bat, you could give an elevator pitch view of what happened. Kind of the premise of your book. 100 words or less. A 30,000 foot view of Alzheimer's Disease. Kind of where we are and how we got here. That kind of thing.

DR. HERRUP: Well, it's a pretty steep challenge. Let me say the premise of the book really is that -- and I think it fits very well with the topics you're trying to cover in your podcast -- the premise really is that the field is stuck. It's in a log jam of ideas and forward progress. And I took on the chore of writing the book in the hope of sort of laying out where I think, and how, the logjam developed, and to offer some thoughts as to how that logjam could be broken. The 30,000 foot view really, is something which is almost not explicitly spoken about in the book. And that is that we've mis-defined Alzheimer's Disease. And in many ways, I characterize it as three inflations of the original definition of the disease. And each of those inflation's distorted what we accept as Alzheimer's Disease. And, I think in the end, the disease has been inflated beyond beyond the point where it's useful as a research definition. It may still have some value clinically -- although you can question that -- but certainly, as a research definition, what we now call Alzheimer's Disease is not something you can productively work on.

CHRIS O'LEARY: One of the things that concerns me is seeing assumptions and paradigms getting baked into the definition where Alzheimer's now is Amyloid and Tau, and that's the definition of (Alzheimer's). And if you could get into the Amyloid Hypothesis and some of what that means and why it might be problematic to bake the presence of Amyloid into the definition of Alzheimer's Disease.

DR. HERRUP: So that itself is a long story. But let me give this thought. The important point in the history of Alzheimer's Disease goes back actually to the work of Alzheimer himself. He entered the field as a practicing pathologist -- actually a psychiatrist -- with his pathology as an avocation. And he was quite enamored with the idea that brain structure predicted brain function. And so, when he examined a single case study, and found these abnormal deposits -- that he had not really seen before -- in the brain of this woman who had died with with an aggressive case of early onset dementia, he made the leap and speculated that, in fact, it was those deposits that caused the disease.

That set the stage for the entire field. And that hypothesis is now baked solidly into the cake of the way we approach Alzheimer's Disease, both clinically and, again to reemphasize, as basic researchers.

The problem is what Alzheimer actually described was a correlation. He had no way to know causality. But he brought his bias to the program. And that led to the hypothesis that it was the deposits that caused the disease.

And then that disease that definition just sort of lay fallow for decades, until in the United States, the National Institute on Aging was born. And they needed a boogeyman to become the face of aging. Something malevolent and that could be described as an enemy.

Aging per se is is too squishy a target, but something like Alzheimer's would be great. But they realized that, in the current definition, that was prevalent at the time, Alzheimer's only referred to this early onset form of dementia, known as pre senile dementia; before aging dementia. And they said, "Well, now we got to we got to do better than that." And so, based on a number of arguments, they suggested that, well, actually, all senile dementia, meaning even later onset dementia, since it also has these deposits that Alzheimer's saw, then all senile dementia has got to be Alzheimer's Disease.

And that worked really well, because it did provide a lot of impetus for a lot of funding to the National Institute on Aging (NIA).

The problem is that it it was like a Trojan horse because it brought in the unspoken but necessary assumption that therefore these plaques and tangles must be the causative element of the disease.

Otherwise, why would we be studying them?

And the field has never looked back.

And the history is long, the book is long -- I urge all your listeners to pick up the book and actually read it; it explores all the nooks and crannies here -- but let me try and summarize the rest of our history as quickly as possible.

What happened next was even almost more outrageous than the first.

For reasons having to do with this... I guess, as we (said when we) started talking, with a stuck paradigm, you know, a hypothesis that has become axiom and instead of being treated as hypothesis. People discovered -- after they looked at enough samples from brains of people who had died with totally normal cognition -- they discovered that almost 30% of them had deposits of amyloid and tau that would be perfectly consistent with a diagnosis of Alzheimer's disease, if it were given to a pathologist who was unaware of the diagnosis. That observation, when it came out, was my first red flag and started my thinking that, "Well, wait a minute, if 30% of normal people have the same deposits that are supposed to cause Alzheimer's disease, there's something wrong here."

CHRIS O'LEARY: In (Thomas) Kuhn's terms, that's the Anomaly.

DR. HERRUP: I accept that completely. Because that's exactly what it is. And it's the core Anomaly, I think, in our field.

But as I say in the book, what happened is the field turned that weakness into a strength. And they said, "Ah, of course, these people have Alzheimer's Disease because they have plaques and tangles. They just aren't showing the symptoms yet."

So an entirely new class of disease... A new class or stage of Alzheimer's Disease was defined called Preclinical Alzheimer's. And we just never recovered from that.

I just don't feel that, in any way, that that's a useful concept. I wouldn't say either clinically, although there, you know, I'll defer to my physician colleagues, for the final say. But I can tell you, without question that, from a basic research point of view, that is just a complete nonsense.

And makes it worthless.

And what we end up with then, is a situation where our our definition is distorted, inflated, as I called it, and it's my strong opinion that you can't cure what you can't define.

And then that's where we are right now.

CHRIS O'LEARY: It's kind of amazing. The dancing and the redefinitions. And I'm not gonna put a name to this, but I get a sense of, from The Wizard of Oz, the idea of the saying, "Pay no attention to that man behind the curtain," is a sense that I get. As we mentioned before, you know, my mom has Alzheimer's Disease. I seem to have her brain. I have had injuries. And I will certainly tell you that from a well informed, but naive observer perspective, a lot of the conversations that I hear... They don't encourage confidence. There's a lot of happy talk, a lot of redefinition. A lot of, "Well, obviously, that happened, we knew, you know, we knew that was happening, we couldn't make it and we didn't make it into the study. We didn't predict it before the study. But obviously after the study, that's obvious that that's what's going on." You can leave that line there or address it, if you want to. There is the you know, the word cabal that Sharon Begley used. I would... That's a little heavily weighted, I would use the term paradigm or school. I'd be interested in your comments on the personalities involved in what may be involved there in terms of... I think it's Dr. Hardy, who's said, "Hey, it was just a hypothesis." And I've got no problem with putting forth a hypothesis. It's just that it got so baked in, I guess the fact that Dr. Alzheimer proposed it 70 years prior is one of the reasons why it got baked in. I'd just be curious to kind of your thoughts to your responses to those thoughts.

DR. HERRUP: Yeah, so let me take them one at a time.

Certainly, that article by Begley was a that was just a brilliant piece of writing.

CHRIS O'LEARY: And it does seem like an inflection point to a degree.

DR. HERRUP: Yes, I do think so. And whether it was just correlated with a shift in the in the field or actually drove the shift, I don't know. But it... I just remember nodding my head very, very vigorously when when I first read it, and in fact, I actually contacted her and interviewed her for the book. And I was shocked to find out later that she passed away from cancer. A terrible loss to the field.

CHRIS O'LEARY: Yeah, she was a force.

DR. HERRUP: But it's an interesting question, to take on the issue of, "Is it a cabal?" So, a cabal has the implication of evil intent. And there I would take issue. I don't think the people who are in that group have evil intent. I don't think they're going out to hurt people or to block progress in the field.

But to the extent that a cabal is a group that is organized around principles that are not grounded firmly in reality, I think that I think it's a perfect definition.

And in fact, I use "cabal" in my own speaking about the disease.

There are caveats, of course, but I'm comfortable with calling the... It's a Groupthink, to use Orwell's description. That takes away the evilness of it. But it's hard to get away from the negative consequences of this Groupthink, because they exist.

CHRIS O'LEARY: Can you give some examples of why you would characterize it as Groupthink? What exactly are you thinking about?

DR. HERRUP: I guess I would say it in two ways. The first is, as we discussed before, this idea of an Anomaly. And you put the Anomaly together with the idea that the (Amyloid) Cascade Hypothesis is a hypothesis. In a perfect world, the conjunction of those two would say, hmm, maybe we need to rethink and go back to basics and just check all our assumptions.

What happens in Groupthink, though, is you all look at each other and you say, "Well, there's no reason to do that. We KNOW Alzheimer's is caused by deposits of Amyloid. And oh, yes, let's not forget to mention Tau, but we always do." So that's, to me the strongest negative consequence. I also would like to...

This didn't make it into the book, but it's a story that that I think, has sort of helped sort of mature my own thinking. So I recognized the Anomaly -- that is to say, this weird observation that 30% of cognitively normal individuals have deposits of amyloid that would be adequate to have the diagnosis having Alzheimer's -- I recognized that Anomaly many, many, many years ago. And talked about it extensively.

But to this day, I remember, it was almost a decade later, that I allowed myself to think, "Well, gee, let us think about Alzheimer's without Amyloid."

And I know that sounds crazy.

But the point I'm trying to make is that the power of Groupthink is that even for someone who could recognize that there were problems, the Groupthink is is so strong, and the desire to work in the Alzheimer field was obviously strong in me -- I wanted to find a solution -- I couldn't let go of Amyloid, even though I knew it had its weaknesses.

And to this day, I remember the feeling when I finally allowed myself to say, "NO. Let's put everything down. Let's get a clean sheet of paper. And let's just lay the facts on the paper without the preconception that Amyloid drives the disease." And just... How would we put the facts together in a way that's logically consistent, and not merely consistent with a extant hypothesis?

CHRIS O'LEARY: Can you go into a little more into how you got to that point. Some of what your training is how your stream came to parallel the Alzheimer's stream? How long you were with the orthodoxy and then kind of when and why you broke? I'm just, I'm very interested in those kind of origin stories of where the the scales fall off the eyes.

DR. HERRUP: Yeah, um, I do tell the story in the book, and it was certainly a major moment where this announcement of the of the conclusions of the workshop -- NIA and Alzheimer's Association workshop -- was held at a meeting in Honolulu in the I think 2009 or 2010. And I just vividly remember sitting there, just furious that, rather than doing what what needed to be done -- I mean that Alzheimer's in its definition had really not been reconsidered in 20 years -- it was time for reconsideration.

CHRIS O'LEARY: Where there drug failures? Were drug failues cuing that?

DR. HERRUP: We had already started to have some drug failures. But we didn't have any Aducanumab's to beat on. But but there were already signs... The originally Elon trial had had failed to meet endpoint. And, and others were planned. But it was just that...

So, to talk about the origin of my train of thinking. A lot of it grew out of that anger at just saying, "Wait a minute, you know, this is this feels more like a cabal than it feels like a scientific reexamination." And it was that... I literally left the lecture hall and went up to my hotel room and got a clean sheet of paper. That was the origin of my reimagining. The Alzheimer's Disease paper that I wrote for the Journal of Neuroscience, which I called an age based hypothesis. And it was exactly as I described.

I said, well, wait a minute, let's get rid of Amyloid. Let's just start with age, since we know that that is a major driver of disease. Young people don't get Alzheimer's, and your risk goes up the older you get. So, okay, if we if we start with age, and we start with a clean piece of paper, how do we get to Alzheimer's? And I guess as the saying goes, the rest is history.

CHRIS O'LEARY: If you think in terms of paradigms, one thought that struck me, especially with, like conversation with Dr. Ruth Itzhaki is whether the Blood Brain Barrier is functioning as a paradigm? That's keeping people from considering certain, you know, ideas; the microbial aspect of things and whether Amyloid is a response to microbes, and whether people think that's impossible. And that's keeping people from going there. It seems like you've certainly considered that. Or, you know, you went back to the clean sheet of paper. So I'm curious what you think about that.

DR. HERRUP: It's not my favorite hypothesis. But I am absolutely open minded about it. And I believe that there's a lot there. As I say in the book, there are impressive pieces of evidence that stand very much in favor of it. It's just that... Mechanistically it's hard to envision how it happens. But the idea that there is an infectious origin, I'm as open minded about that as I am to the idea that Amyloid causes Alzheimer's Disease. I think, you know, they both have little factoids that that are quite persuasive. And Itzhaki is... I've listen to her comments as well. And what resonated very strongly with me was not so much what was her own hypothesis, but the extraordinary resistance that she felt in the field.

And that gets back to the Groupthink we were talking about. There was absolutely no reason for that. None.

CHRIS O'LEARY: Well, it was in... It made it into my conversation with her beforehand where she talked about that she doesn't understand what the objections are. People haven't bothered to state their objections to her ideas. Which is a point she made in the interview. And a point she made after the interview that didn't make it onto the tape. Basically, I turned off record and she's like, "If anyone can tell you what's going on -- why they don't like this idea -- can you please tell me because I still, to this day, have no idea." And I would be interested in where you would put your money.

DR. HERRUP: Where I would put my money? Oh, boy. Well, let me start by going back a bit and saying what I did...

One of the topics I DO cover in the book -- and her argument fits perfectly with that -- is that, for the Groupthink to proceed, it actually wasn't enough just to promote their own ideas.

It actually became a part of the Groupthink that other ideas had to be suppressed.

And I am 100% with the bemusement as to why you have to suppress the other ideas. And the point I make in my book is that a lot of them -- and I would put the viral origin of Alzheimer's right up in there -- a lot of these other potential mechanisms, potential origins of Alzheimer's Disease, they fit very comfortably within Amyloid based mechanism. It's just an Amyloid is now in context. It's not a sole and necessary and sufficient driver of the disease.

CHRIS O'LEARY: Right? It gets overwhelmed or it there's this huge Amyloid bloom that eventually causes all these problems. But it was in response to something else rather than a primary problem.

DR. HERRUP Correct. So where would I put my money? I would go back... I mean, I'm sorry, to deflect your question. But I would go back to my first statement, which is that we fundamentally don't define Alzheimer's Disease in a productive way. So we can't, we were probably and I'm not, and they actually even the field is willing to come up and admit this.

We're probably dealing with a multiplicity of diseases.

The word spectrum is coming into vogue at this point. And I, I'm a little bit cynical about that. It's, I mean... I like the idea of spectrum. I even talked about it in the book. But it's, I think it's used as a fudge more than it is as a useful descriptor. So I do think some of the main avenues in our...

It seems to me that problems with the vasculature are really key. Let me say to dementia. Rather than put the title of Alzheimer's on it.

The idea that what's good for your heart is good for your brain, I think, comes out over and over again.

The finger study out of Scandinavia is an excellent example of that. And recent work showing that, you know, aggressive management of blood pressure can have tremendous protective effects is quite, quite impressive to me.

There's a gray sort of boundary -- a fuzzy gray boundary -- between vascular dementia and Alzheimer's Disease; what we know is Alzheimer's Disease. But I think attention to vascular health would be something I would be focused on.

I'm still kind of partial to the role of Inflammation.

CHRIS O'LEARY: In that model, the Inflammation model, what is causing the Inflammation? Because in my understanding the Inflammation is a response to something. So what's it responding to?

DR. HERRUP: Good question. I think it's been called Inflam-AGING. Which is that, just as with the aging of our body, our innate immune system seems to slowly but inexorably ratchet up its activity in a way. And the consequences of bad are not good for our brains.

That's, in my mind, how you would link genomic integrity or, you know, DNA damage to nIflammation.

But, and here's where Amyloid comes in. Again, I mean, you know, having a deposit in your brain, certainly your innate immune system is going to recognize it as a foreign object and will respond. So it's one of the ways in which Amyloid and Inflammation can coexist.

And to bring it back to Dr. Ruth Izhaki's hypothesis, certainly if you had a viral infection or a bacterial infection, your innate immune system is not going to sit around passively just looking at the virus and saying, "Oh, hello there." It's going to respond. And it's going to do its best to get rid of it.

So I don't think inflammation is a very focused cause. What I mean by that is that there are many, many stimuli that could trigger it. And I think what makes it worse is that, as we age, we are more and more susceptible to triggering it. And, equally important, we're less and less able to shut down the immune system once it starts.

And, I don't know, I like myelin.

As I say, and I've been accused both positively and negatively, I think we've got to try them all.

CHRIS O'LEARY: That was one of the points that I was going to make is this Rifle versus a Shotgun disctinction. It seems like the Groupthink, and some aspect of the Groupthink, encouraged the Rifle approach. Made the Shotgun approach unthinkable. And you can get into lots of reasons, there. We are at time, and I want to respect your time. So, last question. In terms of Aduhelm, the brand name for the compound Aducanumab... My mom has Alzheimer's. Aricept isn't working, right now. She's getting weaned off of it. So she's struggling. I'm not even THINKING about Aduhelm. For one thing, it's $56,000. Maybe I could get it for $11,000. Which is still a lot of money. But Aduhelm does make any SENSE to me. And my concern is that it could actually HURT her if, as some of the theories go, that A-Beta is an anti-microbial peptide, then SUPPRESSING amyloid could actually do more harm than good. Especially if you're doing it earlier on in the process, when it might actually be accomplishing things. Before things have gotten out of hand. I'd be curious what you think about Aduhelm (Aducanumab) and that whole... I'm gonna call it a disaster because it feels like a disaster to me.

DR. HERRUP: Well, I would agree with you. To the extent that we take Amyloid out of the brain, we actually don't know that that's benign. So you're correct that A-Beta functions as an anti-microbial peptide, so why would you want to get RID of it.

CHRIS O'LEARY: And, even if we don't know (for sure), you don't get rid of it if you don't now what it does. That's Chesterton's Fence.

DR. HERRUP: Yeah. There's some evidence that it functions to buffer metals. Some evidence it serves an anti-oxidant function. Not directly. And we know from the clinical trials themselves of Aducanumab that a good fraction of the people on the therapy develop significant brain swelling: ARIA.

CHRIS O'LEARY: Which is a lot for what might just be the Placebo Effect.

DR. HERRUP: ARIA-E and ARIA-H. Although the latter was somewhat less common, it's nothing to mess around with. I think all of those come together to speak directly to the idea that we just don't know that you want to pull Amyloid out of your brain. That you can do it safely. And let's not even say Amyloid. Let's just say A-Beta.

Any drug comes with a certain amount of risk, and let's look at the other side of the equation. For that risk, if I'm willing to take it, what's my benefit? And I would argue that...

I've been totaly unimpressed that there is any significant clinical benefit from (Aduhelm).

I would not take it.

Even if I felt I had an elevated, a priori risk of the disease. I just think there are other things you can productively do.

CHRIS O'LEARY: Again, the book is, "How NOT to Study a Disease: The Story of Alzheimer's" by Dr. Karl Herrup.