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

Alzheimer Prevention: Prevention

See, if you don't do enough exercise, you will start chronically to have some vessels that will basically constrict and collapse and disappear.

"See, if you don't do enough exercise, you will start chronically to have some vessels that will basically constrict and collapse and disappear."

Protein Aggregation: Protocol

See, if you don't do enough exercise, you will start chronically to have some vessels that will basically constrict and collapse and disappear.

"See, if you don't do enough exercise, you will start chronically to have some vessels that will basically constrict and collapse and disappear."

Blood Brain Barrier: Protocol

See, if you don't do enough exercise, you will start chronically to have some vessels that will basically constrict and collapse and disappear.

"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."

Protein Aggregation: How To

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"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% of their pericyte 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 its 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. Is yours? As with all of my podcasts, I bring them to you from an incredible place of privilege. This podcast is fan funded. When you enjoy our free content, this interview, the topic pages that go in depth on my website, like the one on small vessel disease and the blood brain barrier, it's because some of you, those with the initiative have stepped forward to say, I want more of this in my life and in the world. So here's how the premium membership works. Every other week, I put out a member email called the Science Digest, where I cover some recent studies or work that has piqued my interest. I also participate in a monthly Q&A session. Sometimes we talk about questions surrounding recent episodes or other things. I take live questions. I take them in advance. After the session is recorded, I release it to a members-only podcast feed. They're chaptered and there are dozens of them covering hundreds of topics. The members-only podcast also features an extensive collection of members-only episodes ranging from the Q&A sessions to short members episodes we call aliquots, which feature a 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. 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?"

Blood Brain Barrier Discussion

I mean, the main dementia form. There is also small vessel disease.

"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 is also small vessel disease."

Blood Brain Barrier Discussion

They have to stay there to maintain the integrity and to avoid leakages. There is gene therapy.

"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 wrapping the smallest vessels in the brain don't detach."

Alzheimer Prevention: Risk Factor

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?

"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 mid you know I'm..."

Alzheimer Prevention Discussion

Same with Alzheimer's. We haven't talked about this, but there is the sporadic form, the most common form, and the genetic form.

"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."

Blood Brain Barrier Discussion

It's HTR1, HTR, HTR, A1, sorry, protein that is involved. White-manner disease, microbleeds, lacunes, and blood-brain barrier issues.

"White-manner disease, microbleeds, lacunes, and blood-brain barrier issues."

Omega 3 Discussion

I think glucose is playing a big role here, and it's currently investigated. I don't know much more than that.

"I think glucose is playing a big role here, and it's currently investigated. I don't know much more than that. Sorry."

Alzheimer Prevention: Prevention

He looked at Alzheimer's and healthy controls. He looked at their plasma and he has looked at using proteomics, looking at different proteins, Alzheimer's story and normal aging.

"He looked at Alzheimer's and healthy controls."

Blood Brain Barrier Discussion

I think glucose is playing a big role here, and it's currently investigated. I don't know much more than that.

"He looked at their plasma and he has looked at using proteomics, looking at different proteins, Alzheimer's story and normal aging. And what he found, I think the most striking finding was normal aging."

Omega 3: Epa

She's at Gladstone University, UCSF area, where I think she developed an antibody that blocks the interaction between fibrinogen and microvia to avoid that overexpression of information or overactivation of microvial cells, because she's also...

"She's at Gladstone University, UCSF area, where I think she developed an antibody that blocks the interaction between fibrinogen and microvia to avoid that overexpression of information or..."

Blood Brain Barrier Discussion

that do have blood-brain barrier issues.

"You have less chance to bite to LRP1, which will induce a cascade within the pericylates that involve NSKPB, it's a bit complicated, cyclophiline, which then will lead to expression of MMP9 from pericylates and on the teal cell."

Protein Aggregation Discussion

At least we know it partially works in animals, but it might be another possibility, might be to target MMP9. This has been also studied quite a lot in the context of stroke.

"This has been also studied quite a lot in the context of stroke. But as you know, there's a thousand compounds that failed in stroke for many reasons."

Blood Brain Barrier Discussion

At least we know it partially works in animals, but it might be another possibility, might be to target MMP9. This has been also studied quite a lot in the context of stroke.

"This has been also studied quite a lot in the context of stroke. But as you know, there's a thousand compounds that failed in stroke for many reasons."

Alzheimer Prevention: Prevention

Again, I'm not the expert on that.

"So that's the intramural periarterial 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."

Sauna: Cardiovascular

it goes back to I think just the final point is I think it's very important the duration the chronic part of hypertension is very critical if you have that for many years same thing...

"So that's the intramural periarterial 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 alphacinuclein 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, you'll lead, you know, having that dysfunction first will then lead to more, you know, 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 amyloid, although recently there's the lakanumab, which targets the protofibril. 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? 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 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. There's evidence of that. What is a bit more controversial is the impact on cognition. So there is some improvement, but it's not what you would hope for. So which goes back to targeting amyloid only is probably not the way to go. And it's probably not sufficient or might be 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 pericylate function, clearance, undertale function, plus the drug of like an anti-amyloid N4, 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 know we need 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, age 18 to 39. So how does high blood pressure affect the brain and dementia risk? No, that's very important. So there is a, I would say the three, at least the three major, to at least in my research, I'm not saying major, is the three major cardiovascular risk factors. Hypertension is one, but there is diabetes and hyperlepidemia. 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 a sustained, like if you have hypertension sustained over many years, it can impact the stiffness of your blood vessels. It will impact, as we talked, the pericyte function at some point. So yeah, I mean, bottom line is yes, hypertension is known to impact the brain and various, 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 is a few studies that show that hypertension also triggers a prevalent barrier leakage and pericyte 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 causes 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 patients 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 damaged 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 are some studies showing that giving antihypertensive drugs has 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 if you have early, like 30s, 40s, if you have early hypertension, you will have a likelihood and more chance to develop cognitive decline quickly as compared to a normal, like a normal intensive person of 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. it goes back to I think just the final point is I think it's very important the duration the chronic part of hypertension is very critical if you have that for many years same thing for incline aging as you age you have a chronic slow low grade inflammation that will disrupt your vessels very slowly. Probably the same thing with hypertension. If you have too much hypertension, your arterial stiffness will be disturbed and damaged over time, and this will degrade your plebrenate barrier much faster than a normal tensive person. And this has the regional specificity 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's always comorbidities, obesity, other things. So it's hard to disentangle what pure hypertension is doing to the blood vessels because there's always other things. You can try to correct statistically with covariates and things, but it's quite hard 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, 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. Yeah. 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. I think it's partly true for sure. But you may 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. And exercise, as you mentioned, it is one of the best ways to improve vascular function. It improves blood pressure, arterial function, all those things. And interestingly, the sauna also does that, the heat stress, a lot of the physiological aspects of elevating your core body temperature. I didn't know that, but that's interesting. And there's a lot of research. In fact, there's, of course, with observational data, you never can establish causation. As you mentioned, there's all sorts of covariates and things. But 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 prevention, 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, a sex effect. So the males tend to have, if 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 blood-brain barrier. It has been shown. But if a woman drinks the same, that's age mass and everything, they will have almost preserved vascular function. That's very interesting. But it's, again, a few studies. But the hypothesis that they bring are 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 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 other studies that show that moderate drinking doesn't do anything. It's even positive in 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 front so yeah you probably know better than me what it does but yes to some extent just the alcohol itselfbrain-barrel functions just by increasing the level of cytokines in the blood, which will increase the inflammation of the blood vessels. So yes, and if we go back to dementia and inflammation, if you do that chronically, obviously, if you have sustained level of inflammation of your blood vessels, we know what it does. It's going to impair pericyte functions all the time, possibly leading to leakage, which is a bit bad. So chronic drinking is, of course, people will have more chance to develop dementia very quickly. 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, 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 others 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. And then, of course, it all comes down to each study how they defined moderate or light drinking actually was different as well."

Blood Brain Barrier Discussion

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.

"Do you know about, you mentioned like, you know, obesity and type 2 diabetes and these things also, I mean, does obesity accelerate the blood-brain barrier breakdown or leakiness?"