CETP Inhibitors and Future Research

Hey everyone, welcome to the Drive podcast. I'm your host Peter, Ati. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness and we,'ve established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level , it's our goal to ensure members get back much more than the price of a subscription. If you want to learn more about the benefits of our premium membership, head over to PeterataMD forward slash subscribe. My guest this week is Dr. Tom Daysp ring, who returns to the drive for another deep dive into lipidology, but this time through the lens of the brain. Tom's been a frequent guest on the podcast and has had an extraordinary career. He's an extraordinary teacher, a mentor to me personally along with, many others, and of course a colleague of mine for many years now in the practice. He's one of the most thoughtful lipidologists I know with a very remarkable ability to take complex physiology and make it not only clinically relevant but understandable. In this conversation with Tom, we covered the fundamentals of cholesterol transport in the body, mostly just so that those who are coming to this for the first time or frankly don't remember our earlier discussions on this have the baseline. But then we really focus on the brain. We talk about why the brain 's cholesterol system is almost entirely separate from the peripheral system, that is the rest of the body. We talk about the role of ApoB, which I've talked about a lot in ApoA one , and specifically ApoE as it pertains to cholesterol . So we talk about how the APOE genotype relates to Alzheimer's disease risk, which is something we referred to a lot, but then the link between APOE , cholesterol, homeostasis, amyloid and tau. What we know and what we don't know about the effects of statins is etambe omega three fatty acids and then the emerging CETP inhibitors on brain health. This is a technical conversation. I won't shield us from that, but it is an important one, especially for anyone trying to understand the relationship between lipid lowering therapy, cardiovascular disease risk and neurodegenerative disease. There's a lot of misinformation around this . And so unfortunately, you have to kind of get into the details if you want to understand these complex relationships. So without further delay, please enjoy my conversation with Dr. Tom Daysbury. Hey, Tom, great to be with you again as always. For sure, Peter, this has become a bit of a routine for us. We've done it, but I love the way we interact on this topic. Today we're going to talk about some different things. We're going to really focus on a topic that's really become an enormous passion of yours and your curiosity drives so much of your learning and then by extension our learning in the practice. So I want to kind of go on a journey with you into this idea of cholesterol in the brain. It's obviously a very important topic for reasons that we'll get into , but I think before we do, it is worth making sure that everybody 's starting from the same sort of knowledge base or singing from the same sheet of music as some might say , as it pertains to lipids. So I know that you and I have discussed this in great detail elsewhere and I realize that not everyone will have seen that and even if they have, they might not recall. So let's start at the very beginning in a very short sort of five minute version , let's talk through the idea of cells in the body making cholesterol and how they have to move that cholesterol around the body in the periphery, just the sort of the nuts and bolts of it. Yeah, as you've stated many times, cholesterol is essential for human life because it's used for making some critical things, but its most important function is it positions itself in the cell membranes in every cell in our body and cell membranes are regulate the integrity, what gets in, what gets out of c . So evolution has given every cell in the body the power to de novo synthesize cholesterol a little bit. Now each cell needs a minor number of molecules or so . But if it does that, we got great cell membranes and those cells are functioning happily or so . But we also know and people sometimes don't understand this, like so many things, an excess of anything can be harmful . So if any cell somehow has over synthesized cholesterol, accumulated cholesterol and has excess molecules, cholesterol has the ability to crystallize , which is toxic to a cell . It will kill the cell. So evolution has also given cells the ability to export cholesterol out of its cytosol into the plasma. But you know, we've talked many times, lipids are hydrophobic. They cannot circulate in plasma which is an aqueous or water solution. So again, evolution said no problem. Evolution has given us proteins that can bind and adh ere to lipids and enrap them into particles that are the lipoproteins. And that's how lipids, cholesterol, triglycerides and numerous other lipids that we don't have to mention circulate in our bloodstream. So if a cell fluxes cholesterol out, it joins on a protein. The protein happens to be called ApoA one, which is sort of the structural protein of our high density lipoproteins . So that's how HDLs are created. They accept cholesterol from whatever cell in the body is effluxing it or so. We have another family of lipoproteins that are much bigger than the HDL , and those are produced in the liver. One type is produced in the small intestine, and they belong to the ApoB family of lipoproteins. And the difference between them and HDLs is their structural protein is this very large peptide called Apolipoprotein B. The intestine makes a full size ApoB, the intestine makes a truncated one. We call the excuse me the hepat APOB APOB one hundred and the intestinal produced one because it has forty eight percent of a molecular weight of one hundred is APOB forty eight. So when the intestine makes a kyomlicron to which traffics absorbed fatty acids which become triglycerides absorbed cholesterol into the bloodstream. It's in an APB forty eight particle, a very transient postpranial particle . The liver manufactures ApoB particles . One is a very low density lipoprotein. It's quite big because it's packed in the triglycerides, which like the kilomicrons, it transports to musc les and fat cells primarily and then returns to the liver . Some of the VLDLs as they lose the triglycerides, they shrink and they become something called either a VLDL remnant, a very transient particle called an intermediate density lipoprotein, which rapidly becomes an low density lipoprotein or LDL. But the liver also has the ability to de novo manufacture and secrete LDLs also. So our LDLs that are floating around have two sources. They're sort of like the sun of the LDL or they're a liver produced one. Now the Apollb particles carry a lot of lipid, triglycerides primarily in the VLDL. The LDL is very interesting . It's pretty much a cholesterol carrying particle, excellent amount of triglycerides, but it has the longest plasma residence time of anything in the Apollbe family. It can last three to four , even five days in some circumstances. Ultimately, just like the VLDL, it gets cleared by the liver expressing and sticking into the plasma, something called an LD L receptor which binds to these apoble particles and pulls them into the liver, and then the liver digests them and does whatever it wants with the component parts of the lipoprotein. The LDL s hang around for that amount of time and this is not well recognized because they interact with the HDLs . Something totally not well known. If we look at all the lipoproteins in the body , ninety percent of them are HDLs in the rest of the APLB family. Now the APLB family traffics far more lipids because of their size . You know the volume of a spear is a third power of the radius. So a couple of nanometer increase in diameter, boy, a lot more lipids can be carried . But after the HDL has sucked out all of the cholesterol from wherever it has , it becomes a big fat, mature HTL. Now it has to do things with that cholesterol . It has the option of delivering it to steroidogenic tissue that may cortisone or gonadal hormones. It can bring it to the adipocytes, the cholesterol storage organ, or of course it can return it to the liver and even now the small intestine . But a lot of what an HDL does is it transfers its cholesterol mass into the Apoll B particles , the majority of which are LDLs because of its long plasma residence time. So if an HDL we've always been taught, they do reverse cholesterol transport and they can, they can bring it back to the liver or the gut. But interesting, if they send their cholesterol to an LDL , the HDL becomes very small and it starts its journey all over again. And then the LDDL says, Thank you, HDL, I'll take your cholesterol and I'll return it to the liver. So what we used to think was a very simple reverse cholesterol transport system becomes an indirect RCT , meaning an LDLs bring it back to the liver or direct where the HDL will bring it back total RCT is the sum of both . Most people are not aware that the primary function, why we have LDLs, is to return cholesterol to the liver. Everybody thinks it's delivering cholesterol to cells almost never , because every cell can make all the cholesterol it needs. Now in an emergency , a cell any cell can up regulate an LDL receptor and pull in the NLDL if it needs it, but just doesn't happen for the most part . And this is one reason and we're going to talk about it because it's pertinent to the brain. If LDLs are bringing cholesterol back to the liver, if we can induce that with some of the drugs that we have that make LDL receptors express and stay expressed longer, we will drop LDL cholesterol levels in the plasma extremely low and we're as we get deeper into the brain, you know, unfortunately a prevalent belief out there in the real world is I don't ever want to lower LDL cholesterol too much because I'll deprive the brain and I'll injure the brain and soon we'll talk about why that is not true . So that is what you said. This is the peripheral way that our body handles cholesterol. And by peripheral, anytime we say peripheral, we mean anything that's not in the brain. So the brain lipid and lipoprotein system that we're going to talk about has almost nothing to do with the plasma a transportation of lipids and lipoproteins. And that is such a crucial concept that must be understood . So what didn't I explain, Peter? I hope I've touched on that in a rapid fashion. Yep, let me just maybe synthesize some of those points . So first off maybe just even adding a little bit more context, the body does shuttle a lot of things around plasma. Plasma is kind of the highway of the body or at least the major highway of the body. Obviously there's the lymphatic system, but and plasma is, as you said, it's water. It has proteins in it, like hemoglobin and things like that within red blood cells, but it's essentially water. And therefore, things that are water soluble can transport easily. So glucose doesn't need a transporter. We just have glucose floating around our bloodstream. IOS, sodium, potassium, chloride , they don't need to be bound to anything to move around. Conversely, steroidal hormon es like testosterone or cortisol, they actually are virtually all bound. There's a slight amount that's free, but they're bound to albumin or sexominblinoglobulin or things like that. And of course, to your point, cholesterol , given how important it is that we can transport this thing, we had to come up with a carrier. These carriers are called lipoproteins , which gives rise to the name lipid, protein, lipid on the inside , where it repels water, protein on the outside, where it dissolves or is soluble within water . And then again, you mentioned the two families, the ApoA family, the ApoB family . We always want to make sure people know that when we're talking about the ApoA family, it has nothing to do with LPLittle A. That's a totally different apo liprotein, which we're not going to talk about today, although we've got lots of content on that. You also mentioned how much the ApoAs outnumber the APOBs in absolute numbers, but because they're so much smaller , the total cholesterol carrying capacity is much greater in the APB family. And I wait for a person to appreciate that is to look at their lipid panel. If you see that your total cholesterol is two hundred milligrams per decoliter, you'll easily notice that the sum of your LDL and VLDL cholesterol , it could easily be one hundred and forty of that two hundred milligrams per decliter, whereas the HDL cholesterol might only be sixty of that. So again, many more in number, but much less in cholesterol carrying capacity. And then of course,, you talked about this idea of reverse cholesterol transport. We have the indirect and the direct . We've talked about those in the past. But again, I think the most important takeaway that I get from what you said is the old version of that, which is that it's HD Ls that do at all is untrue. The LDLs do more by volume . I guess one question I would have for follow up is for the person who says, but Tom, I buy I understand everything you're saying , but if LDL is so important for reverse cholesterol transport in the periphery , what happens as LDL goes down ? Is that a bad thing? Am I losing the ability to return cholesterol to the liver? No, that just means that if LDL cholesterol goes down, if you really even look at your total cholesterol , it's going to go down too. So LDL's function is to bring choles terol back to the liver. So if your LDL cholesterol is there's just not a need to get cholesterol back to the liver. The cells are not effluxing as much cholesterol because they're in cholesterol balance , the HDLs are sending transferring less cholesterol to the LDLs . And so the system is in it's a very operational system and they all talk to one another, the nuclear transcription factors that regulate all of the some of the mechanisms I spoke to are imbalanced. So low LDL cholesterol, yes, there would be less cholesterol going back to the liver, but there 's no need for cholesterol to go back to the liver because it's in balance in all the other cells. Tom, another question that might be worth addressing here is what is the amount of total cholesterol in the body that is in the plasma i. e. that which we measure versus not in the plasma. I mean cholesterol is this essential molecule for life. We've talked about how it makes up cell membranes, it forms the basis of producing many hormones. But if I were to measure somebody's serum cholesterol and I measured again, total cholesterol of two hundred milligrams per decoliter, I could calculate how much cholesterol is in their blood because I know what their circulating blood volume is. And presumably I could do the math and it would be a few grams of cholesterol. How does that compare to the total body store of cholesterol? Well, it's much smaller . I mean most of the cholesterol in the body is within the cells of our body . And we've already divided it, hey, the body is the peripheral system and the brain system and if you look at total amount of cholesterol, most of it in sum is in all of the periphery. That means your liver, every organ you got, your skin, your membrane and every cell in our body. So that's the mass of total cholesterol . And the brain has its own component because they don't interact. But in the plasma it's interesting mostly, of course you would think all of the circulating plasm a is within lipoproteins, but it's not. There's this comes to a surprise to many people too. The biggest carrier of cholesterol in our bloodstream is in our red blood cells. Yeah. Yeah. Because they're cells, they have cell membranes and they're big. They're vastly larger than a lipoprotein. So they actually carry more milligrams of cholesterol than do our everybody thinks it's the lipoproteins , it's not. So that's how it's distributed in the blood. There is no free cholesterol. I mean, there's a minuscule amount on albumin, not much, but that's it. It's in a lipoprotein or it's in a red blood cell membrane. Then we have the organs of the body and it's another question that you can trick up people because if you ask the average person or even physician, even lipidologist , where's most of the cholesterol in the body or what organ has the most cholesterol? And everybody says the liver and wrong. It's not even close. The brain of all the organs in the body has twenty times more cholesterol than does the liver. The liver, I've read, the brain has like twenty to twenty five grams. There's like one hundred forty grams total in the body of cholesterol, where the liver would have three to five grams. Now one reason is and we're going to get into this , the brain holds onto cholesterol like the bank holds on to its gold and the bolt and everything. It doesn't, but where's cholesterol, the liver is just sort of a hand ling station. Whatever cholesterol a liver has, it's sent out or it's effluxed into the bile through bile acids or free cholesterol. So the liver is like a transfer station. So it stores a little bit of liver because it always has to have a pool of cholesterol to do what it does, whereas the brain holds onto its cholesterol and this is another physiologic point we'll have to get into. Yeah, the liver is the brain. Yeah, sorry, the brain is sort of like, pardon me, the liver is more like a bank with money, which is it's got a high flux. It goes takes a lot it takes a lot of deposits in, but then of course, the only way it makes money is by loaning out or distributing that capital and putting it to work. So yeah, it's a good point which is as we'll talk about, it's the storage of cholesterol within an organ versus the transfer through the organ. So going back to finish the swing on that point, of course , I just want the listener to be to be cognizant of the idea that if your peripheral cholesterol goes down by fifty percent , seventy five percent, right? If you if your total cholesterol falls from two hundred to one hundred milligrams per deciliter , it's it's, you know, tempting to think, Oh my gosh, my total body cholesterol has fallen by half. In reality, it's fallen by a couple of percent because it's almost tiny tiny in that between cellular cholesterol and circulating cholesterol. Yeah, so this is this is definitely one of the misconceptions people deal with. And again, although we're not going to focus on it, we'd be remiss to be sitting at this point in the game and not mention why one might want to have a total plasma cholesterol of one hundred milligrams per deciliter as opposed to two hundred gloss. Like why are we in the business of lipid lowering if we're trying to help people avoid certain diseases? And how does just lowering that tiny fraction of the total body's pool have such an outsized effect on atherosclerosis . Yes. So now we're into the pathology associated with cholesterol and we know the leading global killer is atherosclerotic disease. It's not hay the industrialized countries. It's all over. People are dying of heart attacks for a variety of reasons. And I always like to say if you have atherosclerosis, there's one synagon , you have cholesterol buildup in your artery wall. If we do not have cholesterol buildup in our artery wall, you do not have the disease called atherosclerosis and you can't suffer the consequences thereof. So the next question is, all right, Tom, well, how in the world does cholesterol get into that artery wall? It's not like the artery is oversynthesizing cholesterol and building it up. That is not happening. So that means we've already described the cholesterol is floating in our highways in the plasma. So how does cholesterol get from the dump trucks, the lipoproteins that are carrying it into the artery wall? And this is why one of the reasons we talked about the ApoB containing lipoproteins. By the way, henceforth, we may refer to beta lipoproteins. That's the ApoB family. The HDL family somet,imes call we them the alpha lipoproteins . But we now know and this is really not even up for discussion. You've done podcasts on this and the references on it. You have that great slide, the ferrin sl ide, where every single trial that's ever been done, every Mendelian analysis of lipids and lipoproteins shows the more you lower cholesterol , the less atherosclerotic events happen. So we now know, we've already told you it's the beta lipoproteins that are carrying most of the cholesterol in the bloodstream . So if a beta lipoprotein, an LDL or a VLDL and because of its resin stein, the vast majority of those are LDLs exceed a certain threshold number they will enter the artery wall. It's a simple diffusion process. You could have end othelial dysfunction and they get pulled in, they get in a little easier, but they get in even in healthy artery walls once you exceed a certain concentration of ApoB particles. So once they enter the artery wall on this would be another whole podcast, all sorts of things, they get trapped, they get aggregated, they get oxidized, and the immune system sends in white blood cells that engulfs them, and that creates a cholesterol laden macrophage the foam cells, they stick together creating plaque . So it's the particle number . And we can there are assays that we can get LDO particle numbers or VLDO particle numbers if you want them. But since there is one APOB on every one of those particles , we simply measure Apo B . One Apo B per particle. Once your Apo B level starts to exceed certain threshold s , aph erosis is very likely to occur. The main driver of your APLB concentration is two things. Of course, a little bit of production out of the liver , but the most of the escalation becomes is due to defective clearance of the ApoB particles from the plasma, meaning those LDL receptors , the liver for whatever reason is not expressing enough of them to clear to keep the APOB concentration physiologic in the bloodstream. So once APB particles are not cleared, there's only one other option for them. They have to invade an artery wall. So it's the APLB concentration and they deliver cholesterol and that explains atherogenesis . And in the old days we used to and still do , what are our ways of estimating A poB concentration. Most of it is LDL particles. We look at LDL cholesterol . And for decades, that has been the poor man's surrogate that you have too many APLB LDL particles floating around . We use VLDL cholesterol, triglycerides divided by five is sort of an estimate. Is there too much cholesterol in the VLDL particles? We don't have as great a test on that, but the vast majority of these dump trucks entering the artery all are LDLs . So ultimately this podcast is not directed at it, but if we can make the liver express more LDL receptors or let the LDL receptors recycle more , you will have increased clearance, you will lower the APOB , and every APB particle that goes into the liver is one less that's going into your artery wall . And that's basically the pathophysiology of atherogenesis. It's those APOB dump trucks. Follow up on that point. Again, let's take two individuals whose APOB concentration and documented LDL cholesterol level is above that physiologic threshold , such that diffusion is going to favor entry of the LDL, the low density lipoprotein into that subentothelial space to begin that cascade that we talked about . Everybody has the story of, you know, my grandmother is ninety years old. She's got an LDL cholesterol of one hundred sixty milligrams per decolitor. Her total cholesterol is over two hundred . I mean, she probably smokes and she hasn't had a heart attack . Whereas you can see another person with that same lipid profile that's having their first heart attack at fifty one. I don't expect you to have an answer for this because I just think there are certain things we can't understand. We don't understand why not all smokers get lung cancer. Like we just don't understand a lot of things, but what do you think are the most compelling explanations for why we don't have complete and total homogen eity of risk factor and disease . And when we confine it to this disease, I mean, we don't have it for any disease, but what do you think is the best explanation for a disease in which we so well understand physiologic steps . Sure. Well, as I mentioned, if cholesterol gets in your artery wall, you have the disease, and it's the ApoBarticles bringing them in, but that is not the only ideological reason why one would have atherosclerosis. There are a number of other factors that go into play and it's the rest of your health. Your metabolic health is a major concern. If you are insulin resistant up to type two diabetes , you have chronic inflammation in the body. You have endothelial cell damage in the body. So it's easier in those people for these particles to get in earlier in life and generate and plaque. We should make the point that this APOB entry into the artery wall is an incredibly slow process. It takes decades to develop. And this is why the concept now is not only lower is better, but the longer you keep things low with APLB is better. So your blood pressure would be a factor. Smoking, as you said, if you have some autoimmune disease that's contributing to inflammation, we know people who have chronic inflammation , have increased atherosclerosis , collagen diseases, rheumatoid arthritis, they have lifelong inflammatory factors going on and other abnormalities that weaken the arterial defense against atherosclerosis. Oxidative processes is a big part of atherogenesis. So if that is going on in the body , but sometimes we do see, like you said, great grandma who smoked all her life and has high LDL cholesterol and Yino plaque . And there are forces at play that we just do not understand . There's other protective whatever going on in their body that we have not been able to identify even genetically or we're testing this test. They got some elevation of molecule Z . It's protecting them. Something's going on and one day we'll ascertain that. You know, as the polygenic risk scores come into if we do them early in life, it can sort of predict who he is going to make it to eighty and never have a heart attack and who is not because they're looking at a multitude of genetic things that you are never looking at one at a time in an individual patient. So look, genes control everything, they are genetically blessed those. But important thing to make is don't ever think because your LDL cholesterol is two hundred that I'm one of them because there's no way to know that. Why play Russian roulette and think it's not gonna bother me when for the vast majority of people it does create havoc in pathology . Yeah . So let's now talk about the brain. So we've got these ApoB and ApoA liproteins, the HDLs and the LD Ls predominantly . You mentioned, though, that the brain has the greatest source of cholesterol in the body, greatest storage source of cholesterol in the body. Does the brain need to rely on any of the peripheries cholesterol . And if so , can ApoB and ApoA lipoproteins get in there and deliver cholesterol as needed? Well, the quick answer to that, and then I'm going to elaborate is what's going on with cholesterol in the brain, how much cholesterol is stored in the brain has zero to do with what is floating in the plasma. So there are certain lipoproteins that we'll talk about that can work their way into the brain, but the ApoB containing particles which carry the vast majority of cholesterol cannot. They're much too big to pass through that what we call a blood brain barrier, which is actually a barrier that separates the brain from the periphery as we've talked . But I'd like to start to give you an idea about why has the brain got so much more cholesterol? Why is it storing it so much more than say the liver or any other organ in the body . Well, as we are in utero with mom, in the second and the third trimester, the fetal brain is already starting to de novosynthesize its cholesterol evolution knows it's going to need cholesterol because the brain probably has more cell membranes than any other tissue put together , especially our neurons, those cell membranes are kind of critical on do our neurons work or not, whether the neurons work or not is do we work or not normally or so ? So every brain cell starts producing cholesterol in utero very quickly. Brain cellss, it' very easy. You have neurons, the ones I alluded , but any cell that is not a neuron in the brain is called the glial cell. And there's only three of them. You have astrocytes which which in the adults produce a lot of the cholesterol. We have oligodendrocytes. It's a big word and they produce about seventy percent of the brain cholesterol because one of the mega things the brain does with cholesterol is create myelin which she axon and dendrite, the nerve endings that are in our body . So that is a big, big reason why the brain stores and has so much cholesterol , it's in myelin. The other glio cell in the brain is a microgliocyte and they are the brain immune cells . So they are the last remaining cell. So in utero, the day were born there's no more mom contributing cholesterol to the brain. It's the brain making it itself. And every cell I just mentioned is overproducing cholesterol because the brain knows as it grows and grows it's going to need more and more cholesterol for alley cell membranes so everybody that can produce cholesterol has to do it knowing that the brain cannot extract any cholesterol from what's circulating in the plasma. You've mentioned it many times on your podcast. If you take a two year old and measured their LDL cholesterol, it might be thirty milligrams per decoliter, yet that is the time when the brain is growing more than it ever will. Between birth and age of ten, the brain is expanding to its adult size and it's can't do that without cholesterol. So it's super manufacturing cholesterol, but it's doing it in people who little children who have very low detectable LDL cholesterol. So that tells you basically physiological levels of circulating cholesterol have nothing to do with a growing or a normal brain . At around the age of ten , pretty much the adult brain size is form. So at that point there's a readjustment of cholesterol synthesis in the brain . Olygodendrocytes keep making it. They always will. Microglocytes, they don't have to make that much . Astrocytes continue to produce it at a high form, but there's one cell that stops producing cholesterol and it's the neurons . When the brain is full adult size, the neurons says no, no, no, I'm not going to make anymore. I want the astrocytes to make it and send it to me. And there's a simple reason it does that. We even our earlier podcast discussed the very complex cholesterol synthesis pathways . It's actually thirty seven steps . Every step is a different enzyme. Every step requires ATP . So to synth any cell to synthesize one molecule of cholesterol consumes over thirty molecules of AT . The neuron, of course, is the most active cell in the brain because it's firing off all these action potential in their synapses all day long . And that requires ATP. So the neuron does not want to waste ATPs making cholesterol if it can get it elsewhere, the neuron starts using ATP for its functioning . So and then it falls on the astrocy te. So that's a little bit about cholesterol production in the brain. All of the cells can do it, but at a certain point the neurons say, I don't want to do it anymore. Astrocytes, can you please make cholesterol and get it over to me? And this is where we get into the brain lipid transportation system because in the blood , as you've enumerated , lipids travel within the lipoproteins in the pl asma. Well, in the brain, the cholesterol that's going back and forth between cells doesn't use the blood . It uses the brain interstitial tissue, which is called the matricome . So if we take the brain, it's this connective tissue and there are absillions of these cells in them gallocs in the neurons. Now they're very close together , but they're not contiguous, they're not binding to each other. So if an astrocyte produces cholesterol molecules in the neurons over there saying, hey, I need that send it to me. We have to have a brain cholesterol transportation system or a brain lipid transportation system . And so what do the astrocytes do? Same thing that happens in the periphery. It makes a lipoprotein . But there's going to be a big difference here. So the first thing the astrocytes are going to have to do is synthesize cholesterol . Very quickly. We won't elaborate in depth, but we've had podcasts on this before . One of the cholesterol synthesis pathways goes through the next to less stir ol p,enultimate sterol and in the astrocytes it's called desmosterol. And then desmosterol becomes cholesterol . So we'll probably talk about this is one way where we can measure desmosterol in the cerebral spinal fl uid. That's kind of hard to do, but in the plasma it correlates with brain cholesterol production . So the astrocyte makes cholesterol, it's now going to obviously have to wrap it with a protein an apoprotein so it could shoot it out into the matrosome where it can travel, swim over and get to the neuron. And here's the difference. In the periphery we said, hey, the structural proteins are ApoB and ApoA . In the brain, it's the famous Apolypoprotein E . And ApoE , many people know, that has something to do with the brain because we know there are types of AOE that are associated with cognitive disorders and Alzheimer's disease. But let's just stick to the APOE protein. So the astrocyte synthesizes it binds the cholesterol and it becomes a little lipoprotein, which it secrets into the matricome . But it's an ApoE containing lipoprotein. Now, if we could take out those AOE containing lipoproteins and put them in a centrifuge , they would sink right to the bottom of the centrifuge. But what else would be sinking to the bottom of the centrifuge? High density lipoproteins in the plasma. So the brain lipoproteins are referred to as HDLs because they have the buoyancy and density of a plasma HDL . But they're very different because the plasma HDL will have two, three, four copies of ApoA one . The brain HDL will have a couple of three copies of Apo , and that is the big difference. Now once it's in the matrosome, this particle , it continues to mature. Cholesterol becomes cholesterol ester, goes to the center of the particle, and it becomes a big fat particle. But remember, its mission is to deliver cholesterol to the neuron . So the neuron's going to have to grab that APOB containing particle and internalize it or grab it and delipidate it. So guess what, the neuron expresses low density lipoprotein receptors . And that creates confusion because if somebody says, oh, I know the brain and neurons have LDL receptors, so there have to be LDLs in the brain. No , because the LDL receptor has affinities of just a couple of apal proteins. In the periphery, the LDL receptor is looking for ApoB one hundred . But in the periphery, even Apollo can bind to an LD L receptor , but in the brain, the LDL receptor only binds to APOE containing lipoproteins because there are no APOB containing lipoproteins. So it's the same barn receptor. And this is why I think we should stop calling it the LDL receptor and we call it we should call it the APOB APOE receptor that's what it recognizes. So Tom, I'm actually quite confused by this. So there's a lot I want to back up on. I'll just start with that point. So let's back up to the liver for a moment. The liver's got this receptor, which we will continue to refer to as an LDL receptor. When an APOB particle , an LDL, a garden variety LDL makes its way to the liver . It has one and only one APOB around it. Can you briefly explain confationirmally how that LDL interacts with the LDL receptor. What is it about the APOB protein that enables the key to fit into the lock. There's a very small segment of the APOB receptor that's called the LDL receptor binding domain. Excuse me on the APOB. There are certain amino acids that line up and they create a they have surface charge and here's the LDL receptor. Now the LDL receptor has a certain segment that is called the APOB recognition domain. There's certain amino acids there that create creat electesrostat ic forces . And if the domain on Apollb and what determines is that sticking out properly is the confirmation of ApoB, that explains the difference clearance rates between LDLs and small LDLs as opposed to normally constructed in size LDLs that have a normal AOB confirmation, they have much higher clearance. The small LDL where that domain may not be exposed as readily or the big LDL where it's not where it should be, the LDL receptors don't as easily recognize big LDLs or small LDLs. And that's why people with small LDLs or even big LDLs often have very high LDL particle counts because clearances decrease . So there are certain just small areas on the LDL receptor and the APLB that if they align properly, you have great clearance . News is just discovered and published last year from our friends at the NIH LDL receptors act as a dim mer. There's actually two of them that express at the same time. It's like two lobster claws and they grab two LDL particles at the same time. So that's sort of irrelevant to just understanding the LDL receptor clearance process . So that explains part of the extended plasma residence times of LDLs. How is the APOB conformed? So Tom, given that the size of the LDL within within a variation of normal can impact clearance. It really surprises me that same LDL receptor can easily find somewhere on the ApoE wrapping a very, very, very small lipoprotein in the brain , enough of a confirmational match to make that work. So that is new not only news to me , but very difficult to wrap my little cholesterol rich brain around because I would think that the ApoE lipoprotein being so much smaller than an LDL and being much closer to an HDL would never be able to find it, even with complete homology between that section of APOE and APOB, which presumably must be the case or you wouldn't have to match . Yeah . The primary reason where APOE gets involved with clearance of lipoproteins is on chylomicrons and VLDLs they carry several copies of APOE per particle, unlike the AOB, which is one copy per particle . So when they are fully full of triglycerides, they're very big. The APLB is distorted in a certain way. Now, the receptor in the liver that's going to clear VLELs and color microns is called the LDL related receptor one . So it only has an affinity for APOE . So it's the LRP that clears most of the APOE contain ing particles, the kylos and the BLDLs , and that's why they have such short plasma residence time. I'm going to mention it now. Sorry, but Tom, I was asking a different question, which maybe is maybe I misunderstood something you said . I was asking about the neuron with its LDL receptor. How does the neuron with an LDL receptor tag and pull a tiny, tiny, tiny lipoprotein with an APEO on it out of real reason and this is why I'm explaining to you how the liver clears VLDLs and chylomicrons because the LRP only recognizes APOE and the brain not only expresses LDL receptors, but it expresses a lot of the LDL receptor related proteins . Okay , which is an APOE affinity clearance. Understood. Yes, the LDL receptor can clear some of the yep APOE part, but it's the LRP that's doing most of it. The last receptor that the neuron expresses and we've talked about this is called the scavenger receptor B one . That binds to the HDL and it dilipidates it, but it's an APOE recognizing scavenger receptor also. So everything in the neuron is basically looking for AOE and it gets it through especially the LRP, which is only an AOE recognizing receptor and the scavenger receptor recognizes APOA one , typically not in the brain, but it can be and we'll get to that also, but APOE works well with the scavenger receptor too . So very few LDLs in the periphery , I mean, maybe two percent of your LDLs have an APOE on and mostly there's no APOE. That's although the LDL receptor can recognize it . It's a minor clearance pathway APOE on an LDO. I want to go back to the synthesis. You alluded to this briefly. We have two cholesterol synthetic pathways. I mean, one pathway that branches and bifurcates into two pathways . And in each of those pathways, they make cholesterol , but the intermediaries are quite different. So different enzymes and different intermediaries. And we often refer to them thinking of what their penultimate molecule is. So you already refer red to one , which is the path that turns desmosterol into cholesterol . And then the other one, of course, turns lithost ol into cholesterol . What is the relative balance of cholesterol synthesis in the brain between those two pathways . Very interesting. In the periphery, the vast majority goes through the lapsterol pathway. Very little goes through the moster pathway. In fact, the primary cells that use the desmoster pathway in the periphery are our steroidogenic tissues . All of our other cells, I mean a little bit will go through the desmoster pathway, but most is lithosterone. So if you are measuring ster les in the blood lathesterol is up, you know, it's the peripheral cells that are overproducing cholesterol . Very interesting in the brain, when I told you up to the age of ten, all of the cells are producing cholesterol , including the neurons , the neurons synthesis pathway actually does go through lithosterol , but at the age of ten when the neuron decides I don't want to make cholesterol anymore, there's no lithosterol being produced by the neurons. It's all desmosterol that's winding up. If there's cholesterol molecules winding up in the neurons , it's through the astrocyte, the block pathway going through desmosterol. Now, in a pinch, if there's a cholesterol deficiency in the brain, the neurons can start synthesizing cholesterol again. But in normal brain physiology, that doesn't happen. So lithosterol is not used as a marker of brain cholesterol synthesis . For the big reason, even though there is some lithosterol pathway going on in the brain , if you measured it in the blood , ninety five percent of it is your other cells making it. Whereas if you measure desmostrol in the blood, the majority of it reflects, correlates extremely high with cerebral spinal fluid desmostrol and brain tissue desmostrol. So that becomes a very cool marker that we can actually measure in the bloodstream because desmostrol in the plasma correlates very highly with cerebral spinal fluid and brain cholesterol. And why is that?, Tom That's counterintuitive to me because they seem like completely independent pathways. Why should the desmosterol you measure in the blood tell us anything about the cholesterol synthesis of the brain? I think and you're better at figuring out these tele ological reasons than I that evolution decided there's one pathway that we're going to do in very critical areas. The brain which only makes its own cholesterol and stores and in the storage tissue. We want them to be dependent on that pathway . Why? I don't have an answer for you on that, but that's what that pathway reflects. All right, we'll come back to that because I know there's a there's a clinically relevant reason that we might want to think about that. Okay, so we've established that the neurons once they reach a certain age , want to start optimizing less around general contractors and construction workers and more around being architects because of the energy cost . And we've also established that you have a different lipoprotein that is transporting cholesterol in the brain so that the neurons can still acquire plenty of it from their neighboring oligodendrocytes and presumably to some extent astrocytes. I do want to just make one point clear for the listener , which we haven't really explicitly stated, but the astute listener, of course, has already picked up on the fact that we've talked about APOE, and as you said, ApoE has a relationship to Alzheimer's disease. I just want to make sure people understand the difference between ApoE Genes and Apoe the protein because to date , through this discussion, we have only spoken about Apolypoprotein E a protein. And this is denoted with a small A, small A, small P , small O, big E, and that's when we're talking about APOE the protein. But if you were to write all caps APOE, you'd be referring to the gen oty pe. And of course, you have two of these. So you could be a three, three, or three, four, four, four, two, three, et cetera. You want to just explain the relationship between those different six combinations of genotypes, everything from a two, two to a four , four , and how the different genes different proteins. And then we should talk about why that's relevant . Yeah, and it's a big part of this discussion. So the ApoE protein comes in different shapes. They're called isoforms. Peter has explained this many times. It's really only one different amino acid in the Darn protein that separates these, but just removing or replacing or putting the wrong amino acid in the entire peptide changes its ability to bend in shape and that will affect what it can bind to, which is the crucial function of apal proteins. So there are the you inherit the genes from mom and dad and that means one gene from mom, one from dad. So you get one allele in your gene and the other allele from each. So was your mom an APO E two, three or four or and likewise with dad? And you're gonna inherit, there's several potentials. You can be an E two, E two , E two, E three , E three , E four , E E two , E two E four , E four or E double homozygo for E four . So depending which of those genes you attack, your APOEE protein is going to be constructed a little bit differently, which is going to affect its ability to function whatever APOE is doing when it's stuck to a lipoprotein. And the main thing it's doing, it's serving as a ligand to what things are going to bind to or even what the APOE will bind to other than the lipoprotein . So the type of AOE you manufacture is critical to certain disease patholog ies. Peter can give you the exact indices. The average person has an ApoE three E three genotype. I believe it's about two thirds of people that have that far less people carry the APO two gene and especially APO E two homozygosity. Bader, why don't you tell how many carry the E four heterozygotes and the E four homozygotes? You have those percentage? Yeah, I mean, you know, again, it depends on the series you look at, but it seems about fifty five percent of the population are E three E three, that the so called wild type. twenty to twenty five percent might be E three , E four , and one to two percent would be E four E four. As you pointed out, E two E two is the most rare phenotype by far. That's significantly less than half a percent. I think E two E three is probably on the order of two to three percent. E two E four is also quite rare . So the two most common by far are E three E three and E three E four . And as we've talked about many times on the podcast, the risk associated with Alzheimer's disease between three , which is always the reference case and three four and four , those go up nonlinearly. So the three four individuals , the people that have one copy of three, one copy of four, they make a version of APOE, the protein that's not as good as the wild type. And their risk of Alzheimer's disease is about two times higher than someone who has a three . And again, it depends on the series. Sometimes you'll see that at three times higher, but directionally that's about the level. Conversely, if you have two copies of the four , that risk is significantly higher. There was a day Tom, fifteen years ago, the literature was calling that twenty to twenty five times higher. That number has come down considerably and I think most series would talk about that as being an eight to twelve fold increase. So it's, you know, it's a full log increase in risk for sure to have two copies of the E four gene, which means you're making an ApoE protein that is far less effective. Yes, and this is going to have ramifications . We've done podcasts and Peter has had Dan Rader on here . The most important thing about the peripheral HDLs is not the amount of cholesterol they traffic. It's kind of trivial and it gets transferred here and there. And it almost tells us nothing if you're measuring HDL cholesterol tells us nothing about what the HDL particles. Remember, there are ninety percent of your lipoproteins out there . So clearly what they're doing to cholesterol is not their major function . So that means HDLs do other things. And as we're learning, they do innumerable other things that regulate all aspects of human health. They're actually a part of the innate immune system, so they're involved with fighting inflammatory diseases, infectious diseases, chronic diseases cancer . So what we wish we had is not HDL cholesterol, which tells us very little . We wish we had tests that would tell us are the HDLs in a given patient's body doing what they're supposed to be doing, are they functional or not? But there's so many different functions that HDLs perform . It has to do not with the cholesterol they're carrying, but yet the types of proteins they might be carrying. Well over two hundred proteins have been described in the periphery as being found on HDL particles . Now that doesn't mean there's an HDL particle carrying a hundred peptides on it. Impossible. They're too small . But each HDL might carry one or two peptides, and each of those peptides might have some function that it's hard to even know what they are. Are they helping the immune system or are they involved with coagulation or what? So we have actually numerous arms of HDLs each constructed with one or two of those peptides in addition to ApoA one in ApoA two, some of the lipo lipid related ap otale prin s . And so there's no way to know for us to measure these HDL subpopulations. Now all of the HDLs that are carrying these proteins , they're not carrying cholesterol. So they are the really small HDL particles . They have the highest density because really what determines the density of a particle in the centrifuge is its lipid content. The more lipids, the more buoyant they float. HDL's carries the least amount of lipids compared to the APO B particles. That's why it sinks in the centrifuge tube. But the tiniest HDLs, the discoidal HDLs, Apollo one by itself , they're sitting right at the bottom because there's zero buoyancy to them . So if we have this whole army of very tiny high density HDL particles that are p acking probably critical proteins . Geez, don't you wish we could measure them? But here's where it gets interesting. We've hinted earlier in this podcast that there is a lipoprotein that can traverse that blood blood brain barrier and get into the brain . And it's these extremely small HDL particles, either free APOA one or an APOA one that's bound to a couple of these other proteins. And maybe some of these proteins are very important, antioxidative proteins, anti inflammatory proteins. So if those tiny HDLs that we cannot measure jump into the blood brain barrier or through it, and they're now in the matricome , where do they go? They immediately bind to the first APOE containing brain HDL that they bump into . So all of a sudden, this ast rocyte Apoe constructed brain HDL particle is also carrying a copy or two H OA one that actually originated from the plasma. The brain s sy cann'tht esize APOA one. The brain cells. So if it's in the brain and we know it is, they do pass the blood brain barrier. It is believed that is receptor mediated. It might be this good old scavenger receptor again expressed at the blood brain barrier that facilitates entry of ApoA one or the really small dense HDO APOA one s carrying accessory proteins . And the hope is , hey , number one, if they get in great, so now the brain HDLs, you have different subpopulation of brain HDLs. You might have only AOE containing brain HDLs . You might even have some APOA one brain HDLs, but most of them are going to be ApollE plus Apoll A one brain HDLs. And those other proteins that came with the Apolla one maybe can do start doing some good things in the brain . And where this might be really good . So in the periphery we have brain functionality . I did not introduce it, but it's easily you can deduce that wait a minute, if there are functional HDLs in the periphery, I'll bet there are circumstances where there are dysfunctional HDLs in the periphery that are not equipped with the proper protein or they're carrying proteins they shouldn't be carrying proteins that can do harmful things to tissues . They would be dysfunctional HDLs . Don't I wish we had a blood test for that? And we do not. So in the brain, now you have these APOE particles maybe contrying A poA one . But now if you're an ApoE four producer , when your astrocyte produces Apoe, it's going to be an Apo E four type of and that tends just like in the periphery, it's a dysfunctional type of APOE. So if you have the Apoe four genotype and your astrocyte is producing ApoE four peptides and they're what's constructed on the HDL, that's likely to be a dysfunctional HDL in the brain. And what would that mean ? It means that it doesn't bind to the neuron receptors as well as an E three or an E two to m thoseite receptors and therefore you have disrupted cholesterol transport into the neuron. Now all of a sudden the neuron is not getting the cholesterol it needs and that will create havoc because the neuron puts it right into cell membranes . If you don't have the proper amount of cell membrane membrane cholesterol , this is where something called amyloid precursor protein sits. And if you don't have the right cholesterol balance , it's acted upon by certain enzyme called secretases . That's where you start producing beta amyloid and even tau because you don't have the right amount of cholesterol in your neurons cell membranes. And this is how E four , one of the many reasons why it's associated with Alzheimer's. I'll stop there perhaps for you to jump in before I maybe describe some of the other things that APOE four brain HDLs don't do that an AOE three or an AOE two HDL would. Well, I actually want to take us backwards for a second, Tom, because one thing that we've danced around, but I don't think we've explicitly addressed is what is the relationship between brain cholesterol movement and something that people are very familiar with if they've listened to this podcast, which is amyloid. So people are obviously familiar with the accumulation of beta amyloid and p tau in the brain, and people are now really starting to understand that we actually have great biomarkers or we can start to track those things. Is there any relationship between those? In other words, as you talk about all of this dysfunctional movement of cholesterol in the brain , and we know that that is highly associated with your APOE genotype. And we also know that your ApoE genotype is highly associated with Alzheimer's disease. So the one thing we haven't put together is what's the relationship between amyloid tau and cholesterol. There must be a link, right? Definitely. We go way back, you can read the studies of autopsies on patients with Alzheimer's disease and they're really cholesterol overloaded tissues, especially the neurons . So remember the neuron , the main thing determines its function is its cell membrane integrity. And if you have the proper cell main construction, signaling occurs properly, the synapses fire properly or so . Now what will happen if you have too much cholesterol in that cell membrane and this is what happens in the Alzheimer's patients . What I just alluded to a few seconds ago , also located in the cell membrane is am yloid precursor protein. That's a protein that is going to evolve into the production of beta amyloid . So and whether it produces there's two types of that amyloid forty forty and two with forty two being the more injurious type of amyloid beta and the forty being a less toxic type of amyloid beta. So when there's too much cholesterol in the cell membrane of a neuron . There's something called beta and gamma secretase . They're enzymes that make the amyloid precursor protein cleave into the production of amyloid forty two . If there is the proper amount of cholesterol in the neuron cell membrane , it's a secretase alpha secretase that sort of slows the cleavage of amyloid precursor protein into ApoB and you wind up producing more of the beta amyloid forty, which is the less toxic form . So obviously it's the cholesterol content in your cell membrane that is a major, major factor. There's one other aspect of cholesterol homeostasis that we might as well introduce now because too much cholesterol in the cell membran is a danger to the neuron because the membrane isn't going to function . The neuron is the one cell in the brain that has the ability to get rid of cholesterol. We've spent a lot of time saying the brain makes cholesterol and it retains it. In fact, the half life of cholesterol in the brain is five years as opposed to a few days in the periphery. So that tells you the brain is reserving cholesterol . But early early I told you too much cholesterol in any cell is toxic. In the neurons, not only will it disrupt membrane function, but it crystallizes in the cytosol of the neuron and it kills neurons . You don't want to kill neurons. You're going to have some sort of chronic brain disease if that happens over time. So evolution has given the neurons the ability to change cholesterol into something called an oxystero . And the one it produces is called twenty four S hydroxycholester . People who know what cholesterol looks like biochemistry wise, it has one oxygen molecule at the third position of the first ring. twenty four S hydroxycholesterol not only has that one cholesterol molecule, it has a second one at Carbon twenty four . So now you have a hydroxy group on both ends of the cholesterol molecule . That makes it a little bit more water soluble . So when the neuron says I've got to get rid of cholesterol , it has an enzyme twenty four S hydroxycholesterolase that will make cholesterol change into twenty four S hydroxycholesterol , which is water soluble. It comes out of the neuron, it floats right through the matricome to the blood brain barrier where it can pass right through it because it's sort of a hydrophilic lipid with an oxygen hydroxygroup on each end. When it hits the blood brain barrier , the fatty acids and the phospholipids hate the hydroxy groups so they separate and it just creates a little tunnel through which the twenty four S hydroxy cholesterol can jump into plasma. Now wait a minute it',s a lipid. It can't jump into free plasma, but what's floating in the plasma that rapidly binds to the excreted twenty four S hydroxycholesterol, either albumin or any brain lipoprotein that floats by . Now it's part of a protein. It's on algumin or it's on a lipoprotein. They bring it back to the liver . Now here's the cool thing . What's the only other tissue in the body beside the brain that can produce an oxy sterole. It's the liver . And what does the liver do with oxysterols ? Well, the liver has cholesterol. You know, Pete that the liver is our major only man areufact ured bile acids, which are oxysterols. So cholesterol gets transformed into an oxysterol in the liver, same enzyme that the neurons express and the oxysterols. They go through several step s, but they become your bile acids down to your gut. Goodbye, fecali. So the brain actually has this cool way of getting rid of excess cholesterol by that transformation, it send it to the liver where it could be fakely excluded or so. So this twenty four S hydroxycholesterol gets very important . But if again, you start to build up too much cholesterol in your neuron cell membrane , it's in the cell membrane now. So there's less cholesterol in the cytosol of the neuron. The neuron stops making twenty four S hydroxychol esterol, brain is not escaping into the plasm anymore. This is why researchers use twenty four S hydroxycholesterol in the plasma as a mar biomarker of brain health . It shouldn't be there because the brain is retaining all its cholesterol. The neurons not trying to excrete any cholesterol . But if it does, the concentration of that in the plasma goes up, the liver doesn't secrete oxysterols into the plasma, but the brain does. So it's a great biomarker on brain health. So too much tells you the brain is in danger . This is why people who are developing drugs for the brain to try and prevent dementia, they monitor twenty four S hydroxycholesterol because they think if their drug is helping the brain prevent Alzheimer's disease, you won't find twenty four S hydroxy cholesterol in the bloodstream . And that's one of the star biomarkers as is the desmosterol that we alluded. So we actually have two things that we can measure . Here's the bad thing. In the real world , we can get desmoster measurements fairly easily . There's no commercial laboratory that twenty four S hydroxy cholesterol has become available outside of research studies. I wish we could measure that in our patients because it would just be another of the many biomarkers that are starting to emerge on brain health. So finally, back up, it's this disruptive , this Apoe four that is going to the receptors that should be internalizing the ApoE HDL in the brain into the lysosomes in the neuron, which will generate cholesterol for the neuron to use . But since there is markedly decreased clearance of the E four brain HDL , just when it touches the membrane, the cholesterol can jump into the cell membrane of the neur on, but it doesn't get to the cytosol. So it's very complex these lipid mechanics that are going on in the E four patient . And I'll let you ask about that before we get into other attributes of what ApoE four might not be doing well in the brain . Well, I kind of want to ask a question that brings it even further to something clinical, which is we've come this far in the discussion without really talking about the impact of pharmacology. So I want to sort of make that bridge now. Obviously we're not going to get into all the reasons why one would lower APOB pharmacologically. It's implied in so much of what we already discussed in the periphery. And when you talk about that, the thing that comes to most people's minds, I mean, most people aren't thinking of benpidoic acid and azamibe and PCSK nine inhibitors or bilacid sequ estrsant or CPEP inhibitors or CTP inhibitors rather. When you say lipid lowering therapy, everybody defaults into one class of drug and that class of drug is called the statin . So let's talk for a moment about what statins do , if anything, in the brain , and I'll bracket the discussion by saying maybe we can formulate it through the lens of the two types of statins, those that tend to be more hydrophobic and those that tend to be more hydrophilic. So maybe talk a little bit about that class of drugs. I don't think we have the time to go into the entire history of them so we can we can even do it through the lens of the modern versions of those drugs as opposed to going back in time. But talk a little bit about how those drugs work in the brain specifically. And of course, statins are the number one drug to lower APLB in the periphery because that no doubt about it, it reduces atheroscronic heart disease . But of all and Peter rattled off the classes of Apollbe lowering drugs that are primarily used nowadays , of all of those, there's only one that can penetrate the blood brain barrier and get into the brain. is And the it stat in class. All of those other drugs mentioned either wack work solely in the liver or no way they could penetrate the blood brain barrier. It didn't do anything to brain cholesterol homeostasis. So if a statin gets into the brain, now a little bit, Peter mentioned what we call hydrophilic, hydrophobic statins lipophilic, lipophobic, you know, a hydrophilic loves water , lipophilic loves lipids, hates water . And early on there was lots of data showing just traversing a cell membrane border, the lipophilic statins get through easier. Because the border itself has got a lot of lipids in so they all come right in. So it's a little for the hydrophilic statins to penetrate a barrier. Pretty much there has there are receptors that pull them into even the liver , the hydrophilic statins there are receptors that pull them into the liver and they get in quickly . So techicallyn , the lipophilic statin should get into the brain a little easier than the hydrophilic stats . But more modern studies have shown that really doesn't matter as much because once you're in a steady state, meaning you're on a statin, you have your blood level of the statin, ultimately they're all in the brain. Yes, the lipophilic ones may get in a little easier, but the hydrophilic ones get in also . And they all have the ability therefore to various degrees inhibit cholesterol synthesis in the brain. So I don't think you necessarily have to pick a statin based on its lipophilicity or hydrophilicity worrying about the brain , I think because in real world practice resuvistatin, a hydrophilic statin is used more commonly , it certainly can get into the brain maybe a little less slowly than lipid lipophylic statin, but if you're in a steady state, they're all in. They all have the ability to reduce cholesterol synthesis in the brain. So is that size driven, Tom? Is it just that the size of a statin is such that it can get across the blood brain barrier whereas the other classes can't? It's just the construction of the statin drug on how, you know, what converts a hydrophilic or lip aophilic property to that given statin. You know, if you look at we put up a slide here showing all the different stats, they're all a little bit different and there are certain aspects of that construction that gives them hydrophilicity and other aspects of that alignment or construction of their molecules gives them the lipophilicity or lipophobicity . So anyway , since we earlier we just said, hey, Alzheimer's disease is too much cholesterol in the brain, too much cholesterol in the neurons . You could hypothesize that if statins did get into the brain, which they do and all of them do, and in a steady state they, all have the potential to affolesterol synthesis in the brain . It might actually be good in a lot of people to slow down a little bit of the cholesterol synthesis in the brain because too much cholesterol results in pathology of the neurons and tissues . And this is why and we're not going to review them here. If you look at all the statin trials, the met analyses , most of them show statins really have no harm to the brain, but there are a few that do show statins seem to reduce the incidence of Alzheimer's disease or cognitive impairment in the brain. None have shown that statins injured the brain. Yeah, just for the listeners, we'll link to that in the show notes. We did an AMA on this a few years ago where I went through all of the meta analyses. And yeah, the TLDR is that every study we looked at for either MCI or Alzheimer's disease or dementia otherwise not specified , showed either neutrality or improvement . And these are all RCTs, of' course , though these are not studies that used dementia as a primary outcome. These are studies that are using dementia as a secondary outcome . And I always find this to be interesting, Tom, because it's both intuitive and counter intuitive, right? It's intuitive in the sense that you just laid it out, which is look, if we if cholesterol accumulation is highly toxic to the neurons, then a drug that reduces cholesterol synthesis in the brain should be beneficial . But at the same time, cholesterol is essential to the brain. So if we overcook it and we reduce cholesterol synthesis too much in the brain, could that also be problematic? Yes , and this is more in the hypothetical range right now because nobody's going to do these studies to prove it one way or the other. But because as Peter just says, cholesterol is so important , you would never want to over suppress cholesterol synthesis in the brain. That would not be good . So can that happen ? I think intuitively we know anybody who's prescribed a bunch of statins to people have known . A few of them get brain fog . Hey, I'm on the statin, I'm not thinking right . You know, my addition isn't as good as it used to be. And we stop the statin and rather quickly that goes away. So one hypothesis would be that is the person that is that is over suppressing cholesterol synthesis rather rapidly and severely, and that's why they got neurologic symptoms and they stop it . Obviously, you've stopped the statin and you're you're restoring whatever synthesis was going on in the brain or so . So that becomes a plausible hypothesis . And I said, nobody's ever going to do a study that proved that or disprove it . But you could also say Alzheimer's disease takes decades to develop . So again, if you're I give you a statin and you don't get that acute brain fog , it's probably safe to oversuppress cholesterol a little bit over time . And maybe especially so if you're an E four or you have a family history putting you at risk for Alzheimer's disease. Again, a theory, but it would be supported by the trials you just said that tend to show here not much going on or benefit, and that could be the plausible reason? Now we go back to you've went through the desmostrol and the phosphorol pathways . There's a nice study published almost a decade ago where they were doing cerebral spin al fluid desmostrol levels and plasma desmostrol levels and measuring it by mass spect. And there was high correlation between the CSF desmosterol and the plasma desmost saying that, wow, desmostrol in the plasma reflect desmoster in the central nervous system . And even more interesting, that study showed that the people with low desmost ril have the higher incidence of cognitive impairment and Alzheimer's disease . So if and you've talked about this many times on the podcast too, if we are administering statins to our patients , even the E four patients on the hope that we are going to help lessen their incidence of Alzheimer's disease . Maybe keeping an eye on plasma desmosterl ort makes sense. And if you do over suppress it with your statin therapy, maybe you can change the dose of that statin therapy or maybe you can just abandon statin therapy and lower APLB to reduce heart attacks with the several other drugs that you ran through very quickly there or so . So gets very interesting. And last thing to tie it into that twenty four S hydroxycholesterol. Remember, if you're on the way to Alzheimer's disease that's increased in the plasma. There's studies showing that if you prescribe a stat in, the twenty four S hydroxy cholesterol disappears . That would again be proof that the statins are lessening cholesterol synthesis in the brain and maybe to a level that's really desirable because you don't want to see that. But then you would back it up with the desmosterl because if that was low, ooh, I've maybe suppressed it a little bit too much. All wonderful hypothesis has a lot of data can easily provide twenty references on desmostrool in the brain how critical it is. So this is a very plausible theory right now and don't expect a clinical trial to prove or disprove this hypothesis right now. We'll link to those sources, Tom in the show notes. One other drug I just want to talk about really quickly is etamibe. Again, Azetamibe is a, you know, a drug that really works outside the body so, to speak, right? It works in the gut. It's blocks the Nemen Pixy one like one transporter . And in people who are not hyper absorbers, it's not even a particularly effective drug. Yet there is a kind of a suggestion that it might have some benefits in the brain, which is the furthest place from where we think of it working. What can you say about that? You know, it's kind of amazing. Like you said, who would ever even hypothesize that there's drug that Axony intestine might have beneficial effects in the brain or so . And I think have a couple of neurologic colleagues, Richard Isaacson and Kellyanne Otis who are very involved with these diseases . And it is their anecdotal belief that as etomibe, in addition to helping them control their APLB in their patients , there is seems to be some cognitive benefit in the people they deal with or so. So now there's some actual plausible reason. Now Zetamibe is one of those drugs that just cannot cross the blood brain barrier. So how in the world could it be helping dementia or so ? But it has a metabolite called z aetamide glucoronide that actually can pass through the blood brain barrier in small amounts, but unlike a zetamide it gets in. And there are animal studies showing that it interferes with hexokinase and the glycoylation of brain proteins . If you reduce that, there's some benefit, less inflammation in the brain or so. So there is that and again, it's a study I will definitely give you the reference to that people can read that there's some plausibility to it. And there's an anecdotal belief among neurologists who live in this field that it's a helper. So wouldn't that be cool? You know, Peter and as we control ALB aggressively in your patients , we use a lot of azetamide because we prefer to use low dose statins and if we don't get to the A poB goal, we're adding a zetambe. We also day one, check synthesis and absorption. So there are patients where we use a zetambe day one because they're hyperabsorbers and that's where you get the most efficacious APO B lowering . So in the future, as we have people who carry the Apoll E four alleles and they have APOB issues , we might pick a statin first, we might pick a zetamibe, but I think there might be a patient where you need a little bit of a statin and a little bit of azetamibe until somebody proves this. And I would not hold your breath waiting for a randomized controlled trial that azetamibe, what it's doing to even some of the Alzheimer's biomarkers in the blood only emerging drugs are they starting to do those type of studies on nobody's going to go back and look what is etomibe those to PAW or the amyloid ratios or so. I wish somebody should. You'd only need maybe a small buddy. Well, I'm surprised you could probably pull it out of a bio bank for an existing study that was already done on a zetomybe. So that's not we could at least get the suggestion of that from such a study because we do have at least one well I know we have Statin versus Statin plus Zetamibe trials. Don't we also have a monotherapy setia trial? Only in Japanese elderly people and I don't think cognition was one of the things. It was just and it was not a blinded trial. So it was an open labor trial. Yeah. Just the show. It was efficacious in lowering Apoll B in a primary prevention setting , but they certainly didn't look at cognition or biomarkers and that stuff. But if they still have serum banked, you could at least look at pre and post levels of PTO. You definitely could . Yeah , forty two, forty. Yeah. Be a great research project for some young PhD or buddy lipidologists . Hopefully listening right now. Let's talk about something else that is half drug, half supplement that gets talked about a lot for brain health, which is the role of EPA and DHA. Again, they're readily available as supplements over the counter. And there are certainly some brands out there that are legitimate, which is to say you're getting what the label says you're getting and they're free of contaminants. But they also make pharmacologic variants of both of these fatty acids. So take that in whichever way you'd like, but what do we know about EPA and DHA and brain health? We're not talking about specific products. Let's talk about if an EPA and DHA are both important to the brain. There's far more DHA, but we're finding out that even EPA is important for the brain now also . So since we can't produce omega three fatty acids, we have to eat them. And we're eating when you eat them, they're mostly in the form of a triglyceride carrier or a phospholipid carrier. And that's exactly how the supplements deliver omega three's to us. They're packaged in as a triglyceride. Typically one of the fatty acids on a synthesized triglyceride would be an omega three . And there is a product that delivers omega three s a phospholipid from kryll oil . So now once you ingest a triglyceride or a phospholipid , remember the only thing that can really be absorbed is free fatty acids. So pancreatic enzymes, lipases , leave off the fatty acids from the triglyceride or phospholipid vehicle, and then the free EPA or free DHA, which joins with other lipids in the biliary mycells gets absorbed by f aat ty acid absorber CD thirty six . Interestingly , not only can a free fatty acid be absorbed, but a lysophospholipid can be absorbed. A phospholipid has a phosphorus moiity in a head group and two fatty acids attached to it, that's called a diarratal phospholipid, two fatty acids . But if I took one fatty acid off of a phospholipid , it's called a lysophospholipid. It's actually a smaller monocule and they're easily absorbed . So in the light paces either makes free fatty acids or it could make lysophospholipids. But hey, if the remain ing fatty acid on that lysophospholipid is in omega three, it gets in. So once they're in the enterocyte, what happens to them? The enterocyte immediately resynthesizes them to a full phospholipid or attaches them to a triglyceride molecule which goes in the core of the chylamicron. The phospholipid goes on the surface of the chalamicron . It shoots them into the lymphatics and they rapidly get into the plasma, they undergo rapid hydrolysis at the fatty at the muscles and fat cells by light paces and that frees up these phospholipids . Ah . Now phospholipids are a lipid. They can't circulate in the bloodstream. They immediately bind to something called a phospholipid transfer protein. And the phospholipid transfer protein will bind to either a full phospholipid or a lysophospholipid. And it's that delivery truck of an omega three phospholipid transfer protein which goes up butts into the blood brain barrier and there's a specific receptor in the blood brain barrier that will internalize the lyophospholipid form of DHA or EPA . And once it gets into the brain, it's in the brain. It can be trafficked in these brain HDL particles and it's part of the things they do too or it can jump right into the cytosol or the first cell that it bumps into while it's in the mattressome . So that's the journey. So look, it almost doesn't matter the vehicle you're ingesting an omega three whip, we would prefer that you've established that a supplement is actually has the amount of omega three's they say they do. Don't trust the labels of every supplement you may buy and they get in. Now in the periphery there's a lot on and there's a big trial that shows perhaps for preventing lessening residual risk in people who have APBO controlled, E thePA is a little bit more important and the DHA plus the EPA, there's a trial where that didn't work as well as the EPA , but you know, once they get into the brain, the brain has its omega three fatty acids. So and used to be old DHA, but I know the thought on that is changing. EPA is required or two. Some people can convert EPA to DHA, but not every body can . And that's how they get up into the brain. And obviously, since their concentrations in the brain are so high compared to other tissues , it's an integral part. And why wouldn't it be? Because where do Ome threega's go in the cell membranes ? And that's everything, cell membrane health in the brain cells. And I guess where do you stack this in terms of evidence, right? Like in the hierarchy things that we really know are as close to capital T true as possible when it comes to brain health, right? Which is lipid homeostasis , good blood pressure , you know, sleep, exercise. I mean, things that just demonstrably matter when it comes to brain health , where in that pantheon would you sort of put having a serum or EPA DHA level in the RBC membrane of ten percent versus six percent . What's your level of confidence? Well, the data is all going to come from observational trials for the most part. So and in those trials , there are ones that specifically looked at certain brain functions and correlated omega three index with the observational outcomes related to neurological issues and they seem to be positive. An academician would tell you, Tom, don't even talk to me. There's no level one randomized blinded controlled study doing what you say, so it's irrelevant to me. But if you look at all the observational data, just like we did with the statins where it's in general pretty good, I think if you went through all of that data with omega three's in the brain, you would find it. Bill Harris has studies relating it to brain size or at least certain sections of the brain size in omega three contexts, I believe in the hypothalamus or other areas of the brain. So again, it's this plausible stuff, but there's no level one evidence. We certainly have evidence in the blood that low levels of omega three index are certainly associated with sudden death and increased atherosclerotic heart disease . Again, we lack the randomized controlled trials that ch anging that will reduce events other than that one trial of EPA and insulin resistant high risk people who had APLB well controlled . So you're in that gray zone area with the clinical trials on this, and they're not the type of trials that any guideline is going to tell you. This is what you have to do. But again, it's just like our dismostro hypothesis. This is a plausibility error. I see little downside to using omega three's. Bill Harris, who you've interviewed , has looked at his trials and he's pretty content that when you hit the eight to nine percent Omega three index, you pretty much have the proper amount of omega threes in the scenarios cell membranes of your body There is no study. You can allude to that, hey, therefore, so it's so important in the brain. Let's make it ten percent other than if there's no harm to it, why not try for it? So you're going by that type that's all a little bit of guesswork right there. Yeah . Well, Tom, I want to close with something that's you and I are very excited about. I did a brief podcast on it a little while ago, which is a new drug in a new class . I alluded to this class very briefly a few moments ago. The CTEP inhibitors, you and I've spoken about these drugs in the past on a podcast. We've got several podcasts on this topic, including most recently one with John Casterland , probably God about four years ago. But since that time, we've had some exciting data which I talked, about in my podcast, but maybe just we could remind people about that drug obesetropib and the Broadway trial specifically, and how we tie it into what we've talked about today . Yes , basically CETP inhibitors of which Obi Setropib is the latest have been investigated to see what they do to atheroscrotic heart disease and LP Little A and maybe brain functioners. There's a signal that if you have CETP loss of function genetically those people have less Alzheimer's disease or cognitive impairment. So that makes it plausible. Well, if we inhibited CETP pharmacologically, we almost convert you into the genetic status, maybe there would be less Alzheimer's disease . And now in that broadway trial, look, the people at New Amsterdam Pharma recognized this. So they're actually putting a little money into clinical trials, perhaps investigating this hypothesis . And in that Broadway trial where you administered obeset cetera. remember And, it was given to them primarily to reduce APOB and ultimately reduce mace in those people . But they actually looked at some of the biomarkers of Alzheimer's disease , the phosphorylated patau, the amyloid four thousand forty two ratio, the other various ratio of these markers, the hibrillatory markers, all things you can measure . And they saw some very interesting movement in the right direction of those Alzheimer's associated biomarkers . Now the next step would have to be in a clinical trial, continue to monitor them , and that was a very quick study. You would monitor it over time, but maybe you'd throw in some cognitive function in some of the studies to see, geez, could obiestropib actually because it's improving these biomarkers really affect what we want to do, better brain function . And the plausibility is because they make your HDLs very big and they have many copies of ApoA one on them which can break off. So you generate some AP OA one in the plasma. But when the HDLs are big on a CETP inhibitor , the liver's senses, oh we have a deficiency of APOA one because they're not seeing it. It's all on the H DL particles . So the liver actually starts overproducing ApoA one . So ApoA one goes up in the plasma . But once ApoA one goes up, what does it start doing? It starts binding to some of these potentially protective proteins we've talked about . And guess what? So if you're increasing if obi setropin is increasing either apo APO oneA or the really tiny protein lading HDL species that can cross the blood brain barrier . They believe the potential would be that, hey, some protective proteins are getting into the brain. They've looked at some anti inflammatory, antioxidative aspects of those proteins , and they believe the ApoA one can jump on an E four Apollo brain APOE HDL particle and rescue it and maybe turn dysfunctional brain HDL particles functional brain particles . So it's a wonderful story on paper right now, but the fact that the biomarkers are moving in the right direction, I think gives us all great hope. And I believe the company is going to put money into investigating this with further cognitive studies and more advanced studies and perhaps even some imaging studies. PET things like that. Although these biomarkers really, if you have those biomarkers, some people say you don't even need that pet scanning anymore because they reflect that easier. So that's the quick story with Obi Setrap . Yay for its ALB ability, we're all going to certainly be using for that. That'll be its FDA indication . But if we get more and more information like this that's looking good, especially in the E four carriers, I think the real people would look at any downside, so far not any or they would have had arrested their trials , but it's not FDA approved yet. So they have more data to collect yet . And we'll see, but the hope is high. Yeah, I remain very optimistic based on the data so far. And I think the key is going to be doing the right clinical trial. Again, I think a lot of these things , if you look too late in the pathology, you might not make enough of a difference . So the key, I think, is going to be patient selection and duration. You've got to be able to select people who are high enough risk, E four carriers and catch them right at that window. You know, I always go back to a study that I think did a great job of this, even though it was a completely unrelated study, which was the Predamed study. This is more than ten years ago , which was a primary prevention trial of dietary therapy for at a minimum mace , but also I believe it even looked at all cause mortality or maybe it was cardiac mortality . And again, it was primary prevention, which I always thought was I thought I thought the study would fail. I really did. I was like, you're not going to do a diet ary primary prevention study, come on. And not only did the trial succeed in demonstrating the superiority of a Mediterranean diet to a low fat diet , it was halted early . And again, I think that's just a great example of if you pick the right population as I thought, you know, I thought of it as people who were just about to drive off the cliff but weren't quite there, you could get an answer to a question in a few years. And I think that 's that's the way to think about doing this and I hope they can do that. Yeah, look, I'll just say you know Michael Davidson, your friend and John Castellan, your friend. They are really driving all of these studies and they are well experienced trialists so they will do the right studies. Tom, this has been an amazing tour of a topic that is sort of new to the podcast. We haven't done sort of a deep dive into brain cholesterol. But I think it's been such an important discussion because I think there's a lot of confusion out there on this topic. I think that the completely different way in which the brain goes about doing its business with respect to cholesterol from the periphery, I mean, hell most people don't even understand how the periphery deals with this. So why would we expect somebody to understand the role of oligodendrstites and neurons in the different pathways and Apoe versus ApoB? So again, I know that this podcast was a little technical, but I think you did a great job of explaining it, anthropomorphizing it when appropriate. And obviously, this might be the podcast someone has to listen to or watch a couple of times and the show notes will be robust . So I want to I want to thank you and as always Tom, it's been gosh, it's been fifteen years since you took me under your wing and helped me develop my understanding of this field of lipidology so I can never I can never waste an opportunity to thank you publicly for your generosity, your personally with me. So thank you very much, Tom. And look, I'll wrap this up by saying, yes, I was your lipid mentor for a while, but over the time we've known each other a long time and I've got to experience your immense knowledge on things I had never even considered before. So you've taught me just as much about so many things if I think it's a great partnership that we thank God we bumped into each other and we've evolved into this role and I'm still going and have the honor of still working within your practice not as a prescriber but just to keep the staff educated. And you know, I'm shipping you out. Here's the newest, latest and greatest stuff all the time. So it's just been a phenomenal , wonderful hui for me to continue my career. So I love you eternally , you know that and hey, sooner or later it'll be another topic we're going to have to expound on again because lipids keeps changing and getting more and more exciting. So I love doing it. Thank you Tom., Thank you very much . Thank you for listening to this week's episode of The Drive. Head over to PeteratiaMD forward slash show notes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter all with the handle Peter Ati MD. You can also leave us review on Apple podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional healthcare services, including the giving of medical advice. No doctor patient relationship is formed. The use of this information and the material s linked to this podcast as at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis or treatment. Users should not disregard or delay in obtaining medical advances any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. 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