Next Steps for Research on Infection and Alzheimer Disease
In this video, Paul Schulz, MD, discusses the next steps for research on the relationship between infection and Alzheimer disease. This is part three in a three-part series.
Additional resource:
- Harris K, Ling Y, Bukhbinder AS, et al. The impact of routine vaccinations on Alzheimer's disease risk in persons 65 years and older: a claims-based cohort study using propensity score matching. J Alzheimer's Dis. 2023;95(2):703-718. doi:103233/JAD-221231.
Watch part one of this three-part series here.
Watch part two of this three-part series here.
TRANSCRIPTION:
Paul Schulz, MD: My name is Dr Paul Schultz, and I'm a professor of neurology at the University of Texas Health Science Center in Houston.
Consultant360: What are the next steps for research in this area?
Dr Schulz: Well so one of the challenges we have in studying diseases in humans is that we all eat differently. We exercise differently. We're exposed to different things. We have different amount of exercise, etc. And also some people get the flu and we don't report it to our doctors. So it wouldn't show up in our studies as being something that was prevented or not prevented. So what we're doing now is going to the animal model of Alzheimer's disease. So we have mice that get what looks a lot like Alzheimer's disease. It's a little different in a mouse, but very similar in a lot of ways. And the nice thing about mice is you can have an entire room full of cousins, and brothers, and sisters. They all have exactly the same genetics, so you don't have to worry about differences in genes, they all eat the same chow and they don't complain, "We've had this for three days in a row, I'm going out for a steak now." They don't complain like that. And if you put a wheel in the cages there, mice will get on it and they run and they love to run and they all do the same amount.
So what I'm getting at is that in animal models, you can really bypass a lot of the variation that as humans, of course we all have and we enjoy that, but this way we can get to the bottom of it. So we're going to animal models. And then in the animal models we can study several things about the mechanism that we're really darn curious about, about how this works. So for example, number one, when we sacrifice the mice we can count how many plaques they've got in their brain. So one idea would be that what the vaccination does is somehow get rid of plaques either by turning on the immune cells and getting rid of the plaques or something else.
So we can see that. We can count the plaques in these animals compared to controls and we can tell if it's the same amount or not. On the other hand, if our theory is correct that all we're doing is leaving the plaques there, but turning off the immune cells around the plaques, then guess what that would look like under the microscope. We could count the number of activated microglia - those are the white blood cells of the brain - around the plaques. If it turns out there's very few of them compared to normal, but all the amyloid is still there, then we know that the effect was not on getting rid of amyloid, it was actually just on turning off the immune cells that are reacting to the amyloid. And then of course, it's also possible that microglia can eat a little bit of amyloid. We know that because we'll see amyloid inside of them, but they obviously don't eat near enough to get rid of the amyloid. And of course the result is people come in with Alzheimer's disease eventually because the amyloid is accumulated.
Dr Schulz: It could be that with the vaccination we're actually turning on the microglia, making them hyperactive so to speak, and they may actually then be able to eat more of the amyloid. So again, it's possible that we'll find a lot of amyloid in the microglia and fewer plaques out there.
So what I'm getting at is we can test a lot of different potential ways that the vaccinations are helping in Alzheimer's. There's one other that's also important, and that is there's diffusible factors, we call 'em. So like I mentioned when you get the flu, even though the flu is in your lungs, you feel terrible and all that. And that's because the white blood cells release things into your blood that are called inflammation factors, cytokines, interleukins, etc. And they make us feel different. They give us a fever. They cause a lot of immune cells to come to that location and fight the virus and all that. So we can measure all of those diffusible factors in blood of the mice. Spinal fluid, and I hate to say this, but we can take pieces of the brain tissue from them and measure other factors in them. So we can learn a lot of things about what's being turned on or turned off in the immune system by studying the animal model. And we can move out a lot of the differences between humans.
The other thing we can do, which I think is really cool, is let's say we do this and we find that there's no change in the animals who get the Alzheimer's. So we vaccinate them and it looks exactly like the controls. Then we have to ask the question of whether we're actually just preventing the virus that makes the Alzheimer's worse. So then our plan will be if we don't find anything initially, our plan will be to give the mice the flu. Some will be controlled, some will get the flu, some will get the flu after they get the vaccine, and then we can see whether or not preventing the disorder, the disease, the inflammatory disease is the mechanism by which they're working. So we can do a lot in the animal model that we can't do in humans.
C360: Is there anything else you would like to add?
Dr Schulz: Yeah, yeah. Thank you for the opportunity to answer my own question, so to speak. I think what the vaccination studies have done is they've highlighted to another level the immune system involvement in Alzheimer's. We already knew about it again because people who get infections, it accelerates their Alzheimer's or brings it on, but now we have vaccines in the other direction seeming to turn off the immune system and being helpful. You're also probably aware that in the last few months we've had several of the first treatment trials ever be positive in Alzheimer's disease. And by positive I mean phase three, which is like a thousand people on treatment, a thousand not. It's been devilishly difficult to find anything that affects the course of Alzheimer's. And now we have three drugs that do that just in the last couple months, one of them has gone through full FDA approval. The other two are pending, so they're not quite ready. But they all work through the immune system. They're all antibodies. So just like when you get the flu vaccine, you make antibodies against the flu. So if someone coughs on me, I can get rid of it. Well, all three of those antibodies you might've heard of Leqembi is the one that probably is in the news to the greatest degree because it's gone through full approval from the FDA and now we're just waiting for insurance companies to go ahead and cover it. Some are covering some not yet.
But the point there is that what we're doing in that case is we're specifically jazzing up the immune system. So as I mentioned, the microglia in the brain, they can get rid of amyloid plaques, but they don't do a very good job of it. And what we're doing with these antibodies is it's antibodies against amyloid plaques. They attach to the amyloid, then suddenly the microglia do a much better job of getting rid of the plaque. You literally clear the brain out of plaques. We will have someone with a positive amyloid PET scan, amyloid everywhere, and 6 to 18 months later when we repeat the scan, there won't be any amyloid that we can see there.
So the big picture here is that the immune system seems to be involved in causing the cell death, and infections seem to aggravate that. But we're finding now that we can actually turn on the immune system in a good way with specific antibodies. And maybe we're turning it on or turning it off with vaccinations. We don't know which yet. We'll discover that from the animal models. But the immune system is very involved and we're taking advantage of that fact to try to make the outcomes for Alzheimer's patients better.
Alzheimer's disease is very common in the United States, six and a half million people. So everything we can find that helps prevent one more family or a million more families from suffering from this is really valuable and worthwhile, and it's a real honor to be doing this work right now. Thank you.