Dr. Montagne: Yes. Hi, thank you for the invitation first of all, very happy to be here and talking about that. Yes, so I think the word new paradigm, it's correct and not correct at the same time. It's been several years and there are many studies back from 20-30 years ago that shows that when you look at postmortem brain samples on tissue, just the tissue of people that died from Alzheimer's disease, you can see a lot of vascular problems on every single case. And it has been shown like 20-30 years ago but people didn't really pay attention to that vascular phenotype that we were seeing on the postmortem brain. It's just I would say probably the last 10 years or so that we are really tackling this because we have more and more evidence that shows that the vascular dysfunction, and we're going to go into details a bit later, but the brain vessels or the blood vessels start to be dysfunctional and leaky and not doing their job to make sure the brain functions normally.

And that's something that we can detect very early on, that is something that is happening with normal aging, and we know now that this is something that is accelerated in people that go towards dementia. And this is true in Alzheimer's disease, which is the major cause...I mean, the main dementia form. There's also small vessel disease, we'll talk about this, we have vascular dementia, there's different kinds. But the commonality about all these dementias is they have a vascular component that is quite early in the disease. And we want...me as a lab and different groups in the world try to understand how vascular dysfunction contributes to dementia and that's something now that people pay really attention on.

Dr. Patrick: You are a co-author on a paper showing that about 50% of all dementias start with the breakdown of the smallest vessels in the brain. And, I mean, this seems very important. So, let's talk about how a leaky blood-brain barrier could be even more important than beta-amyloid plaques or amyloid beta plaques and tau tangles. What causes that breakdown of the blood-brain barrier?

Dr. Montagne: Yes. So, the paper you were mentioning, I guess there's a paper we published in 2020 in "Nature," where we show...and we had a few other papers prior to that, where we show that just the fact...so just the fact that we age normally, the vessels start to be normally dysfunctional as we age, like the whole bodies, it's not only the brain, it's not only the vessels, we are just aging. And these vessels, we've developed a way to measure how leaky...if I can use that term, which is easy to understand for everyone, how leaky, meaning that things from the blood can leak out to the brain and we can measure that with magnetic resonance imaging, MRI.

So, we developed that technique in the U.S. in California, at the University of Southern California, where we can really detect small leakiness of the blood-brain barrier. And what we've noticed is when we scan cognitively normal individuals, young and old, just normal aging, we start seeing some brain regions that are leakier than others. So, first of all, there's what we call the blood-brain barrier. There's not only one blood-brain barrier, in my opinion, there are several, and we are trying to understand how they have different properties depending on where we look in the brain. But we see special brain regions that start to leak with normal aging.

And these regions, it's a bit in the region of the hippocampus that we call medial temporal lobe. So, that's this part of the brain, medial temporal lobe, where we have the major...you know, the learning and memory region that is called the hippocampus. That region somehow, we still don't know why at the time, is leakier than normal in people that are older versus controls, young, and we know that this region is the region that leaks the most early in dementia as well. So, we developed that MRI technique where we can really see visually, "Okay, where do we have these vascular problems?" And interestingly, we also...I guess we're going to talk about this, but not only neuroimaging is important, but we also developed new biomarkers to look at in plasma.

So, in the blood or in cerebrospinal fluid, we can measure markers, new markers that give us an idea of how leaky are the brain-blood vessels, basically, to make it simple. And so, we have this neuroimaging marker, this biofluid marker, and we show on both that we see with normal aging, an increase in what we call blood-brain barrier breakdown, so the vessel disruption in the brain. And we know also in this paper that you mentioned, we can predict future cognitive decline. So, the people having more leakiness at baseline when we scan them or when we're measuring their plasma or CSF, cerebrospinal fluid, the level of the vascular problems in the brain, we know that there are more...they're going to decline more faster than the people that have low levels of these biomarkers. So, we have some predictive value of looking into vascular dysfunction.

So, to try to link amyloid and tau, which are the classical Alzheimer's hallmark, what we found is the leaky areas that we see in the brain have nothing to do with the areas where we start seeing the buildup of amyloid plaques and tau tangles. So, it seems to be two different...two independent pathways, I would say. So, you have people that have vascular dysfunction and in some brain regions, they are going to start having some amyloid plaques and it doesn't seem to relate to each other. So, that's the first point I wanted to make. But also, what is interesting to know is when people start to have amyloid plaques, they tend to have what we call cerebral amyloid angiopathy, CAA, which also will disrupt vessels.

So, you have two schools in research right now. We have people that think that amyloid is something that happens very quickly and very early that will disrupt the vessels and you have the other school that I'm part of, that we say that we can see vascular problems without amyloid happening at that stage and we know that having vascular dysfunction will promote also the formation of amyloid plaques in the brain. So, it's still unclear how this is going. What we know for sure is there's early vascular problems and we need to fix that to make sure that the brain doesn't develop plaques and functions normally to avoid dementia, possibly.