Tag Archives: Alzheimer's Disease

So whatever happened with Aduhelm?

Aduhelm and Leqimbi were hot news a few years ago. They are both antibodies that work as anti-Alzheimer’s disease drugs by binding to and hopefully destroying amyloid beta. The hypothesis that amyloid beta is the causative agent of Alzheimer’s, and that reducing amyloid beta will lessen the disease, is known as the Amyloid Hypothesis. And while the Amyloid Hypothesis is still the most widely supported, I wonder if the failures of Aduhelm and Leqimbi to make much of a dent to Alzheimer’s disease has damaged the hypothesis somewhat.

Because think about it, the whole job of an antibody is to help your body clear a foreign object. When antibodies bind to something, they trigger your immune system to destroy it. And this is why you get inflammation whenever you get a cut or scrape, antibodies will bind to whatever microscopic dirt and bacteria that enter your body, and your immune system flooding that area to destroy them is felt by you as inflammation.

And we know that Aduhelm and Leqimbi are working as antibodies against amyloid beta. They bind strongly to amyloid beta, they induce inflammation when given to Alzheimer’s patients (although inflammation in the brain can cause multiple side effects), and tests show that they seem to be reducing the amount of amyloid beta in the patients who take them.

Yet the prognosis for Alzheimer’s is not much better with these drugs than without them. Maybe they just aren’t destroying *enough* amyloid beta, but they are barely reducing the rate at which Alzheimer’s patients decline in mental faculty, and are not at all causing patients to improve and regain their mental state. Maybe the brain just *can’t* be fixed once it’s been damaged by amyloid beta, but you’d hope that there would at least be some improvement for patients if the Amyloid hypothesis is correct.

This has caused the field to seemingly split, with many still supporting the Amyloid hypothesis but saying these drugs don’t target amyloid beta correctly, with others now fractured in trying to study the many, many other possible causes of Alzheimer’s diesease. Tau, ApoE, neurotransmitters, there’s lots of other stuff that might cause this disease, but I want to focus on the final hail mary of the Amyloid hypothesis: that the drugs aren’t targeting amyloid beta correctly.

Because it’s honestly not the stupidest idea. One thing I learned when I researched this topic was the variety of forms and flavors that *any* protein can come in, and amyloid beta is no different.

When it’s normally synthesized, amyloid beta is an unfolded protein, called “intrinsically disordered” because it doesn’t take a defined shape. Through some unknown mechanism, multiple proteins can then cluster together to form aggregates, again of no defined shape. But these aggregates can fold into a very stable structure called a protofilament, and protofilaments can further stabilize into large, long filaments.

Each of these different structures of amyloid beta, from the monomers to the aggregates to the filaments, will have a slightly different overall shape and will bind slightly differently to antibodies. One reason given for why Aduheim causes more brain bleeds than Leqimbi is because Aduheim binds to the large filaments of amyloid beta, which are often found in the blood vessels of the brain. By siccing the body’s immune system on these large filaments, the blood vessels get caught in the crossfire, and bleeding often results.

Meanwhile other antibodies are more prone to target other forms of amyloid beta, such as the protofilaments or the amorphous aggregates.

But what amyloid beta does or what it looks like in its intrinsically disordered state is still unknown, and still very hard to study. All our techniques for studying small proteins like this require them to have a defined shape. Our instruments are like a camera, and amyloid beta is like a hummingbird flapping its wings too fast. We can’t see what those wings look like because they just look like a blur to our cameras.

So maybe we’ve been looking at the wrong forms of amyloid beta, rather than the filaments and protofilaments which are easy to extract, see, and study, maybe we should have been looking at the intrinsically disordered monomers all along, and we only studied the filaments and protofilaments because we were *able* to study them, not because they were actually important.

There’s a parable I heard in philosophy class about a drunk man looking for his keys. He keeps searching under the bright streetlight but can never seem to find them. But he’s only searching under the streetlight because *that’s where he can see*, he isn’t searching because *that’s where his keys are*.

Endlessly searching the only places you *can* search won’t necessarily bring results, you may instead need to alter your methods to search where you currently can’t. And if the Amyloid hypothesis is to be proven true, that will probably be necessary. Because right now I’ve heard nothing to write home about Aduheim and Leqimbi, many doctors won’t even proscribe them because the risk of brain bleeds is greater than the reward of very marginally slowing a patient’s mental decline, not even reversing the decline.

I no longer directly research Alzheimer’s disease, but the field is in a sad place when just 4 years ago it seemed like it was on the cusp of a breakthrough.

So what’s going on with Amyloid Beta and Alzheimer’s disease?

This will be a very #streamsofconsciousness post where I ramble a bit about my work.

As I’ve said before I study Amyloid Beta in Alzheimer’s disease. I am very new to this field, so much of what is surprising to me might be old hat to the experts. But I’m quite flummoxed on what exactly Amyloid Beta is doing both in diseased and healthy brains. When I started this job, I read papers indicating that Amyloid Beta (henceforth AB) forms these large filaments, and like a bull in a china shop those large filaments will sort of knock around and cause damage. Damaging the brain in that way is obviously a hazard, and would lead to exactly the type of neuro-degeneration that is a hallmark of Alzheimer’s disease.

So because of this, it’s my job to extract these large AB filaments and take pictures of them. That way we can see exactly what they look like and why it is that they do so much damage. But then this simple picture changed. AB is made up of thousands of individual peptides, and I read papers saying these individual peptides might actually be what causes the disease by disrupting the neurons and causing them to die. But if that’s the case, then what are the filaments doing? Are they still causing damage by being big and huge, or are they entirely benign and a red herring? If they are benign, then my studying them and taking pictures of them might be leading us down a dead end.

And now I found that AB is also necessary for the development of a healthy brain. Now this in itself is not too out there, any medicine can turn into poison if the dose is wrong. So this could easily be too much of a good thing, or a good thing in the wrong place, that while normally AB helps a brain, in Alzheimer’s disease something has gone wrong to cause AB to kill nerve cells. But still it’s surprising.

The paper I read indicates that AB is necessary for process of synaptic plasticity. No time to get into the whole details, but synaptic plasticity underlies the formation of memories in the brain. Mice who do not have AB have a harder time forming memories and completing tasks than mice with AB. So now I’m at the point where actually AB is necessary for the formation of memories of a healthy brain, but then sOmEtHiNg happens and it caused Alzheimer’s disease, which is characterized by deficiencies in memories. So what is happening?!?!?

I… don’t know. I don’t know if anyone knows. But I wish I had the tools to study this further. The difficulty is that I’m not sure if I do. My setup is geared towards looking at those giant AB filaments I talked about earlier. Filaments have a big, rigid form and you can do structural analysis on them to get what is essentially a 3D model. But all these papers talking about the role of AB in healthy brains, they are talking about it in the small monomeric form. Small monomers don’t form rigid structures in quite the same way, they are more akin to a floppy noodle, there’s no rigid form to hang your hat on and so no clean 3D model can be made for them. So maybe I’m using the wrong tool for the wrong job. Or maybe it really IS the filaments that are doing the damage. I’m just not sure at this time and it’s racking my brain trying to know where I should go next.

Why do we still not know what causes Alzheimer’s disease?

Between 1901 and 1906, Alois Alzheimer began collecting data on the disease that would eventually bear his name. A patient with memory deficiency was autopsied after her death and her brain was found to contain amyloid plaques and neurofibrillary tangles. Around a half century prior in 1861, Guillaume-Benjamin-Amand Duchenne had described a disease that would bear his name, a form of muscular dystrophy, and like Alzheimer he had patient samples for study. In the next century and more both diseases would be studied and reported on, Duschenne Muscular Dystrophy was eventually linked to a single protein called dystrophin, and a number of FDA-approved treatments exist which target dystrophin and improve patient outcomes. Alzheimer’s disease was also linked to a protein, the amyloid plaques found by Alois contained a protein called amyloid beta. But while both diseases seem to have known causes, treatments for Alzheimer’s disease remain ineffective. What’s more, there is a growing body of evidence that the amyloid beta hypothesis for Alzheimer’s disease is on shaky ground. How is it that more than a century of study has not allowed us to even understand Alzheimer’s disease?

First, it must be said that the amyloid beta (Aβ) hypothesis for Alzheimer’s Disease (AD) didn’t come out of nowhere. Not only were the amyloid plaques found in Alzheimer’s patients coming from Aβ, but genetic evidence showed that the mutations associated with AD all seemed to affect the Aβ pathway. If the diagnostic criteria for AD included Aβ, and genetic evidence supported a role for Aβ, it seemed Aβ must surely be the cause of the disease. And further biochemical evidence supported a role for Aβ, for example when Aβ was shown to cause neuronal cell death in cultured nerve cells. The Aβ hypothesis even connects well with other diseases, Aβ acts as an aggregating prion and aggregating prions are known to cause other neurodegenerative diseases such as Creutzfeldt-Jakob Disease and Kuru. Note that some biochemists say a protein is only a prion if it comes from the prion gene of the human body, but like champagne this definition is expanding. So the Aβ hypothesis isn’t a hypothesis without support, it has strong biochemical evidence at the genomic and proteomic level, and fits in well with other brain diseases. It can certainly be said that Aβ proponents have ignored or downplayed evidence against the Aβ hypothesis, but that behavior is common in all disciplines. Science advances one funeral at a time.

Second, it should be recognized that AD is a difficult disease to study involving a difficult organ to study. AD affects memory and behavior by affecting the brain, those are processes and an organ that are still very opaque to us in general let alone in the context of AD. So AD is a disease we don’t understand affecting processes we don’t understand in an organ we don’t understand. Maybe we should feel grateful we even have drug candidates to begin with?

To bring this back to my own work, let me give you an example of the very small problem I am working on and the difficulties I am facing in getting data. We have a theory that there are different subtypes of AD. There is the rapid-onset (r-AD) subtype and the slow-onset or traditional (t-AD) subtype. We believe that this difference may be structural in nature, that the proteins causing r-AD and t-AD are the same but that they have different shapes. To this end, I am studying the structural variations of sarkosyl-insoluble proteins from AD patients.

OK what does that mean? I start by requesting patient samples from deceased AD patients matching either the r-AD or t-AD subtype. This is difficult because not everyone really agrees on the diagnostic criteria of these two subtypes (already we have problems!). Then once I have a patient sample, I perform a sarkosyl extraction. Sarkosyl is just a detergent like the one you wash your clothes with. A detergent can dissolve some things (like the dirt on your clothes) while not dissolving other things (like the pigments coloring your clothes). Previous studies have shown that the proteins causing AD are sarkosyl insoluble, so just like how laundry detergent will wash away dirt while leaving behind pigments, I can use sarkosyl to wash away non-AD proteins and keep the AD-causing proteins. These sarkosyl insoluble proteins include Aβ, but also include things like Tau and alpha-synuclein which some people hypothesize are the true cause of AD. The sarkosyl extraction is difficult, and I seem to fail at it as often as I succeed, am I just bad at my job or is this all really really hard? I hope it’s the latter but you never know. Then, once I’ve extracted the material I need from the patient’s brain, I use a variety of techniques to try to test our theory about AD. I can see if the extracts from r-AD and t-AD brains have different affects on neuronal organoids (artificial culture of cells that resembles an organ, in this case a brain), I can image the extracts with electron microscopy, I can take structural measurements with NMR, and so far all the data is frustratingly vague. I haven’t been at this job super long, but I can tell you I am not finding the One True Cause of Alzheimer’s disease any time soon.

And I think my struggles are fairly representative of the AD-researching community at large, or at least the ones I’ve talked to. It’s a disease that can only be studied biochemically post-mortem, the samples you get are both very limited and highly variable, it’s hard to relate the biochemistry back to the behavior and memory because we don’t have very good theories about that stuff to begin with, and we’re trying to use all the latest and greatest techniques to study this but we’re still struggling to get strong evidence to support our theories. After a century and more of study, we still don’t seem to be anywhere close to curing Alzheimer’s, we can’t really treat it, and we barely understand it. It can be frustrating and difficult work

Science has its holy wars too

In my continuing ramblings about what science is versus what it ought to be, I thought I’d touch briefly on a topic that is well understood in the community but doesn’t seem understood outside of it, that is the question of how a scientific hypothesis becomes scientific dogma.  I don’t mean dogma in a negative sense, in my area of science a dogma is simply something that is without question because all the evidence points to it being true.  The “central dogma” of biology for example is that DNA is where genetic information is stored, RNA is the messenger of information, and protein executes the functions that are demanded by the information.  DNA->RNA->proteins is a dogma taught to every aspiring biologist and bored high school student, and it underpins every piece of modern biology we do.

But dogmas don’t become dogmas out of nothing, there must be a mountain of evidence in their favor, and additionally there is usually a prior dogma or competing hypothesis that they must replace.  This last bit is important, it has often been said that you can’t reason someone out of a position they did not reason themselves into, but equally true is that you often can’t reason them out of something that they did reason themselves into either.  People just don’t like changing their mind.  And so when a new hypothesis comes along challenging an old dogma, scientists don’t just accept it straight away, instead they will demand more and more evidence for it while continuing to cling to what they learned in the old dogma.  Science advances not through persuasion but through retirement as these heralds of the old dogma retire and get replaced by people who learned the new hypothesis.  And those people in turn accept the hypothesis fully and turn it into a dogma to be taught to students who don’t yet have the full knowledge base yet to understand why something is true but who can be taught that it is true, hence dogma.

During the upwelling of a new hypothesis though, holy wars can happen.  I don’t mean fighting and purges, I instead mean the kind of holy wars that nerds engage in, the kind of demeaning of those on the “other side” in the sense of “oh you have a Gamecube instead of a PC? I should have known you were a console peasant.”  These holy wars infect science too, scientists try to be nice for professionalism of course but they will spend enormous efforts undercutting each other’s theories and at times even undercutting each other’s professional trajectories in their bid to garner support for their own theory.  This may seem needlessly cruel but there is an element of rational self-interest, if you think your theory is true then supporting the truth against the false is good praxis, and in more base terms there is only so much funding to go around so ensuring that your dogma or theory is held in higher esteem will ensure your side is the one receiving the lion’s share of scientific funding.I know this all sounds like pointless waffle, but I was specifically reminded of this when I recently saw a few talks on Alzheimer’s disease.  The holy war over Alzheimer’s can’t be summed up in a short blog post, but some people think Alzheimer’s is caused by a protein called “A-beta” and some think it is caused by one called “tau”.  A few hold a compromise position that perhaps both proteins are necessary but most of the scientists I’ve seen presenting talks hold to one side or the other, and both sides are competing to become the new dogma.  For the most part these two sides talk past each other, if you think that A-beta is the cause of Alzheimer’s disease then there isn’t as much a point in researching tau, and vice versa.  But occasionally you’ll find both sides present at a symposium and there they will feel the need to defend themselves to the audience and slyly denigrate the opposing position.  Never to the level of insults (in public) but instead to the level of “I respectfully suggest that those other scientists have grossly misunderstood the evidence.”  Which is a very kind way of saying fuck you.