Amyloid, meet Alzheimer’s: correlation ≠ causation
How the recent controversy around amyloid changes (...or maybe doesn’t) how we think about its role in Alzheimer’s disease
TL;DR…
Allegations of falsified research rocked the Alzheimer’s community this summer. However, scientists and clinicians in the field have questioned the amyloid theory for decades as a more complicated picture of the underpinnings of dementia has emerged.
Intro…
Yes, we are writing another debunking article 🙌🏽. And no, we are not becoming a myth-busting Substack. We believe this is another timely and important topic for us to dive into for you (our readers). We hope that you will not only come away from this having learned something about neurocognitive disorders (and Alzheimer’s dementia specifically) but also hope that this post, in combination with our last one, impresses upon you the importance of going beyond the headlines 📰 when it comes to the narrative around deeply complex scientific topics that are often overly simplified and stripped of their nuance in the public discourse.
You may also be asking yourself why two psychiatrists are writing about neurocognitive disorders, which you may consider to be more in the realm of neurologists. Good question; here are three good reasons why:
Psychiatry and Neurology are intimately connected specialties 🧠. So connected that we are overseen by the same governing board (the ABPN).
Psychiatrists (and in particular geriatric psychiatrists) often manage (or co-manage along with neurologists) patients suffering from neurocognitive disorders.
We’re coming at you with our first expert contributor, Dr. Arun Ramamurthy (side note - look at all those 5-star 🌟 reviews - bravo, Dr. Ramamurthy). He is a geriatric neurologist who specializes in the care of patients with neurocognitive disorders. He also happens to be just another kid from Akron and practices at the Wexner Medical Center at THE Ohio State University.
The mystery of Sylvain Lesné…
To understand the controversy around amyloid plaques, you have to understand the work of Sylvain Lesné. Lesné is a French 🇫🇷 neuroscientist and Professor at the University of Minnesota, where he published a seminal paper in 2006 touting the discovery of AB*56 (pronounced alpha-beta-star-56), a specific toxic subtype of amyloid-beta that he claimed was responsible for the pathogenesis of Alzheimer’s disease. This paper helped spark a revolution in Alzheimer’s research and became a cornerstone of almost all of the Alzheimer’s research to come in the ensuing decades (racking up an impressive 2000+ citations and placing itself in the 99th %ile of articles of a similar age in terms of online attention 🔥). However, allegations that broke in July 2022 claimed that the Lesné lab had manipulated images (specifically, Western Blots) in his seminal paper, throwing into question the validity of the conclusions made in the paper and rocking the world of Alzheimer’s research 😲. Before we dive into the allegations - let’s review a bit of the history and get you up to speed.
The history of amyloid…
To be clear, the idea of amyloid plaques being a hallmark of Alzheimer’s was not new. This science of plaques had been established as early as 1906 by Alois Alzheimer (it’s a super interesting story in and of itself, we encourage you to read more about it), and by the mid-1980s, we knew that amyloid-beta was the primary component of these plaques.
To ensure that we’re all on the same page, amyloid is a relatively generic term for fragments of protein that are produced by the body 🧬; they are normally broken down and cause no issues. However, when they start to get tangled with each other and harden, they form plaques that the body is unable to resolve.
Amyloid (brown) surrounds a neuron (blue). Courtesy of Science.
The plaque theory of Alzheimer’s progressed to being amyloid-centric, meaning that we believed amyloid was the primary driver of pathology in neurocognitive decline. This theory permeated the field upon its inception in the 1980s.
And despite how recent articles have positioned the ‘breaking news,’ dissent from the amyloid theory is also not new 💡. Expert dementia researchers began questioning the amyloid theory’s validity in the early 2000s, and this skepticism increased in intensity as the 2010s rolled around. So, what happened around that time to start changing the thinking around amyloid being the crux of Alzheimer’s pathology? Well, there was a medication failure. And another one. And another one. And another one. There were so many clinical trial failures that this post now features DJ Khaled 👑. These medications tested the theory that by reducing/removing amyloid, the disease would be modified. The repeated failures of medications relying on a reduction of amyloid as a mechanism of action fairly increased the questioning 🧐 of the amyloid theory itself.
Still, not all hope was lost; the amyloid theory continued to maintain some traction because of one medication with more hype than any that had come before it: Aducanumab 🧪. The Ohio State University was one of the original sites for Adacanumab’s clinical trials, and, despite skepticism (including from experts such as ourselves), we were very much excited by it. As a monoclonal antibody specific to the abnormal amyloid proteins, Adacanumab consisted of antibodies 🦠 that tagged abnormal amyloid so that the body’s immune system could find and eliminate it. What was different about Adacanumab was how effective it was at getting rid of both insoluble Amyloid plaques AND soluble amyloid proteins, setting it apart from its failed peers. The thought was that these soluble amyloid species played more of a role in brain damage, and Adacanumab’s unique mechanism of action would lead to positive outcomes. The clinical trials told us a different and weird story. One of the trials showed a benefit, while another failed. Some tricky statistics and a subanalysis of the highest dose by Biogen then gave some nice p values, and controversy has since ensued around both the FDA’s decision to approve the medication ✅, as well as CMS’ decision to cover it for a subset of Medicare enrollees 💸.
Back to AB*56…
Now that you understand the history of amyloid and Alzheimer’s research, and that the amyloid theory has never been bulletproof, let’s get back to AB*56, which has been at the center of the controversy sparked by that recently released Science article we mentioned above. To summarize:
A group (specifically, Lesné’s) isolated a type of amyloid oligomer (AB*56) that was hypothesized to be toxic to neurons. Oligomers of amyloid are generally very difficult to isolate and identify, so this was considered a breakthrough. As you now know, this research generated significant excitement in the field and informed many of the clinical trials that ran over the ensuing decade.
Upon further review from peers and experts in the field (which came to a head and the findings of which were published this past summer), it turned out that the data backing up that original article was possibly fabricated, and AB*56 may not actually exist 🚨.
Of course, as soon as the Science article questioning AB*56 dropped, media outlets ran with the news 🗞, and suddenly, the whole Amyloid theory was done (sidebar, do a quick Google News search for ‘amyloid science lesne’ and take a look at the headlines yourself). The work done by scientists stretching back over a century to Alois Alzheimer was moot, and now we had no idea about the cause of Alzheimer’s Disease (...not). Yes, it was true that there was uncertainty about AB*56’s existence. However, there was not necessarily a deep, complex narrative underlying this uncertainty. Just because AB*56 was possibly a farce DID NOT MEAN THAT THE WHOLE THEORY WAS COMPLETELY WRONG AND WE NOW KNEW NOTHING ABOUT THE DISEASE (and this certainly was not breaking news to scientists and clinicians in the field). Unfortunately, Lesné’s original Science article was well cited and became very popular because it showed more of a direct link between oligomers and cognitive dysfunction than had been previously demonstrated, included nice figures, and seemed to fit the amyloid theory narrative perfectly.
The rest of the story…
So, while there is some evidence to suggest the toxicity of Amyloid oligomers and their damaging effects on neurons (brain cells), their overall impact on the brain during the symptomatic phase of Alzheimer’s Disease is likely small. Amyloid oligomers are certainly one part of the disease process, but they are not the holy grail discovery we once thought them to be (we hope you see the parallels to our recent Stack on the serotonin hypothesis of depression 🙇🏽♂️). The scientific community was able to come to this conclusion by utilizing the tried and true scientific method:
By using this method and creating experiments (which failed…at times, frequently), the scientific community focused on researching and treating neurocognitive disorders was able to continue to iterate on the original hypothesis and get closer to the actual science.
So, where do we go from here?
First and foremost, we hope that you can take away some process-y conclusions from this post:
Failure and repetition are part of the scientific process, and in many cases, multiple attempts/trials to justify (or refute) hypotheses mean the process is working as it should. A failed trial isn’t a ‘failure.’ It implies the researcher couldn’t refute the null hypothesis (and still learned something in the process).
Scientific conclusions are often in the eye of the beholder; small P-values and slick figures do not always correlate 1:1 with high-quality research. We encourage you to go beyond the abstract, graphics, and conclusion when reading academic literature; remember - the stamp of peer review should not replace your critical perspective.
If we’re telling you to read peer-reviewed academic literature with a critical lens, we hope you know what we’ll say to you about mainstream media headlines and articles. We feel confident (based on absolutely ZERO quantitative analysis) that the majority of headlines and articles that have anything to do with scientific medical topics are accidentally misleading at best and maliciously wrong at worst. Please go beyond the headlines and even talking points and seek out the primary sources to come to your informed conclusions.
And on the topic of neurocognitive disorders, what experts in the field have known for a long time is that many factors contribute to Alzheimer’s Disease (hyperphosphorylated tau, vascular changes, inflammatory factors, glial cell disruption, and cell transport disruption to name a few), and amyloid is still one of those factors. The fabricated research that led to lots of headlines and controversy this summer means that AB*56 is not the smoking 💨 gun that we initially thought it was. However, it also does not negate the significant amount of learning that has been done over the last 100+ years and DEFINITELY does not mean all neurocognitive disorder research (and related pharmaceutical R&D) has been a scam/farce/conspiracy. So, here’s to all the scientists and clinicians 🙏🏽 (including our very own Dr. Ramamurthy) putting in the hard work researching and treating a disease that impacts more than 1 in 9 Americans over the age of 65. And we sincerely hope to see even more smart and passionate digital health and healthcare technology folks tackle neurocognitive disorders, an area that seems to have been left behind when compared to many of its peer behavioral health disease states.
Two questions:
How do we teach each other (including our children) to critically evaluate the content served to us by traditional media outlets as well as through social media channels?
The peer review process has come under significant (justified) scrutiny and fire over the last few months. How do we fix the biases and pressures that have created misaligned incentives for both scientists looking to get published, and journals looking for readership?
✌🏽 A + A
To read more about our vision for the Stack, check out our intro post here.