FoundMyFitness - #079 Blood-Brain Barrier Dysfunction in Alzheimer's Disease and Dementia | Axel Montagne, Ph.D.

Episode Date: February 28, 2023

Dr. Axel Montagne is a chancellor's fellow and group leader at the UK Dementia Research Institute at the University of Edinburgh Centre for Clinical Brain Sciences. His group aims to understand how, when, and where critical components of the blood-brain barrier become dysfunctional preceding dementia and in the earliest stages of age-related cognitive decline. With this knowledge, they hope to develop precise treatments targeting brain vasculature to protect brain function. More importantly his work, and that of his colleagues, provide a critical lens through which to view the contributions of vascular dysfunction (or, conversely, vascular health – if we choose to preserve it) as a critical common thread in dementia and neurodegeneration. In this episode, we discuss: (00:00) Introduction to Dr. Axel Montagne (11:44) What dementias have in common (12:42) The importance of preserving small blood vessels (in the brain) (13:38) Changes in the blood-brain barrier in aging that cause "leaking" (15:11) Predicting cognitive decline early with biomarkers – an opportunity for intervention? (16:32) Why targeting amyloid isn't enough (18:54) The impact of the APOE4 genotype on brain vasculature (24:19) The cause of white matter damage in the brain (33:47) Why the loss of omega-3 transport affects pericytes (35:25) The role of exercise in prevention of blood-brain barrier dysfunction (35:45) Why high heart rates during exercise preserve brain function (36:49) The role of exercise in preserving vision health (40:17) Why leaky vessels damage myelin and the brain (45:31) Can you have more than one type of dementia? (47:54) Does the breakdown of the blood-brain barrier cause "type 3 diabetes"? (54:03) Why omega-3 may prevent detachment of pericytes (1:14:35) Why a hepatitis drug restored cognition in APOE4 mice (1:19:39) Why blood-brain barrier disruption results in the accumulation of amyloid-beta (1:25:14) Why lifetime hypertension increases dementia risk (1:37:13) Effects of obesity on blood-brain barrier leakage Watch this episode on YouTube Show notes are available by clicking here Join over 300,000 people and get the latest distilled information straight to your inbox several times per month: https://www.foundmyfitness.com/newsletter Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/premium Learn more about the premium podcast The Aliquot: https://www.foundmyfitness.com/aliquot  

See, if you don't do enough exercise, you will start chronically to have some vessels that will basically constrict and collapse and disappear, meaning that the surrounding neurons that are here and they need oxygen and nutrients and everything from these vessels, if these vessels disappear, you're going to lose neurons, right? So exercise is the number one thing. If you're prone to go to cognitive decline because, let's say, you have a major genetic risk, But if on top of that you don't exercise, you're going to accelerate, as we know from study. And that's one of the biggest things we have to put that. We have to put to the world like, okay, need to exercise with that no matter what.

I mean, if you want to stay healthy in terms of brain function, yeah, no other choice. Today's episode asks a simple question. What if we could find some connection or a common thread that ties together most dementias? Could we then use that to intervene and ultimately treat or prevent dementia? Or what if, even in the most inevitable cases, we could add even 10 or more years of healthy cognitive function? Such a radical idea might soon be the new reality thanks to emerging research like that of today's guest, Dr. Axel Montaigne. Axel's work brings into sharp focus the incredibly important role that a type of vascular dysfunction, the breakdown of the blood-braccel. barrier plays in dementia. Alzheimer's disease is usually more defined by its well-known hallmarks,

amyloid and tau. Yet it's in the earliest stages of the cognitive decline, particularly among APOE4 carriers, that the microvascular of the brain begins to leak. The fact that these vascular issues play such an early part in Alzheimer's might come as a surprise, since unlike vascular dementia, the clinical focus for Alzheimer's disease has, up until now, been mostly on amyloid. Yet in the pursuit of treatment, it's the targeting amyloid and towel that's seen at best, mixed but more often downright disappointing results. Nor is Alzheimer's the only disease affected by the failings of the brain's microvascular and progressive leakiness of the blood-brain barrier.

In fact, this degeneration is a component of, of even normal brain aging, but also stands out in other forms of neurodegeneration and dementia. What if there was another approach, not only for Alzheimer's disease, but broader forms of dementia, including other conditions like cerebral small vessel disease? That's probably what most of the research community should be asking right now, some earlier sign of trouble, one that we can impact, one where we could intervene even when other interventions have failed. And what if this one is big, that new insight just happened to also lead the scientific and medical community on a path that helps us basically all better understand why a healthy lifestyle,

one that incorporates exercise and reduces chronic inflammation, can prevent the loss of cognitive function and lead to better brain aging. Even earlier than the significant accumulation of amyloid, for those with the major genetic risk factor for Alzheimer's disease, APOE4, the brain's precious blood-brain barrier begins to leak. And one of those regions most sensitive to developing those leaks is the hippocampus, a crucial center for learning and memory. Moreover, in some cases, it is the amount of leakiness of this barrier, more so than even amyloid, which may have the most immediate and profound impact on cognitive function.

As you'll learn in this episode, the blood-brain barrier is incredibly important to maintaining brain health. Integrity of the barrier is implicated in the glucose regulation of the brain. In this way, the blood-brain barrier also has a role in brain energy metabolism, the disruption of which is a key pathologic feature in dementia. The barrier when working properly also prevents talking. toxic proteins and inflammatory factors from crossing into the brain from the blood and driving neurotoxicity.

What's more, these leaks are detectable using methods rapidly being developed in the lab, some of which may be coming to a doctor's office near you. Techniques ranging from detection of tight junction proteins that are leaked in the blood and cerebral spinal fluid when the barrier is being damaged, to new protocols for MRI and brain scan techniques using standard contrast that enable them to see the barrier leaks in near real time. As Moore is learned about the processes that it culminates in dysfunction of the blood-brain barrier, scientists may find new ways to target it directly. There's already been some success with the drug approach, targeting proteins that are known to damage the brain barrier,

the cyclophilin A pathway, with an experimental hepatitis C drug, has even been shown to restore cognitive function in animal models of Alzheimer's disease. But it's not just about new horizons for drug development. There's potential for stem cell therapies and gene therapies too. But importantly, the health and integrity of the blood-brain barrier and some of the downstream phenomena seen when things go wrong are influenced by our everyday lifestyle choices. Many of these factors are already well known. As the diagnostics improve, the connection between lifestyle and this type of damage may become even more clear. Things like early blood pressure control seem to matter a lot. This seems to come into play with dementia as a sort of lifetime cumulative exposure factor that promotes the development

of white matter damage. Another thing we can do right now is to support the vascular system. We can engage in regular, ideally vigorous exercise that achieves a high heart rate. As you'll learn in this episode, all of these things can play a role in helping us keep the vascular system of our brains in good shape. One of the more intriguing lifestyle factors to me is the sort of circumstantial or suggestive evidence that the omega-3 DHA transporter, which declines with age and in Alzheimer's disease, performs a surprising dual role in forming and maintaining the blood-brain barrier integrity. As we discuss in this episode, losses in the transporter for the DHA form of omega-3

are also hotspots for losses of parasites. Parasites act as key protectors in the neurovascular unit that makes up the blood-brain barrier. And it's the targeting of parasites and promoting their health in particular that seem to occupy a lot of Dr. Montaigne's thoughts on intervening and hopefully treating the cognitive loss that we can suffer as a result of blood-brain barrier dysfunction, which is seen not only in dementia, but also, to a lesser extent, normal brain aging. These sensitive cells can undergo really big changes. A healthy person might lose 10 to 20 percent of their periscite coverage in the brain. A person with Alzheimer's on the other hand, up to 60%.

That means serious barrier leakage and blood flow problems. So all of that being said, whether you're excited about diagnostics, medical interventions, or just learning what to do right now to help prevent dementia, this interview is a goldmine. When you take it all in the big picture of dementia and it's prevention or treatment, not only making serious progress, but actually entering a sort of renaissance of therapeutics, begins to become very clear and a very real exciting possibility. I can feel my heart pumping already.

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mixture of segments taken from our interview series and Q&As and group them together by theme with added commentary from me. Trust me, you would love my member podcast. So check out the premium membership and support the podcast. Support excellence in scientific commentary. Get access now by going to foundmyfitness.com forward slash premium, P-R-E-M-I-U-M, premium. Premium. Hi, everyone. Today, my guest is Dr. Axel Montaigne, who is a professor and group leader at the Dementia Research Institute at the University of Edinburgh in the UK. I'm personally really excited to have Axel on today because we are going to be discussing really a new paradigm for dementia and Alzheimer's disease. Often when we talk about Alzheimer's disease in particular, there's so many

ideas floating around, is it brain diabetes, is it amyloid beta plaques? So, rather than speaking to the role of amyloid or metabolism, today I'm hoping to discuss a new paradigm of research that suggests not only an important way of understanding dementia in Alzheimer's, but also how to prevent it. So Axel, thank you so much for coming on the show today. Can we, can you talk a little bit about this idea that dementia can be a vascular disease? Yes, hi. Thank you for the invitation. first of all, I'm 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 a post-mortembrane sample on tissue, just the tissue of people that died from Azores 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 post-potent 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, so the blood vessels, starts 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. there's vascular dementia, there's different kind. But the commonality about all these dementias is they have a vascular component that is quite hurting in the disease. And we want me as a lab and different groups in the world try to understand how vascular dysfunction contribute to dementia. And that's something now that people pay really attention on.

You were a co-author on a paper showing that about 50% of all dementias start with 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-amaloid plaques or amyloid plaques and tau-tangles. What causes that breakdown of the blood-brain barrier? Yes. So the paper you were mentioning, so I guess that's the 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 body, it's not only the brain, just 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 image, MRI. So we developed that technique in the U.S. in California

and 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 leagier 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's 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 starts to leak with normal aging. And these regions, it's a bit, that's 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 that time, is leagier 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 develop 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 develop new biomarkers to look at in plasma, so in the blood or in cerebral spinal fluid, we can measure markers, new markers of, that gives 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 normalaging

an increase what we call blood brain barrier breakdown so the vessel disruption in the brain and

we know also in this paper that you mentioned is we can predict future cognitive decline so the people having more

leakiness at baseline when we scan them on when we measure on their plasma of CSF

Cerepos spinal fluid the level of vascular problems in the brain we know that they are more, they're going to decline more faster than the people that have low levels of this biomark. 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 own mark, 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 built up of amyloid plaques and tau tangles. So it seems to be two different, two independent pathway, I would say. So you have people that have vascular dysfunction, but in some brain regions, they're 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 cerebral, what we call cerebral amyloid and geopathy, C-8A, 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, very early, that will disrupt the vessels.

And you have the other, the other school that I'm thought 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, function normal to avoid dementia, possibly.

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 were 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, it's obviously there's been a lot of failed attempts to treat, you know, even people with mild cognitive decline that have Alzheimer's disease. So is this, is this something that you see coming into clinical practice? This is, you know, like what, what are your thoughts about that? No, that's a great question. Just to add something from the previous answer question, because people don't know is we have screened people by the major genetic risk factor that for Alzheimer's disease, which is apopolyoprotein E4. So we know that the, 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 prey.

And they are still cognitive in 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, a prior 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, nod, 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's not enough blood flow throughout the whole brain, which is a big problem. So I see that it has 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 underageal cells that are forming tubes, basically that's where the blood is flowing. but around these vessels there is multiple layers of different cell types. One of them that is, to me, one of the most important one is called the parasite. So they 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 is these leakages. So the whole idea of different labs in the world is to make sure that these parasites are wrapping the smallest vessels in the brain don't detach. They have to stay there to maintain the integrity and to avoid leakages. So there is some targets either targeting the undertelial cells themselves or targeting the parasites direct. There's gene therapy, there is a lot of things ongoing.

Stem cell therapy and things like that are very promising. So I would say it will happen tomorrow in a 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 edible 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-amiloid 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 apoigenotype. So if you have the genetic risk, you could get the treatment, but again, we are talking about one-fourth of the population of the world having the apoifortia attack. So, or one third, there's a heterozygous and homozygous people. So I don't think it's realistic to just screen the entire population or just give them a treatment to fix their blood vessels. What would be a bit more realistic is to do a combination of biofluid, biomarkers,

the telequoit, 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 neurotage generation and cognitive decline. So I think it's more like maybe screening for Apoli, 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 bird 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 other diseases,

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 the day, basis, it's a nightmare. So if you can have a decent life for another 10 years, that's a big progress. Hopefully, I mean, hopefully we want to show the disease, but I think we are going to the right direction. So a couple of questions, kind of stemming from, you know, what is causing the parasites to detach or causing the endothelial cells to, you know, become, you know, leaky and the blood-brain barrier. If you have someone with APO-E-4, you mentioned that's happening sooner.

I mean, it's very detectable in people with APO-E-4. And also, is that the parasites detaching, is, you know, these signs of, I guess, you know, what you might call leaky blood-brain barrier, is that something that happens in normal aging? or is it something that happens in abnormal, you know, brain aging that is almost certainly going to lead to cognitive decline? Because the reason I'm asking is, you know, with the amyloid beta plaques, which is one of the pathological features of Alzheimer's disease, you find them in cognitively normal people. And it's a little perplexing, right? Yes. No, I think, so to answer that question, so there's a bit of controversies in the field.

But most of the literature says that, yes, parasites are a particular cell type that are quite vulnerable and quite sensitive. So they do detach and they do die as you age. Of course, we are not talking about that on the extent of what we see in the measure. But we see, just to give you some numbers which will speak to people, we know from mouse studies and human studies, post-mortembrane tissue analysis, we can see that when we stain, when we look at those parasites around the micro-vasculature, there is roughly a 10% to 20% loss of these cells just with normal aging. It's more complicated than that because there is brain regional differences. We have some regions that lose more than others.

Let's say if I talk again about the hippocampus, there are reports showing that there's fewer parasites in the hippocampus than the cortex of the human brain at baseline. So that's why I was saying from at the beginning, there is different blood-brain barrier properties. There's different cell types, different numbers, probably different functions. So we know that these parasites, some regions have fewer than others,

but they do tend to detach and die with normal leaching. The reason why they detach, if I had the answer, I wouldn't do my research right now, we have some answers. The first one is there is a very close cross talk between the endothelium, between the blood basically in the perisite,

there is the endotelial cell. So the underthel cells and the perisites cross talk a lot, and I didn't mention it, but parasites are here to wrap around the vessels and make sure there's no, like a strict barrier between the blood and the brain, so nothing can cross easily,

except glucose and things that we need oxygen to them. The second major property of a perisitis is that they do have contractile proteins, meaning that those cells are able to constrict, so to constrict vessels and dilate vessels. So if they are not here, you can easily assume that your blood flow will be disturbed. So they are here to contract,

to construct and dilate vessels. So obviously when they detach, not only you have the leakage of the barrier, but you also have some flow problems. One of the hypotheses that we are working in the lab, but it's not only in hypothesis, there is kind of growing evidence on that is the leading cause of periscite loss might be

that the undertale cells themselves. So they are what we call in a homeostatic state. So they are normal. They express certain proteins, certain transporters that are there to make sure they transport oxygen and because, as I said, and other things. As you age, these endotile cells will turn to pro-inflammatory phenotype. And that's a normal thing.

As we age, there's a phenomenon called inflammatory Ig. It's a contraction of inflammation and PAG. and there is several things happening as we age. There's what we call, what is called the seven pillars of aging, which basically has very seven things that overlap between normal aging and neurodegenerative diseases. And out of these seven, the central one is inflammation.

So as we age, we have more inflammation going out, and we know that there is more seredged, molecules to site one. So very cell-addision molecules start to be expressed at the under telly, which is normally not there, or a very minimal quantity. And we start having significant amount of these cell-addition molecules throughout the whole body. And the brain is very sensitive to that, because these cell-odigion molecules, what they do is they collect the immune cells from the brain, from the blood, sorry, to bring them into the brain. The more you have, the more inflammation, what we call neuroinflammation, the more inflammation you have in your

prey. So that's a normal aging process. And the fact that those endotial cells turn into a pro-inflammatory phenotype, the parasites that are right next to them will, so there's a cross-stop. I won't go into details, but the parasite will have to detach because to let the immune cells go through. Physically, if the periscite stays attached to the vessel, there is possibility for the immune cells to go through and do their job. So the fact that there is more inflammation of the vasculature as we age, there is more detachment, like I would say physiological detachment of brain parasites. That's one thing.

And there's some report that as we age, there is less. We don't have the capability, I mean, the parasite don't have the capability to reattach, as we can do as we are young. So I don't know if that's clear, but at least there's some in that tells us that the fact that the undertale cells become more inflamed in a way, the vasculature is inslaimed. The parasite will react to that in a bad way. And so they will start shortening their processes also, so I didn't mention it. But perisites, there's a small cell body with a process, small processes, like an octopus kind of thing, sitting on top of a vessel.

And all these processes are here to push the bloodthroat, basically, and maintain the integrity. And these processes will shorten because of the inflammation. And of course, if the parasites are shortening their processes, the flow will reduce. And if it's a chronic thing, if we think about chronically having too much inflammation at the vascular, the parasite will chronically detach more and more and shortening their processes. So the leakage of the barrier will be, will calm at some point because the tight junctions and everything that makes the barrier intact will start to degrade over time. And the flow will be drastically reduced. So short answer, I'm speaking a bit too much.

Inflammation of the blood vessels might be one trigger and that's something we can target therapeutically relatively easily by injecting drugs IV, right, intravenously. So that's That would be a perfect way of targeting the vessels to improve faster function, hopefully. I think also the fact that you're mentioning the role of inflammation being so critical and key in this process kind of makes me think about lifestyle factors, of course, that aren't necessarily the same as, you know, therapeutically targeting, you know, with the drug. But omega-3 being one of, you know, at the forefront of one, you know, omega-3 transport has been shown mechanistically, at least in animal studies, to regulate blood-brain barrier function

through the MFSD2A transporter. And it's also, like many of the metabolites of both DHA and EPA, the marine omega-3 fatty acids, are involved in resolving inflammation. So they have resolvins. They have the specialized pro-mediating molecules, the SPMs, and the Marisons. And so do you think there could ultimately be clinical relevance for omega-3 status in regulating dementia associated,

you know, blood-brain-rary leakiness, you know, in humans, or maybe something worth exploring? No, I cannot agree more. I think there is more and more studies. coming up nowadays, Omega-3. And you mentioned MFSD-2A, which is one of the marker we are studying carefully because it's specific to the smallest blood vessels in the brain, so the capyries, and that's where most of the parasites are.

And there is recent studies that shows that as we age and with dementia, MFSD2A, so the receptor for omega-3, it's reduced at the blood vessels. and there is also a link that where there is a reduction of MFSD2A on blood vessels, that's where we see perisite loss. So we can almost connect what we were saying earlier. Of course, these are just a few studies and it has to be confirmed. But apparently there is more inflammation of the blood vessels to go back to the first question to link it, which as we age also MFSD2A transpose and other transporters,

not only this one, but this one in particular is decreased at the capillary bed, which have an impact apparently on periscite function because we can see that this hot spot of MFSD2A loss are also hot spots of periscite loss, which means that where we have the leakliness of the barric. So yes, I cannot agree more. I think we have to study a bit more DHCA omega-3 and how this impact Breedrain-Barray functions because that would be some preventive interventions, things like that, even like targetable drugs with drugs, but yeah, I cannot agree more.

And just to, we can talk a bit more about this, but just to go back at the beginning of your question, you were mentioning exercise. And I think exercise is very important. Even me at me, you know, I'm not too old. I'm not even 40 years old, and I try to practice every week. knowing all the recent data. So we have, we have to do some exercise,

some hyerobic exercise to make sure that the vessels, we have tiny blood vessels in the brain. So if you don't exercise, you don't make sure that your heart is pumping and high rate regularly during the week, those tiny vessels that are even spoiled in your air in terms of diameter, they will start to collapse. And you're going to have,

and remember the capieries, it represents 90% of your, brain vasculature, all these tiny blood vessels. So if you start not, see, if you don't do enough exercise, you will start chronically to have some vessels that will basically constrict and collapse and disappear, meaning that the surrounding neurons that are here and they need oxygen and nutrients and everything from these vessels, if these vessels disappear, you're going to lose neurons, right? So exercise is the number one thing.

You have to do that not only for the brain, obviously, for the heart. It's true for the eyes, obviously. If you don't exercise, you're going to tend to lose eye vision quickly and a normal person as you age. But very important for the brain. You're going to turn, you know, if you're prone to go to cognitive detain because let's say you have a major genetic risk. But if on top of that you don't exercise, you're going to accelerate

as we know from study. So I think exercise right now is, it's highly funded. There's a lot of work going on. And that's one of the biggest things we have to put that. You know, we have to put to the world like, okay, eat your exercise with that no matter what. I mean, if you want to stay healthy in terms of brain function, yeah, no other choice.

I could not agree more. When you're talking about if not exercising and how this small, all vessels lining the brain, they start to get, you know, basically go away. Is that small vessel disease or is that something different? So we have to be careful. Yeah. It's not like a person, if you don't exercise, you're going to get small vessel disease. I mean, it's a bit more complex.

And I think that's a word I didn't say at the beginning. But these dementia, Alzheimer's disease is one, but the second major, no, major form. of dementia is cerebral small vessel disease. And I forgot what I wanted to say. What was the question again? Oh, I was just, yeah, I was asking about what, I mean, what is small vessel disease? Yeah, okay. So, yeah, so I wanted to, just to mention I want, don't want people to freak out.

Of course, it's a multifactorial disease. You know, it's like, if you have a genetic respecter, on top of that, you can kind of counterbalance that by doing more exercise and eating better and stuff. But we can discuss about this. But small vessel disease is very different from Alzheimer's disease, although there's a lot of commonalities in terms of brain imaging. If you look at two brains, Alzheimer's and small vessel disease, you're going to see a lot of similarities,

meaning that you're going to see what we call microbleeds. So we were talking about Brewerin-Barrick breakdown. So if there is a significant breakdown of the vessels, you're going to start having red blood cells going to your blood. brain. So that are detectable using MRI. So we can see those microbleeds. That's one feature. They also small disease compared to other disease, they tend to have small strokes, like what we call lacquins. So they have small spots, small lesions that we can detect in the brain, which chronically and over time you will have a deterioration of your cognitive

functions. The other, the third thing that is very important is white matter. hyperintensities. So these are white matter disease. It's a hot topic, a heart research area, because it overlaps. As we age, we have white matter disease, normal aging. We do have salt. Alisar disease varies quite a lot of white matter. Small vessel disease varies a lot also. And a brain barrier breakdown, obviously. In Alzheimer's and small vessel disease, these are key features of these two diseases, especially to explain the white malaria hyperintensities. People are, these white malo disease are from a vascular source.

So it's still ongoing research, but we know that these areas do have leaky vessels, possibly the periside detached, there is leakage of blood toxins into the brain, which will damage the myelin sheets and all the axons and the white matter fibers that makes your cognition running properly. So these are the features of small vessel disease.

And small vessel disease is also the common cause of stroke. And so there's many small vessel disease. We have a cohort here in the UK that we are following with the leader is joining a world load. So I invite people also to, if you want, want to learn more about small vessel disease, she is probably the world expert in small vessel disease. But so that's a disease that is, I'm independent of amyloid.

That's the big difference, obviously, from Alzheimer's disease. But they do have, the micro-bassels do have some problems. And I can tell some of them, which we've talked a little bit, the fact that the endotelium gets pro-inflamed. So that's something that is very present in small-bessel disease, and to give you an example, I told you about the cell-addigion molecules that are expressed at the liminal side of the micro-bassals of the brain. When they get shedded, they are released into the blood, right? And we can measure them. And we know that people that do have small-bessal disease, they have very high levels of

soluble form of these cell-addison molecules that can detect in biofluids. So that's already a feature. So what we call undertaleal dysfunction. The endotelium of the blood vessels are getting very inflamed and they don't do a proper job, which imply also and there is some evidence that the parasites surrounding them are also dysfunctional very quickly in those diseases. And we can measure one. I don't know if you mentioned that today,

but the soluble form of a very complicated name PDGF receptor beta. So it's platelet derived growth factor receptor. beta, that's a receptor on the periscides, and that's receptor, same thing. It can be shedded and released into the plasma and into the CSF, and that can be measured. So basically, we know in small vessel disease, they have high level of pericide dysfunction and high level of pro-information of the vasculature. And those things, we can also, what we do nowadays is we try to relate those bio-fluid biomarkers with the neuroimaging features that we see.

in people to try to correlate whether there is, if you have high level of pericide problems, do you have more weight matter disease and things like that? We try to relate what we see in the blood and CSF to what we see in the brain. And obviously we look at cognition, whether there is some predictive value or whether there is some correlation or association between these biomarkers and cognitive problems. But now we are fairly confident that targeting somehow, the blood vessels, the microvasculature in small vessel disease is the way to go. We have to fix these blood vessels very quickly to make sure that these people don't go into

small acunes, microbleeds, and other things that will make them deteriorate very quickly in terms of cognition. And the last thing maybe I forgot to mention is this is the sporadic form of small vessel disease, but there is also the genetic form. Same with Alzheimer's. We haven't talked about this, but there is the sporadic form, the most common form, and the genetic form. So in terms of sporevessel disease, there is two diseases that are quite known now and quite studied. One is called cadazil.

The other one is called carazil. And interestingly, these two diseases involve parasites and vascular muscle cells. So these are the two cells of the brain that are basically wrapping. around the vessels. And eating balls aggregates, I mean for cadizil, it's not three proteins that aggregates in periscite and vascular muscle cells, which makes vessels dysfunctional very quickly, and those people develop weight matter disease at the age of 30, 40 years old, and they go towards community of the time very rapidly. It's very civil. And carazil about the same thing. It's H.T.R1, A1, sorry, protein that is involved.

But there is also the genetic form that has exactly the same features, white malady disease, microbillates, lacquins, and blood-brain-barial issues. And we can measure that. We have all the tools now to measure those things very early before people really go to cognitive problems. So, which means, again, we have to target those vessels to make sure they function properly. How common is small vessel disease and do any, how common is a late onset small vessel disease? And how do any of those people actually that have small vessel disease end up getting Alzheimer's disease?

So are common. So it's very common because AD and SVD, so Alzheimer's disease is small vessel. These are two major form of dementia. So it's very common, more common that we think. And what she said, the second question was about, sorry. If people that have, if you said they're two separate diseases, but I was wondering if people that do develop small vessel disease end up sometimes getting also Alzheimer's, like if there's any.

Yeah, yeah, okay. So yes, that makes the research more complicated, right? Yes, to give you an example, we have the UK Biobank here where we have brain tissue samples, where we can really look at the features of these different things, Alzheimer's, small vessel disease. And a good proportion of small vessel disease diagnosed patients. They do have some sort of CAA that's what we've talked about earlier,

cerebral amyloid angiopathy, and some of them have amyloid. So that's the complexity of dementia. There is no pure Alzheimer's disease, there's no PQOSVD, there's always all the neurological comorbidities that are coming into the play. So it's difficult to disentangle things. But at least when people are alive,

there's good imaging tools and barrenu markers that can measure in blood and CSF that tells us who is what. But some people have both, and that's true. And I couldn't say, I'm not an experiment that I couldn't say the ratio of how many

can have both. Some people have SVD and Lewebidi. Some people also have some Parkinsonism traits. So yeah, unfortunately it's very common

that we can have two form of dementia kind of simultaneously. But yes, I hope that answers your question. It does. Circling back to something

thing you mentioned sort of briefly, you were talking, when you were talking about blood brain barrier not functioning well, you mentioned glucose metabolism and you decrease, you know, it's important for the, you know, the blood brain barrier being intact is also very important for, you know, glucose transport. Reduced brain glucose metabolism can be measured, you know, up to decades even before any Alzheimer's disease symptoms or dementia symptoms occur. hence you hear the term type 3 diabetes. What effect does breakdown of the blood-brain barrier have on brain glucose metabolism? That's another great question.

And ongoing studies are tackling this because it's not that clear and quite controversial. Just to tell you a bit more, so the main transporter of glucose at the brain barrier to make sure glucose comes to the brain is a good one. So that's a receptor glutone that has been found to be reduced in Alzheimer's disease. So people have looked at, again, post-mortembrane tissue bank and looking at the microvasculature and bigger vessels. And they found that Alzheimer's patient, they have much less glitone at the Brebin barrier, which means that there is less potential of the flowing glucose in. the blood to penetrate the brain.

So that's one thing. And we can measure that with several techniques, but one of them, so they expect and pet, so positron emission tomography, and we can measure what we call FDG, which is a marker of what people say, neuronal activity, things like that. So we know that when we inject that tracer,

it's fuel deoxy glucose tracer into a patient. If you have Alzheimer's and if you don't, you will have much less FDG signal if you have Alzheimer's compared to your control. But what is interesting, and there's a bit of controversy, I don't have to tell too much about this, but people are explaining these data, just saying there's less normal activity, and that's all. But what they don't take into account is these people have less good ones. There's less probability that the rate rate. your ligand will go, there is less glutone receptor into the brain.

So I think the FDG PET signal has to be carefully analyzed in the sense that it could be a neuronal activity, but it also could be indirectly the marker of vascular problems because of what I've just said. But again, there is experts in the pet field that will tell you the reason why it is not, and vice versa, it's very technical, and I don't have that. But again, we know that there is less blood one, independently of the reduction of the vascular networking Alzheimer's disease. I think Rucose is playing a big role here, and it's currently investigated.

I don't know much more than that. Sorry. Well, that's, I mean, it's very interesting, and it certainly doesn't seem like the, like we have, you know, the consensus or, you know, on the answer to that question. I'll just mention, I remember reading a couple of studies years ago where animal studies where omega-3 deficiency caused a reduction in glute 1 transporters in the brain. Again, of course, omega-3 deficiency also breaks down blood-brain barrier, you know, so it's kind of what's first, you know, like is glucose, reduced glucose getting into the brain, affecting

blood-brain barrier, is blood-brain barrier affecting the glucose? transporters or both, you know, I mean, it seems tricky to sort of figure out. But that's the chicken and egg question all the time. Same thing with, you know, with the, I mean, I'm not an expert on omega-3, but it's basically the same thing when it comes to pericide loss on the tail of activation, like pro-information, breakdown of the barrier, loss of blood flow. What is happening first? It's always difficult to address those questions because in human,

of the clinical studies are cross-sectional. You look at one time point. Now, I think there's more and more studies that follow individuals longitudinally with scanning, with looking at biomarkers, looking at neuropsychte testing. So we're going to get more answers very, very soon. There's big centers working to that. But for the Omega-3, yeah, I'm not surprised that you said that Apomigia's three deficiency leads to a reduction of good one.

That's what you said? Yes, correct. I haven't read that paper, but it goes well with what we said earlier, right? There is a vicious circle where I think it's likely that, of course, the undertrial periside crossstalk should be very involved in that problems, in my opinion. And that's something I would love to study. I'll send you my paper. I wrote a sort of interactive review article back in, gosh, it must have been like 2018 or something, I think.

And it was on the important role of MFSD2A and Omega 3 in APOE4 carriers. And I have references because for a lot of the studies like the deficiency in omega-3 causing glute 1 transporters to go down. And so I'll send you my review. You might be interested in. Of course, it's a little bit, a little bit of a hypothesis sort of review, you know, so I review the literature, but there's a lot of my sort of thoughts for people that are actually exploring the field because I'm not doing these studies, you know, so you might be interested in that. And it just, oh, sorry, it just rings a bell. I just remember reading a couple of stories and it's very relevant to what we do in the lab. is that, yeah, omega-3, the fact that you give omega-3 to aged animals, and I told you, as you age, you have for information, like an hyper-activation of the brain on the tailium.

And a couple of studies I've given some omega-3 to the mice, and I remember seeing the reduction of one particular protein that I really like to study, and we are currently studying, is V-C-M-1, vascular cell-addegiate molecule 1, and Omega-3 was able to reduce these levels. And we know, in the lab, we know that V-KM-1 plays a major role upstream of perisite detachment. So, again, there's a lot of things that can be connected.

I think it's very interesting, and just another word on VKM-1 is Tony Whis-Coree in Stanford University one of the big lab working on proteomics and all these fancy homics techniques. He looked at Alzheimer's and healthy controls. He looked at their plasma and he has looked at using proteomics, looking at different proteins, which Alzheimer's, sorry, and normal aging. And what he found, I think the most striking finding was normal aging. he found, I think, 30 plus proteins in the plasma that were elevated with normal aging

that were related to bloodline barrier. And if you look down, I think the top five candidates were proteins that are part of the under-the-old cells, obviously. But the number one that stood out as the number one protein that is elevated with normal aging was soluble VK1. So everything, you know, if you put some studies together, it kind of makes sense. There is a bit more too deep, but I think it makes sense and it might go well with also what omega-3 is doing to the vast creature.

So that would be nice to leak further. It's very interesting that you mentioned Tony Weiss-Core as well, because if I recall correctly, he's also been involved in research where he's transplanted. young plasma into, you know, older mice and it's sort of rejuvenated in the brain. And it's like, are there proteins? I think the opposite was done as well, whereas old plasma was transplanted into younger mice and is sort of accelerated. And I think if I recall correctly, blood brain brain breakdown was part of that. And so it's like identifying those proteins that it's causing it. He's doing a fantastic work. And yes, correct, he's doing, he's looking at the,

the proteins that we have in the young blood that will help not only brain functions or anything to help not aging too fast, but also we found a few key proteins that are involved in the maintaining blood brain barrier as we age. So I think it's very interesting. And he's using also the para-biocese model where he can link age and young mice. But I think it's very important studies. Yeah, and, you know, the other interesting thing, this kind of brings me back to some of your work where, you know, I don't know if, I think you mentioned this very early in our discussion about, you know, blood brain barrier when it becomes, quote unquote, leaky, you know, this allows molecules that usually don't pass into the brain to then pass. And you had a paper where you had

published a couple of years ago with, I think it was with your postdoctoral mentor. Dr. Slovivik, about a protein called fibrinogen, which, interestingly enough, is also, like when I go and get my inflammatory biomarkers measured, I like to look at fibrinogen as well as high sensitivity to see a reactor protein. It's an inflammatory marker. I mean, it's involved in blood coagulation, but you found this in the brain. What is the significance of that? Yes. Yes, and it's not only two years ago. I think there's a, I think the first report, it's probably 10 years ago. But the first report was on, again, brain tissue samples,

very valuable tissue samples from the donors, where we see that if you compare a controlled brain, someone cognitively normal, no issues whatsoever, in another cyrus brain or a small-vessel disease brain, you start seeing what we call this extravascular deposition, fibrenogen is one of the, it's one protein that is supposedly in the blood. It shouldn't be in the brain at all, but we start seeing this extravascular deposition of fibrinogen, which means that to cross, you have to have some degree of breakdown of the barrier.

So it has been found in Alzheimer's disease. We also found that in animals that either do have Alzheimer's disease or have some sort of of blood-in-power issues. And we know that this protein that is important for blood coagulation, as you said, and information, has nothing to do in the brain, and it's toxic. It's just toxic. And we found that it's neurotoxic, so toxic to neurons. It's also toxic to oligodendrocytes, where we found that the oligodendosites are basically cells that are making up myelin

and make sure that the white matter is intact, and we can function properly. and those oracles are crucial in the break. And we show that when you have a leaky barrier and you have a fibrinogen going in, the oligos are very sensitive to that fibrenogen. So they take it up, so they internalize fibrinogen, and they die by what we call autophagy. So it's almost like a suicide test.

And which leads to white matter disease. And if we go back, white matter disease is a common feature of Alzheimer's, more muscle disease. And as I said earlier, also, the source of white matter disease is likely a brain breakdown. So fibrenogen might play a role in this formation of white matter disease. So, yes, it's a very important protein that we found.

Interestingly, in animals, we were able to reduce fibrenogen levels systemically in the blood. Of course, at a level that you don't want to increase. to have some coagulation problems or increase bleeding and things like that. So you have to reduce at a level that you don't start doing bleeding or clotting. But just by reducing the fibrogenogenogen level in a mouse model that do have brain barrier issues, we were able to demonstrate that there is less obviously, less fibrinogen going in to the brain, less white metal damage. And also interestingly, by reducing fibrinogen,

we were able to partially restore vascular functions in terms of blood flow and also integrity of the barrier. So fibrillogen has probably different roles, not only cohabulation and inflammation, probably a bit more. But I think that's one other way. We can target toxin things in the blood

to avoid doing damage to the brain. I think it's probably easier to fix, I don't know, but fix the blood vessels rather than that. But at least it's another evidence that, okay, a leaky barrier is leading to your damage to the brain, and you don't want that, obviously. And the last thing on fibrinogen is, just remember now,

fibrenogen can activate the brain resident immune cells that are microveal cells through CD11B, so that's a specific receptor. So when fibrinogen gets in, it can bind to microglia. So it will induce an overreaction, over inflammation of the brain, which will be detrimental for many things, for the functions of the cells surrounding. And that reminds me that there is a fantastic researcher,

Katerina Kasudu. She is at Gladstone University, UCSFaria, where I think she developed an antibody that blocks the interaction between fibrinogen and microvia to avoid that over, like an overexpression of inflammation or overactivation of microbial cells because she's also a strong believer that vascular dysphotididivore very early and a major contributor to dilage. So that's a very interesting research. It's very interesting. Again, like you said, it really shows.

shows the importance of maintaining the blood brain barriers so that it doesn't allow, you know, things like fibrinogen, which is involved in blood coagulation to cross into the brain. And again, as you mentioned, the inflammation, it's activating microglia cells and it's causing then, I mean, that whole process you described earlier, the inflamaging and parricite detachment, perhaps, and all that. It also, as I was reading and doing some background research on some of your work, and because I knew of the inflammatory role of fibrenogen, you know, I'd already been familiar with that protein, you know, separate of what happens when it gets into the brain.

I was looking up omega-3 because I had remembered coming across some studies with it. And interestingly, people, so air particulate matter. So when you have like air pollution, particulate matter, when people are exposed to high amounts of it, it causes their fibrinogen to go up, right? It's, again, an inflammatory marker as well. But people that were taking in high amounts of omega-3, it blunted the increase in fibrinogen in plasma. And so it would be very interesting to see if, in some of the animal models you were discussing,

if omega-3 could blunt, you know, the white matter dysfunction caused by fibrenogen getting into the brain. So, again, it's another prevention, more, you know, easier, low-hanging fruit thing that people can do now, right? I mean, making sure they're taking it an F-Omega-3. Yes, exactly. No, I cannot agree more. We don't need to repeat what we said,

but yeah, there is this kind of vicious cycle where omega-3 may play a major role into vascular functions, of course. It's not even may play. I think it does play a role. And it might be even a more important role in people that's risk for Alzheimer's. It's possible like the apoie for carriers that we've talked about.

And you mentioned, interestingly, you mentioned airborne particles like pollution, right? And I think it's linked to what we've said earlier. So various, Alzheimer's, to keep it simple, if we think about Alzheimer's, it's a multifactorial disease, so you have genetic risk, possibly. You have lifetime, exercise and everything. But there is also on what we call it.

environmental factors. And pollution is what? And there is multiple studies, as you know, showing that if you live in a city, big city, you have more chance to develop some sort of dementia. And I'm part of two studies that we've published four to five years ago, maybe, where we exposed mice to airborne particles from Los Angeles.

We're taking from the highway, the particles and giving it to the mouse. to see what's the impact of the pollution on vascular function? Because there's some evidence also using scans. Those people tend to have more weight better disease and things like that. So we started looking into that and we found, very interestingly, we found a high peak of vascular. It's a longitudinal disease,

but very rapidly a few days after giving the particles to the mouse, we were seeing blood-brain-bauer breakdown and pericite degeneration, very quickly. One of the first sign that we could see. Of course, now there's debate on the mechanisms, whether the particles can penetrate into the brain through the olfactory area,

or whether it's directly the particles in the bloodstream that activate maybe, as we said, the undertaleum a bit too much, which will indirectly cause some vascular issues. That, I think, there's more studies going on. But definitely on environmental, factors and pollution is a big thing to take into consideration when it comes to dementia and especially vascular function because we breathe that every day, right? So this has to do something with vascular.

So it's another factor, but I guess it's not good. I guess if you have a Hapoi 4 and not doing exercise and living in a big city, you probably have much more chance to develop some sort of vascular problems, as we know, but we try to understand how this is happening. Yes, I remember reading a study where babies, you know, in Mexico City, post-mortem they found, unfortunately, in babies, they had like all sorts of amyloid plaques in their brain. And I don't think that's normal. And Mexico City is like, yeah.

Yeah, yeah, it's highly polluted. Highly polluted, yeah. It makes me wonder about. about filtering out the air. I mean, if there's some hepa filter or something that helps a little bit, as well as Omega 3 has been shown. I know I keep going back to that, but it's been shown to help some of the air pollution. I know.

It's, it's, you know, the research shows it, you know, so. Yeah, I mean, I don't know. I mean, if we, that'd be nice to, I'm pretty sure people are working that, but there is some countries or cities that are wearing masks and things like that in China, for example. so that we, I guess it's hard. It would be a long study, but I guess we could compare highly polluted cities and people wearing filtering and masks, things like that,

to see whether they can preserve some better basque functions and things like that. But yeah, I guess there's probably ongoing studies that, yeah. Going back to the APOE4, you know, because it is such a big genetic risk. for late onset Alzheimer's disease. And, you know, as you mentioned, you know, at least about a quarter of the population has one allele. I know you had done some research. We talked about how blood-brain barrier seems to break down. At least you're able to measure it, you know, in earlier, in cognitively normal individuals. But you also mentioned in one of your papers

there was a protein, cyclophilin A matrix metalloproteinase, as a protein that, you know, that seems to be really involved in, you know, it's an inflammatory protein, but how does this affect the blood-brain barrier? Yeah. So in the same paper we were mentioning earlier, that people carrying at least one a little of APO4, they tend to have more leakage in the medial temporal lobe that we can see with MRI and biomarkers. But, of course, it's a great descriptive study, but we went deeper to try to understand how this is happening. And what we found is the people carrying the

Apoi 4 alleles. Apoli, you have to know that the major source of apollo are astrocytes. So when astrocytes makes apollo, so if you have Apu3 makes Apu4, she had four makes api4, we know that there is a different affinity to one of the apolloe receptor that is called LRP1 on perisides. So Astrosites and periscites are close to each other. They are here to maintain the vasculature as well as the ulular function and your vasic coupling. But if you, so the LPOE4 is, I don't want to say anything wrong, but there's a different affinity to the LFP1 receptor. You have less chance to buy to LRP1, which will induce a cascade within the pericides that involve NHKPAB.

It's a bit complicated, cyclophilene, which then will lead to you. expression of MMP9 from perisites and other tail cell. So basically, if you have the APE4 gene, you will induce much more that cascade than people having the AP3 because it doesn't bind to the LRP1 on periside. It doesn't trigger the cascade of expressing cycrophiline, which will release MMP9. And MMP9 is the matrix metalloproteinase 9. that is basically is doing two things that you don't want.

Number one is disrupting and the tight junctions between the undertield cells. So all the undertale cells are tightly close to each other and there is tight junctions in between. So this MMP9 will eat up

those tight junctions. So if you think about this, you're going to get some gaps and that's what we call breakdown of the barrier. So you're going to start to see leakage. And the other thing is there is a basement.

membrane, we haven't talked about this. There's a basement membrane wrapping around the vessels and wrapping around the perisites. And MMP9 is also eating up this basement membrane. So two things that will basically break down the integrity of the blood brain ferry. And interestingly, MMP9, it's good to go back a bit a few years back. It's a very nice marker when it comes to blood brain barrier leakage. We know after stroke when you have a blood clot

in your prey, you have within the next few hours, you have a breakdown of the blood brain barrier and the biggest hemic lesion and things like that. And we know that this breakdown is correlated with high levels

on MMP9. There's a perfect correlation of this breakdown. But very interestingly, when you have an ischemic stroke, you have a second breakdown a few days later. So it's a, what we called bifazic, a bifacic, or bifacic, or bifacic, that's my friend. Bephasic breakdown of the barry, two hours and three days.

And same thing for MMP9, two peaks of expression. So it's a very nice marker that goes very well with a pre-brain barric property. So we found this in AP4, and both MMP9 and cyclophinae levels were elevated in several spinal fluid of people carrying the APO-E-4G. So we were talking about three to four-fold, if I remember correctly, compared to people carrying the APE-3G. So that's a major thing. And so, and we also found that we've used a pluripotent stem cell.

So we also used human-derived pericites. So IPSCs derived parasites in culture. And when you look at them, These are just cultured of human parasites, human on the tail cells and different cell types. And we did that for donors from APOE4 and donors from APOE3. And just at baseline, we were able to also see that the periscite just at baseline, looking at that, they produce much more on our cyclophinae and MEP9 than the parasites that do have APE3. So these are the evidence that we put.

And I think that goes very well with that is we published a follow-up study in mice, where we decided to target cyclofenic, to block cyclophilia, to see whether if we have mice that do have apopti-4, if we block cyclophilia, can we restore vascular function? And ultimately, the goal is to restore neuronal function and cognition. So we did that. We used a humanized apopt-4 mice. These are mice that have the api-4 gene.

of a human. So we have also the mice that do you have the air three. We follow them as the age. We do MRI on them. We look at their blood-brain body function, how the blood flow and everything. And we see exactly what we see in human is they have reduced blood flow in the brain. They have a leakyer blood barrier. They have some behavioral problems also in terms of cognition, what we call novel object recognition of an object location, those memory issues. So these mice are quite, you know, doing what we were expecting to. And we gave every day for one month to the apoiform mice, we gave a non-type, an inhibitor of cyclophaneate that is called at a Debut 025.

So that's a drug that is available currently in clinical trial for hepatitis C. So we gave it to the mouse every day for one month. and we checked the same thing. We did MRI. We looked at brain tissue analysis. We did behavior. And as we were expecting, just by doing that, we were able, again, it's not a full recovery, but we were able to partially and significantly restore vascular function.

So just by broken cyclophinae, we were able to restore tie junctions. We were able to restore the pericide coverage of the vascular. And ultimately, those mice had less neural muscle. damage and less cognitive problems. So it's a good paper that says you should target the vessels, you can have a big impact on the normal function and cognition. So that's kind of the whole story into two papers regarding the APOE4. Yeah.

Is that drug, is it a couple questions regarding it? So is it the same as the Alice Poravir, I think, is what they are? Yes. It is. Okay. How safe is that? I mean, is that, you know, something, I mean, first of all, like, I mean, like, if you have an APOB4 allele, it's like, you know, like, could you take that prophylactically? Would you have to take it like your whole life? Like, is it, you know, like, that would be interesting. Yeah. I mean, these are a good question. I don't know if I'm the expert to address these questions. But at this porivir, is it safe? So, first of all, I wouldn't say it's safe. So there had been few clinical trials, and unfortunately some of them have been stopped. And I think it was for design for hepatitis C. It's also currently used, by the way, it has been used a year ago for COVID-90.

In France, to kind of for the long people having very long, like a lot of long information, things like that, I think. But again, I haven't checked recently. But I know they stopped the trial for one person that had some cardiac issues after the treatment. So I cannot say it's safe or it's not safe. What I think is we need to design the trial and give it to the right people, I think, rather than giving like this. I think you have to go through criteria before being able to give it. I don't know if targeting Cyclophinae is the best.

approach. At least we know it partially work in animals, but it might be another possibility might be to target MMP9. So these are close to each other. This has been also studied quite a lot in the context of stroke. But as you know, there's thousand compounds that filled in stroke for many reasons. Well, I don't think anyone has tried targeting MMP9 to look at a more subtle reverend barriciness and see whether we can kind of seal the barren. Yes, I'm not, yeah, so basically there's a whole purpose of what we are doing right now is we are, we know the few targets that might not be the safest or maybe not the best target, but we have a list of other targets that we are studying, which will hopefully do the same thing.

We want to restore parasite function, we want to restore undertail function, and make sure the blueprint barrier is not leaky, pushing the flow as you need for your brain and make sure also something we haven't really talked, but the transporters of the brain-redge barrier, if you start having a leaky barrier, you can have some transport issues, so it comes back to glucose, oxygen, but also amyloid.

If you have a leaky barrier and if you have your vessels that are not functional, there's a few receptors, Rage, LRP1, there's a few others. If they don't work properly, you're going to, you won't be able to clear your waste from your brain

while you sleep and things like that. So you won't, you will have a tendency to accumulate more aminoid or e-commerce and possibly develop plaques. So everything is interconnected. But again, yeah, I think fixing the blood vessels whether cytruthine is the right target, I don't know. But I think it's promising.

We just have to see who will benefit from getting the drop. So if you're having a dysfunctional blood-brain barrier, you know, if you're basically having blood-brain-brain breakdown, everything you've been describing, the glymphatic system, which is when you sleep, it squirts the cerebral spinal fluid into the brain to clear out the amyloid plaques. Is that also impaired somewhat?

So there's active research in this area, obviously, but that's fair to say, yes, of course, if you have, because at the arterial level, you have the peribascular space, which is enlarge when you sleep, it has been shown. And, yeah, of course, if you have disruption of these vessels, obviously the perivascular space will be the properties and the cells being around. around perivascular macrophages and everything will be highly disturbed.

Yes, it's fair to say. It's just the glymphatic system, it's very controversial nowadays, as you may know. We don't really know whether, I mean, the fact that we clear things from the arterial level and then it gets, there is a convective flow that trains the interstitial fluid back to the veins. that's kind of the theory of the system, but I think it requires a bit more work to prove that this is truly happening, in my opinion. But there's also all the system.

There's the iPad, so that's the intramural peri-arterial drainage. So there's basically either the lymphatic and or the iPad system to clear out toxins out of the brain. Again, I'm not the expert on that, but it's fair to say that, of course, if you have vascular dysfunction, the clearance of toxins, not only amyloid, but a fass nucleine or other things, will be highly disturbed, yes.

In my opinion, that sort of puts, of course, the vascular function and blood brain barrier integrity upstream of amyloid in a way, because you'll lead, you know, having that dysfunction first will then lead to more amyloid accumulation, you know, if you're not able to clear it out, right? I mean, so what do you think of a lot of, so there's been a lot of failed attempts to target amyloid beta plaques, amyloid soluble soluble amyloid, although recently there's the lichenomab, which targets the protofibrile, so it's still like a soluble form of amyloid, but there's some positive results with that drug. Do you have any thoughts about it? Do you think? Yeah, I think I like to be optimistic and I like to be positive.

So, yeah, I think it's good that we have drugs for not only for research, for people also, for people, for the families affected. It's good that we have a drug that can remove, to some extent, the plaques and there's evidence of that. What is a bit less, a bit more controversial is the impact on cognition. So there is some, you know, improvement, but it's not what you would hope for. So which goes back to, okay, targeting amyloid only is probably not the way to go. And it's probably not sufficient or maybe too late also. So it goes back to our important research.

If you tackle things and target things much more earlier than that, you will have a better chance. Yeah, so I don't have much to say. I think I would see more like as a cocktail of treatment. if you give something that will make your blood vessels working as they should work in terms of periside function, clearance, undertail function, plus the drug of like an anti-amiloid in E4, I would bet that you would have more chance to have a bigger impact, a bigger positive impact, very positive impact on cognition.

But again, this has to be done very early. If your brain is full of plaques, it's probably too late already. So that's the importance of the research we do right now. But I see that as a cocktail maybe, improving the blood vessels, because we knew those blood vessels to be functional to clear out amyloid. And, yeah, so the combination would be probably a viable solution in the near future, maybe. So on the opposite end of treatment would be prevention. and I think looking at dementia and Alzheimer's disease more as a vascular disease sort of opens up

the doors for a lot of preventative measures. You know, one, you know, blood pressure. So it's actually very common, you know, at least in the United States, almost 50% of the U.S. adults have hypertension. And 20% of young adults do, 18 to 39. So how does high blood pressure affect the brain and dementia risk? No, that's very important. So there's a, I would see the three, at least the three major, at least in my research,

I'm not saying major, are the three major cardiovascular respiratory respiratory respiratory hypertension is one, but there is diabetes, a hyperlipidemia. But in terms of hypertension, and I think you've sent me a few papers, but I think it's very interesting to know that if you have early hypertension, if you're young and you have hypertension, it's possibly more harmful than if you have it later in life. And I guess it's just a question of duration. If you have sustained, like if you have hypertension,

sustain over many years, it can impact the stiffness of your blood vessels. It will impact, as we talked, the parasite function at some point. So, yeah, I mean, bottom line is, yes, hypertension, is known to impact the brain and very, like the basal ganglia and those deep structures that suffer quite a lot from hypertension. Where we see also there's always an association when people have hypertension,

they tend to have more microbleedings also in this area of basal ganglia. So yes, it does impact the brain and we know there's a few studies that shows that hypertension also triggers a prevalent barrier leakage. and perisite loss. It's not the whole story because in terms of small vessel disease, if we come back earlier, we saw that one of the cause,

or maybe the major cause of small vessel disease was hypertension. But nowadays, we know that's not the case, because to give you an example here, maybe a third even more of the court of small vessel disease patient that we follow, they don't have any hypertension, first of all. So it tells you that there's a big chunk of people that can move to small vessel disease, so meaning having white matter disease that were thought to be due to hypertension and highly damage vessels.

But it's not the case. So that's a bit more complicated, but obviously it's not good to have hypertension, as we know, for the brain. And there's some studies showing that they're giving anti-repretensive drugs, as a positive impact on cognition as well. So it tells you that no matter what, if you have hypertension, you have to try to reduce it, obviously, pharmacologically, because it will have an impact.

But interestingly, to just go back at the beginning of my answer, it's a bit controversial, but she have early, like 30, 40s, 30s, 40s, if you have early hypertension, you will have a light. likelihood and more chance to develop cognitive decline quickly as compared to a normal, like a normal intensive person at the same age. And interestingly, they were showing also in the paper that if you have hypertension during your 70s, if I remember correctly, it doesn't impact your likelihood to develop dementia.

So it goes back to you, I think just the final point is I think it's very important, the duration is the chronic part of hypertension. is very critical. If you have that for many years, same thing for inclamaging. As you age, you have a chronic, slow, low-grade inflammation

that will disrupt your vessels very slow. Probably the same thing with your hypertension. If you have too much hypertension, your arterial stiffness will be, you know, disturbs and damage over time, and this will upgrade your

blood bloodline barrier much faster than a normal intensive person. And this has the regional specific and different sensitivity in the brain. But yes, but that's an active area again. We have tools now to measure these brain regions, how they leak, and try to compare to people with hypertension.

But the difficult part in clinical research is no one is hypertension and nothing else, right? Hypertensive and nothing else. There is always comorbidities, obesity, other things, so it's hard to disentangle what pure hypertension is doing to the blood vessel. because there's always other things. You can try to correct statistically with covariates and things, but it's quite hard to you to study. So it does seem like, as you mentioned, cumulative exposure seems to be the more important thing here.

And again, people that are probably in their 20s, 30s, 40s aren't even, if they have high blood pressure, aren't probably thinking it's a big deal. And in fact, that's probably the biggest deal because they're starting early with the high blood pressure. That's my thought. That's what we read. Same thing with exercise. I think what we hear from these recent studies is the critical window is, I don't know if I'm correct, you may know better than me, but it's like 40, 55, something like that. Where you really have to exercise and to come back to the small vessels,

you have to open them up and make sure they are functional. That's the critical window is that I think it's partly true for sure. But I don't know a bit more than me on that question. But yes, I think that's the time. Yeah, certainly it's never too late to start exercising. And there have been studies showing even in the 70s. You can have cardiovascular improvements, of course. Earlier is better, you know.

And exercise, as you mentioned, it is one of the best ways to improve, you know, vascular function. It improves blood pressure, arterial function, all those things. And interestingly, the sauna also does that. heat stress, a lot of the physiological aspects of elevating. Yeah. I didn't know that. I didn't know that. Yeah. Interesting. And there's a lot of research. In fact, there's, of course, with, you know, observational data, it's, you never can establish causation. As you mentioned, there's all sorts of, you know, covariates and things. But there are studies showing that, you know, dose-dependently sauna use is associated with like a 60%

lower dementia risk and Alzheimer's disease risk. If you're using the sauna four to seven times, a week. If you use it, you know, two to three times a week, there's like a 20% lower risk after adjusting for other factors as well. But we do know sauna, like there's intervention studies. I mean, it's comparable to moderate aerobic exercise in terms of the effects on blood pressure, heart rate variability and stuff. So also sort of just interesting. But exercise being a really important one for, you know, prevention, you know, dementia and Alzheimer's disease prevention as much as you can do. How does alcohol affect the blood-brain barrier?

Again, I think it's a bit controversial. At least what I know from the literature is chronic consumption, obviously, is not good. And interestingly, we can see, I don't know if you've seen that, but there is a gender effect, the sex effect. So the males tend to have, if you, if you, if you, you're a chronic drinker of alcohol, you will have some vascular issues. It has been linked. So if you chronically, drink alcohol, you have a leakier brain barrier. It has been shown. But if a woman drink the same, that's age mass and everything, they will have almost preserved

vascular function. That's very interesting, yeah. But it's, again, a few studies, but the hypothesis that they bring your estrogen and all these that have anti-inflammatory properties and things like that. So obviously, drink too much does impact your vascular function. So

what is a bit more controversial is like moderate drinking. So there's a, you can see things showing that moderate drinking is impacting your brain function, but not only brain function, but vascular properties of the brain.

And there's also all the studies that show that moderate drinking doesn't do anything. It's even positive, some cases. So I think it's, I'm not an expert on that subject, but I guess if you go in details into the design of the studies, you may find the reason why these are different results, but that's the results they put up from. So, yeah, you probably know better than me what it does, but yes, to some extent, just the alcohol itself impact

brain-borne function just by increasing the level of cytokines in the blood and which will increase the inflammation of the blood vessels. So yes, and if we go back to dementia and in from aging, if you do that chronically, obviously if you have sustained level of inflammation of your blood vessels, we know what it does. You know, it's going to impair parasite functions and all the time, it's possibly leading to leakage, which, yeah, it's a bit bad. So chronic drinking is, of course, people will have more chance to develop damage

very quick. So, but yeah, I don't know if you know more than me, but that's what I know about alcohol. Yeah, I know that the same is very, there's a lot of conflicting data. And you'll find, again, as you said, some studies showing moderate alcohol consumption protecting against dementia and other showing it not. As I sort of tried to dig deeper, what I was finding was it was protective in people that were not APOE4 positive. Yeah, okay. And so, you know, and then of course it all comes down to each study how they defined moderate or light drinking actually was different as well. So it's not, yeah.

It's not, yeah, in some cases it's like, okay, well, light drinking is less than one drink a day. Or in some cases it was like they studied it weekly. So it's like, okay, less than three drinks a week. Well, that means some days you're not having any. So there's so many variables here that it seems challenging to. That's an interesting area because, I mean, I'm just thinking when we tell me drinking, I think about red wine and French. And red wine are full of slavanoics that you know from the grapes,

which has been shown to be very important for brain functions and also for vascular function. So there is also the positive of thinking that way. If you take a little bit of wine, I don't know how frequent because I don't know the studies and how much you should drink, but at least one glass every now and then should be helpful and good for your break.

That's another thing. So I think void daily drinking sounds. Yeah, of course. Do you know about, you mentioned like, you know, obesity and type two diabetes and these things also, I mean, does obesity accelerate the blood brain barrier breakdown or weakness? So, yes, so I've seen a few studies showing that, but also interestingly, I don't know if you know,

but William Banks, one of the, if not the one, the most highly cited researcher when it comes to Blueprint Barrier, I think he's in California. He also brought a recent review that Brewerin barrier will trigger obesity and not the other way around as we age. So it's very interesting. I haven't read the review in details, but yes, I found studies that shows that obesity, of course,

these people tend to have higher levels of pro-inflammatory markers, cytokines, chemokines in the blood and things like that, which will have an impact on barrier function. We know that. But the other way around, I didn't know,

I've just found that recently with William Banks. So interesting, but I think he's claiming that there's some sub-epotalamus area that are basically you know, controlling starvation and the way you should eat and things like that.

And if the vasculature in this area are kind of leaky, that's where you're going to start having some dysfunction and this starvation and food intake and things like that so people will start to eat too much. So I think it's interesting. I haven't read the review, but I can send it to you. I think it's an interesting idea.

But I think based on data supporting that. Sounds like a vicious cycle. I mean, I thought the same thing as you was like obesity, visceral fat. I mean, that's inflammatory environment. So to me, it would make sense that it would affect the blood brain barrier in a negative way. What about homocysteine? High homocysteine does, it's a cause of one of many causes of high blood pressure? That I don't know much.

I'll be honest. I was just curious, yeah, because I did see, you know, like, it's also associated with brain dysfunction and dementia, and there was at least one study I saw where... Yeah, I've seen that it's a classic, I mean, not classic, it's a marker we that is often looked at, but I'm not very knowledgeable on the pathways that are involved. Yeah, we've almost stayed.

Yeah, you don't study that, yeah. If you have some, I'll hear more about this, yeah. Yeah, there's a paper I linked to you to and some of the notes I sent that in people that had high homocysteine. When they were treated with a B6, B12, folate sort of concoction to help lower their homocysteine, it improved their cognition and also markers of blood brain barrier. So interesting. But, I mean, I know it's not the focus of your research. I mean, I think this is really great. So, like, looking, it's, it's, there has been a lot of paradigm shifts in people's

thoughts on Alzheimer's disease with them thinking about it being a metabolic disease in a way, right? Type 3 diabetes you'll hear. But, like, I think this vascular dysfunction is, it's so crucial. And, you know, I may go hand in hand with the metabolism, maybe, uh, maybe, uh, that, you know, at the root of it. But, you know, identifying some of these early biomarkers that you were mentioning even in plasma, I don't know how early or if they're even available to people to measure, are they?

It's still at the research phase. So there is a, I don't know, but there's a new technique called electrochemical chemo immunosance and there's two major platforms worldwide. One is called MesoSkilled Discovery, MSD. the other one is the Simoa platform. And the beauty of these two technologies is you can use a small amount of fluid and you can get a lot of data, basically, to make it simple. And so these particular fairly new vascular value markers

are currently being validated and everything in those platforms that will be high throughput and where you can imagine. to do a lot of patients at the time. Right now, the workflow right now is quite long and difficult. So that's why we try, as any biomarkers, we want, like, same as we heard from Japan, you can get, same as you get your blood glucose right from the finger, you can get your amyloid status, right? Ameloid 42 levels now.

And things like that and get diagnosed with a, if you have Alzheimer's, not from just a drop of blood. So that would be the idea, basically, having this, but this will require probably a few years, obviously. But it's available at the research level, but not at the clinical level as of yet. What about the soluble platelet-derived growth factor receptor when you mentioned? So it's ongoing in clinical trials in the US.

So I guess it requires, it has been done in hundreds of patients, participants that now they try to build up, go to thousands. You know, you need some validation step with a bigger cohort and make sure that this is truly elevated,

let's say with Upwee 4 or with aging in a much larger cohort of patients. But yeah, I think it's much closer to be available hopefully talking about months, a year or two. Hopefully, yeah. But I'm

I thought of that validation step, but hopefully this will come quick because I think it's a very, very valuable tool for us. I'm very thankful for the research that you do in your lab, Axel and others, you know, Dr. Slovibik and some of the people you mentioned. I mean, just that people are out there trying to identify new biomarkers of dementia and Alzheimer's, vascular biomarkers, and new treatments, and also opening up more preventative measures and, you know, understanding it in a different way. So thank you so much for all the research you do for coming on the podcast. I know you're on Twitter. I follow you on Twitter. Your Twitter handle is at A-X-L and then underscore M-O-N-T-A-G-N-E for anyone that wants to follow Axel on Twitter. He tweets interesting studies related to the stuff we talked about today.

you also have a lab website, which I was perusing, a very nice one. And montenlab.com. So that's m-O-n-t-a-g-g-n-E-L-A-B dot com. And we'll link to those as well on our episode page. But really, I learned a lot today, Axel, I really appreciate you taking time to educate, to educate everyone on this important role that vascular function. plays in cognitive function, in preventing neurodegenerative diseases, and just healthy brain aging in general.

Thank you very much for invitation. I really enjoyed it. So I hope the listeners will do. Thank you again to Dr. Montaigne for his groundbreaking research and for taking the time to have a discussion with me. If after this episode, you are captivated by the beauty of the perisite, the blood-brain barrier, and capillaries smaller in diameter than a human hair. I would encourage you to stop by Dr. Axel Montaigne's Twitter.

That's A-X-L- underscore M-O-N-T-A-G-N-E. Axel's page in many ways is some of the best of science Twitter, a veritable shrine to the study of small things that have a big impact. One thing I hope that comes through loudly and clearly in this episode, when you get past all of the developments in understanding dementia and the role of the blood-brain barrier is that there is quite a lot we can do to promote healthy cognition throughout our lives,

even with genetic risk factors, even in old age. Every week, every day almost, new evidence emerges and reinforces this fact. We can influence our risk of neurodegenerative disease. If we have it, we can potentially slow it down. Obesity is another of the myriad of forces that influence our individual risk. Even as recently as last week, a new study found the effects of obesity on the brain mimic those of Alzheimer's disease.

Neuroimaging data shows that obesity and Alzheimer's disease are linked to gray matter atrophy in brain regions involved in attention and areas involved in reason, problem solving, and comprehension. We covered this study in a recent Found My Fitness Science Digest, which is part of the membership perks we give our supporters. Supporting listeners get some great benefits over and above what is available for the free podcast. It's called the Found My Fitness Premium Membership, and it's what allows me to bring these

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