Dr. Patrick: You mentioned some early diagnostics, I mean, both more sensitive types of MRI to detect some of these, you know, leaky vessels but also a plasma biomarker and these are in cognitively normal individuals. I'm not sure what age range. But that seems, like, extremely important because if you're talking about a new potential diagnostic well before, you know, cognitive decline is occurring, it seems like intervention. You know, obviously, there's been a lot of failed attempts to treat, you know, even people with mild cognitive decline that have Alzheimer's disease. It's been quite challenging and we can talk a little bit more about that. So, is this something that you see coming into clinical practice? You know, like, what are your thoughts about that?

Dr. Montagne: No, that's a great question. Just to add something from the previous question because people don't know, we screen people by the major genetic risk factor for Alzheimer's disease, which is apolipoprotein E4, so we know that the people carrying this particular gene have more chance to develop Alzheimer's disease than other people. And these people, they have much more vascular problems in the brain and they are still cognitively normal. So, we can detect...as you said, we can detect perhaps...I don't want to speculate, but we know roughly that at least we can detect 10 years, if not more, prior to cognitive decline, we can detect those vascular problems. So, as you said, there is a window where we can intervene and if we have the right therapeutic, we can possibly protect the vessel and what I used to say seal the barrier to avoid this leakage.

So, the way I see it, so first of all the research is ongoing right now, there's a lot of...a lot not, but several targets that are very promising, currently tested in both animals and clinical trials to try to protect these vessels. Because it's not only a question of leakage but if the vessels are not functional, there is not enough blood flow throughout the whole brain, which is a big problem. So, I see that as two vascular issues, blood flow is reduced plus the leakage of the barrier. So, we know that we have a few targets that basically target different cell types that comprise the neurovascular unit, so there's the endothelial cells that are forming tubes, basically, that's where the blood is flowing.

But around these vessels, there's multiple layers of different cell types. One of them that is...at least to me, one of the most important ones is called the pericyte, so they're wrapped around the blood vessels in the brain. And those cells are very sensitive, they detach the vessels and they die very early in the disease. And if they are not there to maintain the integrity of the barrier, we know that there are these leakages. So, the whole idea of the different labs in the world is to make sure that these pericytes wrapping the smallest vessels in the brain don't detach, they have to stay there to maintain the integrity and to avoid leakages.

So, very simple targets, either targeting the endothelial cells themselves or targeting the pericytes directly. There's gene therapy, there's a lot of things ongoing, stem cell therapy and things like that, that are very promising. So, I would say it won't happen tomorrow in the sense that it's going to take a while to do the clinical trials. But I want to stay very optimistic for the people listening because we are talking about less than 10 years, I would say, if these targets are successful, which they already are in animal models, we're going to have some sort of intervention to fix the blood vessels in the next few years. So, I think it's very important. And to do that, the critical part, as you said, there's a lot of failure in anti-amyloid treatments, we have to design the trial very...you know, we have to really think about the design of the trial and what are the category of people you want to treat, right?

And I think one way, as you said, is screening people by APOE genotype. So, if you have a genetic risk, you could get the treatment. But again, we're talking about one-fourth of the population of the world having the APOE4 genotype. Or one-third, there are heterozygous and homozygous people. So, I don't think it's realistic to just screen the entire population and just give them the treatment to fix their blood vessels. What could be a bit more realistic is to do a combination of biofluid biomarkers that are quite...where we can see whether there's things that start to go wrong in your brain and when we know that there is something we can do to fix the vessels before there is a neurodegeneration and cognitive decline. So, I think it's more like maybe screening for APOE but also screening for other things around that will tell you, "Okay, this particular individual will benefit from getting a drug that will fix the blood vessel."

And I truly believe, based on the animal experiment and based on the current literature and clinical trials, that, yeah, if we fix the blood vessels, we may not be able to cure...that's a big word, cure Alzheimer's disease, but at least we will be able to postpone the symptoms by quite a few years for sure, which is a big deal, obviously, for day-to-day. You know, when people live with dementia on a daily basis, it's a nightmare. So, if you can have a decent life for another 10 years, that's a big progress. I mean, hopefully, we want to cure the disease, but I think we are going to the right direction.