Tag Archives: mental-health

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.

Healthcare needs to stop infantilizing its patients

I was once told a family story about one of my great-great aunts, let’s call her Clara. As a young adult, Clara was diagnosed with Lou Gehrig’s disease, or as it was known in those days “turning to stone.” Before Lou Gehrig made it noteworthy, the disease that bears his name was named after its most noticeable symptoms, a progressive atrophy of motor neurons until a person can’t even move at all. They feel like they’ve “turned to stone,” and death follows when the neurons controlling the heart or lungs also atrophy away.

Clara’s doctor told her sister about the diagnosis, but the sister was *adamant* that Clara not be told. “Turning to stone” was a horrific way to go, and conjured ideas of a person being trapped in their own body unable to move or call for help until at last they slowly, agonizingly, died. Clara was never told her diagnosis, and continued to see her doctor while being told lies that she was “improving” and “getting better.” Until at last she died.

And with the fullness of time, I guess she really will “turn to stone,” as will we all.

I don’t know what Clara thought as she was dying. Maybe she never really knew what was happening to her, or maybe she figured it out. Either way, her family probably thought they were doing her a favor by not telling her, and saving her the pain of knowing her inescapable fate.

But were they really saving her? Or did she pass away sad and frustrated that despite her efforts and all the encouragement, she only ever got worse and worse? Maybe knowing would have given her peace of mind, and made it easier for her to understand her condition.

Stories like Clara were common a century ago. It was not uncommon for doctors to hide a diagnosis from a patient, on the assumption that it was better they simply not know. Fortunately now we’re past that, and doctors are willing to treat patients with a lot more respect. Sometimes.

Recently I switched doctors and have been trying to continue taking the medicine I had been prescribed by my old doctor. My condition isn’t immediately life-threatening, but my live is much improved with the medicine. However I have had an absolutely terrible time of it, and have seen first hand how stupid the medical system can be when doctors get it into their heads that the patient is best kept in the dark.

The first thing that happened was that the doctors, with too little information in hand, misdiagnosed me and tried to brush brush off my condition. The medicine I’m taking has some slight psychoactive properties for some (although not for me) and is occasionally used to treat depression or insomnia. I have neither, and I wasn’t taking it for either.

I listed both my condition and the medicine I had been prescribed, and the doctor agreed to set up an appointment with me. But when I arrived for the appointment, the nurse did nothing more than take my weight before telling me that I was in the wrong place, *that* medicine is proscribed by psychiatric care, and I needed to get an appointment with an entirely different department. I made the appointment, but had no idea why I was even doing so.

The medicine isn’t psychiatric, nor is the condition. But because it has alternative affects, someone got it in their stupid thick skull that this was *only* a psychiatric medicine and that I couldn’t possibly be taking it for the *non-psychiatric* reason that I had put in the mandatory intake form. It’s clear neither doctors nor nurses ever read a damn word of the forms they ask you to fill out, because even glancing at mine would have told them what my condition *really* is. And if they *did* think I needed to visit psychiatric, then *they should have told me so before the damn appointment*. They should have realized “oh, this person is in the wrong place” and told me before they wasted my time!

As I said I scheduled the appointment with psychiatric, but after an angry phone call with the original doctor’s office, someone actually realized their mistake and got me a new appointment with someone who could treat my condition.

*Could* though, not *will*. Because see, my condition can also sometimes be treated with lifestyle changes, but I’ve worked on it for years with no luck before I got the medicine, and the medicine is the *only* thing that helped me. But the doctor I spoke to decided to treat me like someone who had never heard of their own condition, the condition *I had to tell these people about*, and started off with the whole lifestyle spiel before I had to cut them off and list off everything I’ve tried before medicine actually getting some help with medicine.

The doctor also decided that I had so *little* understanding of my condition that she had to list all the signs and symptoms, all the ways it will affect my health, even though *I already know all this, which is why I’m here for some god damned treatment*. These people were too stupid to read a form, and now are too stupid to listen to me and understand that I have had this for a while, I know what it’s all about, and I know I both need and want medicine to contain it.

They treated my like a child, quite frankly. They assumed that I was completely lacking in knowledge, that I didn’t know what I needed or wanted, and that I had zero understanding of my own health. I got a prescription but I’ve decided after filling it that I’m unlikely to ever visit this practice again, because for all the horrors of the healthcare system, infantalization of the patient is one thing that should have stayed in the 19th century.