There are at least two Alzheimer’s vaccine efforts making some news, so let’s have a look at them. A problem with both topics (vaccines in general and Alzheimer’s in general, too) is that popular press coverage is often not so great, so headlines about their intersection are definitely something to pick through carefully. Right off, I would say not to continue reading any piece that tries to make this sound like it’s a new consequence of the pandemic-driven changes in vaccine technology. It’s true that we have rolled out both adenovirus-vector and mRNA vaccines into the wider human population for the first time, and simultaneously yet, but the current Alzheimer’s stories have nothing to do with either of those platforms.
People have been trying for an immunological approach to Alzheimer’s treatment for quite a while now. Since the hallmark of the disease (for decades) has been the appearance of excess beta-amyloid in the brain, one of the ideas that naturally occurs is whether you could get the immune system to clear that stuff out for you. That wasn’t considered a very likely prospect for a long time, because the central nervous system is not generally the site of a lot of immune response. But as that first link explains, we’ve had to rethink the doctrine that it’s completely “immunoprivileged”, because antibodies really can get some things done in there. In the 1990s, Elan was (to my knowledge) the first company to take a serious shot at an anti-amyloid antibody, and since then it has been tried again and again and again, with who-can-guess how many billions of dollars being aimed at the idea.
I’ve written plenty of blog posts about this area, but I can summarize the field quickly: none of these antibodies have ever really helped Alzheimer’s patients, as far as we can tell. Now, some of them have definitely cleared amyloid from the brain – that’s not really in dispute. But a lot of other stuff sure is, because the relentless failure in this area, when amyloid plaques seemed for so long to be the most likely causative agent for the disease, is really something that makes you question things. Add in the additional complete failures for every other attempt at the amyloid mechanism (secretase inhibitors, for example) and you start wondering if amyloid really is a cause of the disease or not. Unless you’re Dennis Selkoe.
But let’s be honest: there’s another way out of this dilemma. The amyloid situation is a complex one, and it’s not like amyloid plaques just suddenly appear. It’s a slow process, and it must involve many stages where there are soluble forms of amyloid, then somewhat less soluble ones, and finally the insoluble plaques we see with dying neurons tangled in them. One constant explanation every time an anti-amyloid antibody has failed has been “Well, they weren’t targeting the Right Amyloid”. Equally constant have been the hopes that the next antibody trial will indeed be clearing the Right Amyloid, because now we finally realize what that is, and I have lost count of the number of times I have been told that this was coming up real soon.
That’s the renewed hope for this candidate. The paper describes the discovery of a pseudo-beta-hairpin structure in one region of the beta-amyloid protein, and the development of a stabilized, truncated form of it as a vaccine antigen. Immunization in two different mouse models of Alzheimer’s led to noticeable improvements in function, which is quite interesting. There’s some evidence that such N-terminal truncated forms are in fact early bad actors in amyloid toxicity. The authors believe that this antibody is thus less likely to become trapped in the plaques themselves, which is one mechanism suggested for the inflammatory toxicity that’s been a problem with other antibody/vaccine approaches (most recently Biogen’s).
My take is that this should certainly be tried out. As the authors note, there’s still a lot of work to be done before a human trial is ready, and there’s still a decision to be made about whether you’d got the vaccine route (and have the body produce its own antibodies) or whether you’d infuse such monoclonal antibodies directly instead. As skeptical as I am of the amyloid hypothesis by this point, I think that there is no substitute for running the experiment, because we really are in the dark about the etiology of Alzheimer’s. At the same time, I’m not ready to sound any trumpets yet or declare that victory is in sight, because. . .we really are in the dark about the etiology of Alzheimer’s. Odds are it won’t work, but you can say the exact same thing about every other approach we have to the disease, so let’s find out. But if this one indeed doesn’t work, that will be an especially heavy shovelful of dirt landing on the amyloid hypothesis, right?
The other vaccine news is a bit stranger. It’s a nasally administered vaccine candidate, and although there’s evidence in mouse models for it clearing amyloid, there is actually no amyloid-related antigen present at all. The active ingredient is called Protollin, and it’s derived from bacterial cell wall proteins. It was developed as an adjuvant for vaccines in general, since such bacterial surface components have been used as such for decades, and are still valuable today. But in this case, it appeared that the immunostimulatory effects of Protollin alone were enough to affect amyloid deposition in mice, which lead to the idea of trying it in humans. Anti-amyloid antibodies are not formed; everything seems to be going on via the innate immune system through stimulation of microglia and other cell types. And that also has led to hopes that some of the side effects in the anti-amyloid-antibody world can be sidestepped as well.
I have the same response to this one: try it out, and good luck to everyone. The same warnings apply: even the best-engineered rodents are such great models of human Alzheimer’s pathology in the end, so a lot can go wrong there. And there are all the safety and tolerability concerns that you have for any new vaccine or immunomodulatory therapy, which are things that ultimately have to be proven in human subjects. So I think that these clinical trials, long shots though they are, are appropriate and really represent about the best shots that we can currently take at Alzheimer’s disease. So you can be glad about that, while simultaneously being unhappy about that very same fact and wishing for better
