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Hey everyone, welcome to the Drive Podcast. I'm your host Peter Atia. 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 the subscription. If you want to learn more about the benefits of our premium membership, head over to peteratiamd.com/subscribe. My guest this week is Dr. Tom Despring, 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 cover 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 APOA1, and specifically APOE, as it pertains to cholesterol. We talk about how the APOE genotype relates to Alzheimer's disease risk, which is something we prefer to a lot. But then the link between APOE cholesterol, homeostasis, amyloid, and tal. What we know and what we don't know about the effects of statins is that of my omega-3 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 Despray. 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 becoming 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 it's most important function is it positions itself in the cell membranes and every cell in our body and cell membranes are regulating integrity, what gets in, what gets out of cell. So, evolution is given every cell in the body, the power to denovo synthesize cholesterol. A little bit. Now, each cell needs, you know, a minor number of molecules or cell. But if it does that, we got great cell membranes and it will cells are functioning happily or so. But we also know and people sometimes don't understand this like so many things and excess of anything can be harmful. So, if any cell somehow has oversynthesized cholesterol, a 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 is also given cells, the ability to export cholesterol out of its cytosol into the plasma. But you know, you'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 adhere to lipids and unwrap 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 leaf flux is cholesterol out, it joins on a protein. The protein happens, we called APOA1, 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 HDLs. And those are produced in the liver. One type is produced in a 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 APOA-lipo protein B. The intestine makes a full-size APOB, the intestine makes a truncated one. We call the, excuse me, the hepatic APOB, APOB 100. And the intestinal produced one because it has 48% and I'm gonna like to get away. Of 100 is APOB48. So, when the intestine makes a chylamicron to which traffics absorbed fatty acids, which become triglycerides absorbed cholesterol into the bloodstream, it's in an APOB48 particle, a very transient postprandial particle. The liver manufacturers, APOB particles, one is a very low density lipoprotein. It's quite big because it's packing the triglycerides, which like the chylamicrons, it transports the muscles 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 a low density lipoprotein or LDL. But the liver also has the ability to denove o manufacturer and secrete LDLs also. So, our LDLs that are floating around have two sources, they're sort of like the son of VLDL or they're a liver produced one. Now the APOB particles carry a lot of lipids, triglycerides primarily in the VLDL. The LDL is very interesting. It's pretty much a cholesterol carrying particle, X amount of triglycerides, but it has the longest plasma residence time of anything in the APOB 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 LDL receptor, which binds to these APOB particles and pulls them into the liver. And then the liver digest them and does whatever it wants with the component parts of the lipoprotein. The LDLs 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, 90% of them are HDLs and the rest of the APOB family. Now the APOB family traffic's far more lipids because of their size. You know the volume of the spear is the 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 HDL. Now it has to do things with that cholesterol. It has the option of delivering it to steroidogenic tissue that make cortisol or gonadol 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 APOB particles, the majority of which are LDLs because of its long plasma residence time. So if an HDL we've always been told that they do reverse cholesterol transport and they can, they can bring it back to the liver of the gut. But interesting if they send their cholesterol to an LDL, the HDL becomes very small and it starts it's journey all over again. And then the LDL 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 LDL's bringing it back to the liver, or a 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 LDL's, is to return cholesterol to the liver. Everybody thinks it's a delivering cholesterol to cells, almost never, because every cell can make all the cholesterol it needs. And in an emergency, any cell can upregulate an LDL receptor and pull in the LDL if it needs it, but just doesn't happen for the most part. And this is one reason we're going to talk about it, because it's pertinent to the brain. If LDL's are bringing cholesterol back to the liver, if we can induce that with some of the drugs that we have that make LDL receptor is expressed and stay expressed longer, we will drop LDL cholesterol levels in the plasma extremely low. And as we get deeper into the brain, 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. 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 did night's brain feeder, I hope, I've touched on that in a rapid fashion? Yep. I think 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, ions, sodium, potassium, chloride. They don't need to be bound to anything to move around. Conversely, steroidal hormones 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 sex hormone binding globulin 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 APO-A family, the APO-B family. We always want to make sure people know that when we're talking about the APO-A family, it has nothing to do with LP-little-A. It's a totally different APO-lipoprotein, which we're not going to talk about today, although we've got lots of content on that. You also mentioned how much the APO-A's outnumber the APO-Bs in absolute numbers, but because they're so much smaller, the total cholesterol carrying capacity is much greater in the APO-B family. And a way for a person to appreciate that is to look at their lipid panel. If you see that your total cholesterol is 200 milligrams per desoliter, you'll easily notice that the sum of your LDL and VLDL cholesterol could easily be 140 of that 200 milligrams per desoliter, whereas the HDL cholesterol might only be 60 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 HDLs that do it 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 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 LDLs function is to bring cholesterol 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. LDLs are sending transferring less cholesterol to the LDLs. So the system is in 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 in balance. 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, you know, again, total cholesterol of 200 milligrams per desoleter, I could calculate how much cholesterol is in their blood because I know what their circulating blood volume is. And, you know, 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 some is in all of the periphery. That means you deliver every organ you got your skin, every membrane in every cell in our body. The mass of total cholesterol and the brain has its own component because they don't interact. But in the plasma, it's interesting. Most of the, of course, you would think all of the circulating plasma within lipoproteins, but it's not. This comes to a surprise to many people too. The biggest carrier of cholesterol in our bloodstream is in our red blood cells, yeah. Because there are 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 album and 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 tell us 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 the wrong. It's not even close. The brain of all the organs in the body has 20 times more cholesterol than does the liver. The liver, I've read the brain has like 20 to 25 grams. There's like 140 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 on to cholesterol, like the bank holds on to its gold in the bowl and everything. But where's cholesterol, the liver is just sort of a handling station. Whatever cholesterol the 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 on to its cholesterol. This is another physiologic point. We'll have to get into it. The liver is more like 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 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 cognizant of the idea that if your peripheral cholesterol goes down by 50%, 75%, right? If your total cholesterol falls from 200 to 100 milligrams per desolate, it's 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 tiny. Yeah, it's almost tiny. It's almost tiny. Yeah. It's between cellular cholesterol and circulating cholesterol. Yeah, so this is definitely one of the misconceptions people deal with. 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 100 milligrams per desolator as opposed to 200 calories. 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 the industrialized countries. It's all over people are buying of heart attacks for a variety of reasons. And I always like to say, if you have atherosclerosis, there's one cynic one on, you have cholesterol build up in your artery wall. If we do not have cholesterol build up 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, Ari Tom, well, how in the world does cholesterol get into that artery wall? It's not like the arteries over synthesizing 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 one of the reasons we talked about the APO B containing lipoproteins. By the way, henceforth, we may refer to beta lipoproteins. That's the APO B family. The HDL family sometimes we call 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 fern slide, 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 in LDL or a VLDL, and because of its resonance, find the vast majority of those are LDLs, exceed a certain threshold number. They won't enter the artery wall. It's a simple diffusion process. You could have ended the early dysfunction and they get pulled in, they get in a little easier, but they get in, even in healthy artery walls, want to exceed a certain concentration of APO B particles. So in 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 they immune system sends in white blood cells, then engulfs them and that creates a cholesterol rate and magnifies the foam cells, they stick together creating plaque. So it's the particle number, and we can, there are assays that we can get LDL particle numbers or VLDL particle numbers, if you want them. But since there is one APO B 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 thresholds, at first gross, this is very likely to occur. The main driver of your APO B 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 APO B particles from the plasma, meaning those LDL receptors, the liver for whatever reason is not expressing enough of them to clear, to keep the APO B concentration physiologic in the bloodstream. So once APO B particles are not cleared, then there's only one other option for them, they have to invade an artery wall. So it's the APO B concentration, and they deliver cholesterol, and that explains that through a genesis. And in the old days, we used to, and still do, what are ways of estimating APO B 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 APO B LDL particles floating around. We use VLDL cholesterol, triglythreads divided by five, as 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 dumb trucks entering your artery wall 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 APO B, and every APO B particle goes into the liver as one less that's going into your artery wall. And that's basically the pathophysiology of atherogenesis, it's those APO B dumb trucks. Follow up on that point, again, let's take two individuals whose APO B 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 subendithelial space to begin that cascade that we talked about. Everybody has the story of, you know, my grandmother is 90 years old, she's got an LDL cholesterol of 160 milligrams per desolate or her total cholesterol is over 200. 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 51. 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 homogeneity 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 the physiologic steps? Sure, well, as I mentioned, if cholesterol gets in your artery, well, you have the disease, and it's the APOB particles bringing them in, but that is not the only etiologic reason why one would have after a stroke. So 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 in plaque. We should make the point that this APOB entry to the artery wall is an incredibly slow process. It takes decades to develop, and this is why the concept now is not only lower, it's better, but the longer you keep things low with APOB 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 of collagen diseases, rheumatoid arthritis. They have lifelong inflammatory factors going on in other abnormalities that weaken the arterial defense against atherosclerosis. Oxidative processes is a big part of atherogenesis, so if that is going on in a body, but sometimes we do see, like you said, grandma who smoked all her life and has high LDL cholesterol and a whinoplac. 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. Oh, 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 is going to make it to 80. We 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 important thing to make is don't ever think because you're LDL cholesterol is 200 that I'm one of them, because there's no way to know that. Why play Russian rule less and think it's not going to bother me when for the vast majority of people it does create havoc and pathology. Yeah. So let's now talk about the brain. So we've got these APOB and APOA lipoproteins, the HDLs and the LDLs 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 the blood brain barrier, which is actually a barrier that separates the brain from the periphery as we've taught. But I like to start to give you an idea about why is 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, and the second and the third trimester, the fetal brain is already starting to denobocinthicize its cholesterol because 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 yourself. So every brain cell starts producing cholesterol in utero. Very quickly brain cells it's very easy. You have neurons, the ones I love, 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 in the adults produce a lot of the cholesterol. We have oligodendrocytes, it's a big word and they produce about 70% of the brain cholesterol because one of the mega things the brain does with cholesterol is create myelin which sheaths every axel 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 glial cell in the brain is a micro glial site and they are the brain immune cells so they are the last remaining cell. So in utero the day we're 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 early 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 or held the alcohol cholesterol, it might be 30 milligrams per deciliter, yet that is the time when the brain is growing more than it ever will between birth and age of 10 the brain is expanding to its adult size and it can't do that without cholesterol so it's super manufacturing cholesterol but it's doing yet in people who the 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. And around the age of 10, pretty much the adult brain size is foreign. So at that point there's a readjustment of cholesterol synthesis in the brain. Oligodendrocytes keep making it they always will. Microglia sites 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 into the neurons. When the brain is full adult size the neuron says no no no I'm not going to make any more. 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 37 steps. Every step is a different in design every step requires ATP. So to send any cell to synthesize one molecule cholesterol consumes over 30 molecules of ATP. 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 ATP's making cholesterol if it can get it elsewhere. The neuron starts using ATP for its functioning. So and then it falls on the astrocyte. 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 neuron 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 we've enumerated a lipid travel within the lipoproteins in the plasma. 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 matrosome. So if we take the brain it's it's this connective tissue in our resilience of these cells in them. The glial cells 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 want to elaborate in depth but we've had podcasts on this before. One of the cholesterol synthesis pathways goes through the next to last sterile, panultimate sterile and in the brain 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 fluid. Nah 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 and apoprotein so it could shoot it out into the mattress home 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 in apo A in the brain it's the famous apolipoprotein E. And apoe many people know that has something to do with the brain because we know there are types of apoe 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 you'd see creates into the mattress home but it's an apoe containing lipoprotein. Now if we could take out those apoe containing lipoproteins and put them in the 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 scootry four copies of apoe 1. The brain HDL will have a couple of three copies of apoe and that is the big difference. Now once it's in the mattress home this particle it continues to mature cholesterol becomes cholesterol ester goes to the center of the particle it becomes a big fat particle but remember its mission is to deliver cholesterol to the neuron. So the neuron is going to have to grab that apoe be 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 the 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 apoproteins in the periphery the LDL receptor is looking for apoe 100 but in the periphery even apoe combined to an LDL receptor but in the brain the LDL receptor only binds to apoe containing lipoproteins because there are no apoe containing lipoproteins so it's the same darn receptor and this is why I think we should stop calling it the LDL receptor. No we call it we should call it the apoe receptor because 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 apoe particle an LDL a garden variety LDL makes its way to the liver it has one and only one apoe around it. Can you briefly explain confirmationally how that LDL interacts with the LDL receptor? What is it about the apoe protein that enables the key to fit into the lock? There's a very small segment of the apoe receptor that's called the LDL receptor binding domain. Excuse me on the apoe B. There are certain amino acids that line up and they create they have a surface charge and here's the LDL receptor. L-L receptor. Now, the L-L receptor has a certain segment that is called the APOB recognition domain. There's certain amino acids there that create certain electrostatic forces. And if the domain on APOB and what determines is that sticking out properly is the confirmation of APOB that explains the difference clearance rates between big LDLs and small LDLs as opposed to normally constructed in size LDLs that have a normal APOB confirmation. They have much higher clearance. The small LDL, where that domain may not be exposed as readily or the big LDL, where it should be. The LDL receptors don't 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 clearance is decreased. So there are certain just small areas on the LDL receptor and the APOB that it's they align properly. You have great clearance. No news is just discovered and published last year from our friends at the NIH is LDL receptors act as a dimer. There's actually two of them that express it 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 resonance times of LDLs. How is the APOB conform? So Tom, given that the size of the LDL within a variation of normal can impact clearance. It really surprises me that that same LDL receptor can easily find somewhere on the APOE wrapping a very, very, very small like a protein in the brain enough of a conformational match to make that work. So that is 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 chylamicrons and VLDLs. They carry several copies of APOE per particle, unlike the APOB which is one copy per particle. So when they are fully full of triglystides, they're very big. The APOB is distorted in a certain way. Now the receptor in the liver that's going to clear VLDLs in chylamicrons 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 containing particles, the chylamic and the VLDLs 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 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 APOE on it out of the And the real reason is this is why I'm explaining to you how the liver clears VLDLs and chylamicrons because the LRP only recognizes APOE and the brain not only expresses LDL receptors, but they express a lot of the LDL receptor related protein one which is an APOE affinity clear understood. So the LDL receptor can clear some of the APOE part of it, 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 B1 that binds to the HDL and it delipidates it, but it's an APOE recognizing scavenger receptor also. So everything in the neuron is basically looking for APOE and it gets it through especially the LRP which is only an APOE recognizing receptor and the scavenger receptor recognizes APOE1 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 2% of your LDLs have an APOE on and mostly there's no APOE that although the LDL receptor can recognize it, it's a minor clearance pathway, APOE on an LDL. 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 referred to one which is the path that turns Desmostral into cholesterol and then the other one of course turns Lathostral 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 Lathostral pathway. Very little goes through the Desmostral pathway. In fact the primary cells that use the Desmostral pathway and the periphery are steroidogenic tissues. All of our other cells, I mean a little bit will go through Desmostral pathway but most is Lathostral. So if you are measuring starrals in a blood Lathostral's 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 10 all of the cells are producing cholesterol including the neurons. The neuron synthesis pathway actually does go through Lathostral. But at the age of 10 when the neuron decides I don't want to make cholesterol anymore there's no Lathostral being produced by the neurons. It's old Desmostral that's winding up. If there's cholesterol molecules winding up in the neurons it's through the astrosite the block pathway going through Desmostral. 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 Lathostral is not used as a marker of brain cholesterol synthesis for the big reason even though there is some Lathostral pathway going on in the brain. If you measured it in the blood 95% of it is your other cells making it where if you measured Desmostral in the blood the majority of it reflects correlates extremely high with cerebral spinal fluid Desmostral and brain tissue. So that becomes a very cool marker that we can actually measure in the bud stream because Desmostral in the plasma correlates very highly with cerebral spinal fluid and brain cholesterol. So that's counterintuitive to me because they seem like completely independent pathways. Why should the Desmostral you measure in the blood tell us anything about the cholesterol synthesis of the brain? I think in your better at figuring out these teleologic 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 in stores and in the storage genic 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 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 being 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 oligodendro sites and presumably to some extent astro sites. 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 ApoLypa protein 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 genotype and of course you have two of these so you could be a 3-3 or 3-4-4-4-2-3 etc. You want to just explain the relationship between those different six combinations of genotypes everything from a 2-2 to a 4-4 and how the different genes make different proteins and then we should talk about why that's relevant. Yeah it's a big part of this discussion so the ApoE protein comes in different shapes they're called isophorns. Peter has explained this many times it's really only one different amino acid in the darn protein. 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 combined to which is the crucial function of apoproteins. So there are the Inherited 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 and apoe 2, 3 or 4? And likewise with dad and you're gonna inherit there's several potentials you can be an e2 e2 e2 e3 e3 e4 e3 e2 e2 e4 e4 or e2 homozygote for e4 so depending which of those genes you attack your apoe 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 certain as a ligand to what things are gonna bind to or even what the apoe will bind to other than the lipoprotein So the type of apoe you manufacture is critical to certain disease pathologies Peter can give you the exact indices the average person has an apoe e3 genotype I believe it's about two thirds of people that have that Barless people carry the apo 2 gene and especially apoe 2 homozygocity They don't want you to tell how many carry the e4 heterozygote and e4 homozygote so you have those percent Yeah, I mean, you know again, it depends on the series you look at But it seems about 55% of the population are e3 e3 that the so-called wild type 20 to 25% might be e3 e4 And 1 to 2% would be e4 e4 as you pointed out e2 e2 is the most rare phenotype by far That's significantly less than half a percent. I think e2 e3 is probably on the order of 2 to 3 percent e2 e4 is also quite rare So the two most common by far are e3 e3 and e3 e4 and As we've talked about many times on the podcast the risk associated with Alzheimer's disease between 3/3 which is always the reference case and 3/4 and 4/4 those go up non-linearly so the 3/4 individuals The people that have one copy of 3/1 copy of 4 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 3/3 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 15 years ago the literature was calling that 20 to 25 times higher that number has come down Considerably and I think most most series would talk about that as being an 8 to 12 fold increase So it's you know, it's a full log increase in risk for sure to have Two copies of the E4 gene which means you're making an apoe protein that is far less effective Yes, and this is gonna have ramifications We've done podcasts and Peter's had Dan Raider on here the most important thing about the peripheral HDL's is not the amount of cholesterol they traffic it's kind of trivial and it gets transferred here and there and Almost tells us nothing if you're measuring HDL cholesterol tells us nothing about what the HDL particles remember They're 90% of your lipoproteins out there. So Clearly there are what they're doing a cholesterol is not their major function So that means HDL's do other things and as we're learning they do Inurmable 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 answer 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 HDL's 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 HDL's perform It has to do not with the cholesterol they're carrying but yet the types of proteins They might be carrying well over 200 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 or 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 Armies of HDL's each construct it with one or two of those peptides in addition to APOA1 in APOA2 some of the LIpo lipid related APO proteins and so there's no way to know for us to measure these HDL subpopulations now all of the HDL's 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 flow the HDL's carries the least amount of lipids compared to the APOB particles That's why it sinks in the centrifuge tube But the tiniest HDL's the Squatle HDL's APOA1 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 packing Probably critical proteins. Jeez, 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 brain barrier and get into the brain and it's these extremely small HDL particles either free APOA1 or an APOA1 that's bound to a couple of these other proteins and maybe some of these proteins are very important antioxidative proteins and high inflammatory proteins so if those tiny HDL's that we cannot measure Jump into the blood brain barrier or through it and they're now in the mattress zone Where do they go? They immediately buying to the first APOE containing brain HDL that they bump into so all of a sudden this Astro site APOE Constructed brain HDL particle is also carrying a copier two of APOA1 that actually originated from the plasma the brain scan synthesize APOA1 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 and might be this good old scavenger receptor again Express that the blood brain barrier that facilitates entry of APOA1 or the really small dense HDL APOA1's carrying accessory proteins and the hope is Hey number one if they get in great. So now the brain HDL's you have different plus some population of brain HDL's You might have only APOE containing brain HDL's you might even have some APOA1 brain HDL's but most of them are going to be APOE plus APOA1 brain HDL's and those other proteins that came with the APOA1 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 way to minute if there are functional HDL's in the periphery I'll bet there are circumstances where there are dysfunctional HDL's in the periphery that are not equipped with the proper protein Are they carrying proteins? They shouldn't be carrying proteins that can do harmful things to tissues They would be dysfunctional HDL's 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 can carrying APOA1 But now if you're an APOE4 producer when your astrocyte produces APOE it's going to be an APOE4 type of And that tends just like in the periphery. It's a dysfunctional type of APOE So if you have the APOE4 genotype and your astrocyte is producing APOE4 peptides And there put 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 E3 or an E2 Might to those 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 in the cell membranes If you don't have the proper amount of cell membrane cholesterol This is where something called Amaloid precursor protein sits and if you don't have the right cholesterol balance It's acted upon by certain enzymes called secretases. That's where you start producing beta-amaloid and even towel because you don't have the right amount of cholesterol in your neuron cell membranes. And this is how E4, one of the many reasons why it's associated with Alzheimer's. I'll stop there, perhaps, for you to jump in before I just maybe describe some of the other things that apoe4 brain HDLs don't do that an apoe3 or an apoe2 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 amaloid. So people are obviously familiar with the accumulation of beta-amaloid and p-tow in the brain and people are now really starting to understand that we actually have great biomarkers where 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 amaloid, towel 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 that he terminated its function is its cell membrane integrity. And if you have the proper cell main construction signaling occurs properly, the synapsis 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 amaloid precursor protein. That's a protein that is going to evolve into the production of beta amaloid. So whether it produces two types that add amaloid 40 and 42 with 42 being the more injurious type of amaloid beta and the 40 being a less toxic type of amaloid beta. So when there's too much cholesterol in the cell membrane of a neuron, there's something called beta and gamma secretase. There are enzymes that make the amaloid precursor protein cleave into the production of amaloid 42. 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 amaloid precursor protein into apobene. You wind up producing more of the beta amaloid 40, 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 a cholesterol homeostasis that we might as well introduce now, because too much cholesterol in the cell membranes 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 reserved in cholesterol. But early early, I told you too much cholesterol in any cell is toxic and 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 is given the neurons, the ability to change cholesterol into something called an oxysterol. And the one it produces is called 24-S hydroxycholestero. People who know what cholesterol looks like biochemistry wise, it has one oxygen molecule at the third position of the first ring. 24-S hydroxycholestero not only has that one cholesterol molecule, it has a second one at carbon 24. 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 24-S hydroxycholestero that will make cholesterol change into 24-S hydroxycholestero, which is water soluble. It comes out of the neuron, it floats right through the mattressome to the blood brain barrier where it can pass right through it because it's sort of a hydrophilic lipid with an oxygen hydroxy group on each end. When it hits the blood brain barrier, the fatty acids in the phospholipids hate the hydroxy groups so they separate and it just creates a little tunnel through which the 24-S hydroxycholestero 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 24-S hydroxycholestero either albumin or any brain lipoprotein that floats by. Now it's artificial protein, it's an albumin 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 oxysterol? It's the liver and what is the liver do with oxysterols? Well, the liver has cholesterol, you know, Pete, that the liver is our major, our only manufacturer bile acids which are oxysterols. So cholesterol gets transformed into an oxysterol in the liver, same enzyme that the neurons express and the oxysterols that go through several steps, but they become your bile acids down to your gut, goodbye fecaly. So the brain actually has this cool way of getting rid of excess cholesterol by that transformation, it's ended to the liver where it could be fecaly, excluded or so. So this 24-S hydroxycholesterole 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 24-S hydroxycholesterole, brain is not escaping into the plasma anymore. This is why researchers use 24-S hydroxycholesterole in the plasma as a biomarker of brain health. It shouldn't be there because the brain is retaining all its cholesterol, the neuron's not trying to excrete any cholesterol, but if it does, the concentration of that in the plasma goes up, the liver doesn't secrete its 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 24-S hydroxycholesterole because they think if their drug is helping the brain prevent Alzheimer's disease, you won't find 24-S hydroxycholesterole in the bloodstream. And that's one of the star-oh-b biomarkers as is the desmostral that we elude it. So we actually have two things that we can measure. Here's the bad thing. In the real world, we can get desmostral measurements fairly easily. There's no commercial laboratory that 24-S hydroxycholesterole is 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 disruptive this APOE4 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 they, there is markedly decreased clearance of the E4 brain HDL just when it touches the membrane, the cholesterol can jump into the cell membrane of the neuron, but it doesn't get to the cytosol. So it's very complex these lipid mechanics that are going on in the E4 patient. And I'll let you ask about that before we get into other attributes of what APOE4 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 APOE4 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 benpidoric acid and is at a mhyb and PCSK9 inhibitors or bile acids sequester, C-petin inhibitors or C-tepin inhibitors. 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 statin 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 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 able be in the periphery because that no doubt about it reduces after a scrotic heart disease. But of all and people rattled off the classes of able be 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. It is the statin class. All of those other drugs mentioned either work solely in the liver or no way they could penetrate the blood brain barrier to 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, 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. The border itself has got a lot of lipids in. So they all right come right in. So it's a level 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 haptically the lipophilic statins should get into the brain a little easier than the hydrophilic statins. 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 to 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, a reservist statin, a hydrophilic statin is used more and more commonly. It certainly can get into the brain. Maybe a little less slowly than lipophilic 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? No, it's just the construction of the statins rug on how, you know, what converse a hydrophilic or a lipophilic property to that given statin. You know, if you look at, we put up a slide here showing all the different statins, they're all a little bit different, and there are certain aspects of that construction that gives them hydro philicity 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, all time as disease is too much cholesterol in the brain, too much cholesterol in the neurons, you could hypothesize that if stangs did get into the brain, which they do and all of them do, and in a steady state, they all have the potential to affect cholesterol 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 in tissues. And this is why we're not going to review them here. If you look at all the statins, how's the meta-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 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 stat and I'm not thinking right, my addition isn't as good as it used to be. And we stop the stat and then rather quickly that goes away. So one hypothesis would be that is the person that the statins 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 stat and 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 to prove that or disprove it. But you could also say, old-time disease takes decades to develop. So again, if you're, I give you a stat and you don't get that acute brain fog, it's probably safe to over-suppress cholesterol a little bit over time. And maybe especially so if you're any for or you have a family history putting you at risk for old-time disease. Again, a theory, but it wouldn't be supported by the trials you just said that tend to show you're not much going on or benefit. And that could be the plausible reason. Now we go back to you've went through the desmostral and the thephosphol pathways. There's a nice study published almost a decade ago where they were doing cerebral spinal fluid desmostral levels and plasma desmostral levels and measuring it by mass spec. And there was high correlation between the CSF desmostral and the plasma desmostral saying that wow, desmostral and plasma, it reflects desmostral in the central nervous system. And even more interesting that study showed that the people with low desmostral have the higher incidence of cognitive impairment in Alzheimer's disease. So if and we you've talked about this many times on the podcast too, if we are administering statins to our patients, even the e4 patients, I'm the hope that we are going to help the less in their incidence of Alzheimer's disease, maybe keeping an eye on plasma desmostral sort 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 apobeter reduce heart attacks with the several other drugs that you ran through very quickly there. So so it gets very interesting. And the last thing to tie it into that 24-S hydroxycholestrol. 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 statin the 24-S hydroxycholestrol disappears. That would again be proved 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 desmostral because if that was low, ooh, I've maybe suppressed it a little bit too much. All wonderful hypothesis that has a lot, mylone dad can easily provide 20 references on desmostral in the brain how critical it is. So this is now a very plausible theory right now and don't expect the clinical trial to prove this proved this hypothesis right now. Well, linked to those sources, Tom, in the show notes. One other drug I just want to talk about really quickly is is etymib. Again, etymib is a you know a drug that really works outside the body so to speak right. It works in the gut. It's a blocks that Neman Pixie one like one transporter and in people who are not hyperabsorbers, 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? It's kind of amazing. Like you said, who would ever even hypothesize that this drug that acts in the intestine might have beneficial effects in the brain or so? And I think we have a couple of neurologic colleagues, Richard Isaacson and Kelly and the Otis who are very involved with these diseases. And is there any total belief that is that a mime, an addition to helping them control their apobetan, their patients? There is seems to be some cognitive benefit in the people they deal with or so. So now there's so actual plausible reason. Now Zedomybe is one of those drugs that just cannot cross the blood brain barrier. So how an oral could it be helping dementia or so? But it has a metabolite called Zedomybe glucoronide that actually can pass through the blood brain barrier in small amounts, but unlike a Zedomybe gets in. And there are animal studies showing that it interferes with hexokinase and glycosolation 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 that 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, as we control APOB aggressively in your patients, we use a lot of Zedomybe because we prefer to use low dose statins. And if we don't get to the APOB goal, we're adding a Zedomybe. We also, day one, check synthesis and absorption. So there are patients where we use Zedomybe day one because they're hyperabsorbers and that's where you get the most efficacious APOB lowering. So in the future, as we have people who carry the APOE4 alleles and they have APOB issues, we might pick a statin first, we might pick a Zedomybe, but I think they might be a patient where you need a little bit of a statin and a little bit of a Zedomybe and tell somebody proves this. And I would not hold your breath waiting for a randomized control trial that is Zedomybe what it's doing to even some of the Alzheimer's biomarkers in the blood because only emerging drugs are they starting to do those type of studies on that nobody's going to go back and look what is Zedomybe does to peak calorie, amyloid ratios or so. I wish somebody should, you know, maybe a small spud, buddy. Well, I'm surprised you could probably pull it out of a bio bank for an existing study that was already done on Zedomybe. 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 Zedomybe trials. We also have a monotherapy Zedyotrial. Only in Japanese elderly people and I don't think cognition was one of the things. And it was not a blinded trial so as an openly trial. Open label trial, yeah. Just the show it was efficacious and lowering APOB in a primary prevention setting. But it certainly didn't look a cognition or biomarkers and that stuff. But if they still have serum banked, you could at least look at pre and post levels of P towel. You definitely could. Yeah, maybe 4240. A great research project for some young PhD or a buddy lipidologist. 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 they, 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? Without 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-3 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-3s to it. Their package unit as a triglyceride, typically one of the fatty acids on a synthesized triglyceride would be in omega-3. And there is a product that delivers omega-3s as a phospholipid from krill 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, light paces, 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 micelles, gets absorbed by a fatty acid absorbed by CD36. Interestingly, not only can a free fatty acid be absorbed, but a lysophospholipid can be absorbed. A phospholipid has a phosphorous moiety and a head group and two fatty acids attached to it. That's called a dioratal 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 molecule. They're easily absorbed. So in the light paces, either makes free fatty acids or could make lysophospholipids. But hey, if the remaining fatty acid on that lysophospholipid is an omega-3, it gets in. So once they're in the enterocyte, what happens to them? The enterocyte immediately re-synthesizes them to a full phospholipid or attaches them to a triglyceride molecule, which goes in the core of the chylamycron. The phospholipid goes on the surface of the chylamycron. 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. Uh-huh. Now phospholipids are a lipid. They can't circulate in the bloodstream. They immediately bind to something called the phospholipid transfer protein. And the phospholipid transfer protein will bind to either a full phospholipid or a lysophospholipid. And it's that little delivery truck of an omega-3, phospholipid transfer protein, which goes up but into the blood brain barrier. And there's a specific receptor in the blood brain barrier that will internalize the lysophospholipid 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 to or it can jump right into the cytosol or the first cell that it bumps into while it's in the mattress. So that's the journey. So look, it almost doesn't matter the vehicle you're ingesting an omega-3 whip. We would prefer that you've established that a supplement is actually has the amount of omega-3s. 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. It shows perhaps for preventing, for lessening residual risk in people who have APOB control. The EPA is a little bit more important. And the DHA plus EPA, there's a trial where that didn't work as well as the EPA. But once they get into the brain, the brain has its omega-3 fatty acid. 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 everybody can. And that's how they get up into the brain. And they're obviously, since they're 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 omega-3s 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? Like in the hierarchy of things that we really know are as close to capital T true as possible when it comes to brain health, which is lipid homeostasis, good blood pressure, sleep, exercise. I mean, things that just demonstrably matter when it comes to brain health. And where in that pantheon would you sort of put having a serum or EPA DHA level in the RBC membrane of 10% versus 6%. What's your level of confidence? Well, the data is long going to come from observational trials for the most part. So in those trials, there are ones that specifically looked at certain brain functions and correlated omega-3 index with the observational outcomes related to neurological issues. And they seem to be positive. And that could be a mission we tell you Tom. Don't even talk to me. There's no level one randomized blinded control 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-3s in the brain, you would find it. So Harris has studies relating it to brain size, or at least certain sections of the brain size in omega-3 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-3 index are certainly associated with sudden death and increase atherosclerotic heart disease. Again, we lack the randomized control trials that changing that will reduce events other than that one trial of EPA and insulin resistant high risk people who had able to be 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 gonna tell you this is what you have to do. But again, it's just like our Dismostral Hypothesis. This is a plausibility there. I see little downside to using omega-3s. Bill Harris, who you've interviewed, has looked at his trials and he's pretty content that when you hit the eight, the 9% omega-3 index, you pretty much have the proper amount of omega-3s in the scenario cell membranes of your body. There is no study you can allude to that, hey, therefore, so it's so important to brain. Let's make it 10% 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 wanna 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 have spoken about these drugs in the past on a podcast. We've got several podcasts on this topic, including most recently one with John Kasterlin, probably got 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, Obesetra Pib and the Broadway trial specifically and how we tie it into what we've talked about today. - Yes, basically, CTEP inhibitors of which Obesetra Pib is the latest have been investigated to see what they do to afterscrotic heart disease and LP little A and maybe brain functioners. There's a signal that if you have CEP loss of function, genetically, those people have less Alzheimer's disease or cognitive impairment. So that makes it plausible. Well, if we inhibited CEP 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 Farmer recognize this. So they're actually putting a little money into clinical trials, perhaps investigating this hypothesis. And in that Broadway trial where you administered Obesetra Pib, remember, was given to them primarily to reduce able being ultimately reduced mace in those people. But they actually looked at some of the biomarkers of Alzheimer's disease, the phosphorylated p-towl, the amyloid 4042 ratio, the other various ratio of these markers, the ambulatory 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 Obesetra Pib 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 APOA1 on them, which can break off, so you generate some APOA1 in the plasma. But when the HDLs are big on a CETB inhibitor, the liver senses, we have a deficiency of APOA1, because they're not seeing it, it's all on the HDL particles. So the liver actually starts overproducing APOA1. So APOA1 goes up in the plasma. But once APOA1 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 Obesetra Pib is increasing either APOA1 or the really tiny protein-ladying 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 APOA1 can jump on an E4 APO, a brain APOE HDL particle and rescue it, and maybe turn dysfunctional brain HDL particles into functional brain particles. So, boy, 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 Obesetra Pib. Yay, for a tapal B 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 E4 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 will 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, E4 carriers, and catch them right at that window. You know, I was going 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 10 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 the study would fail. I really did. I was like, you're not going to do a dietary 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 it's just a great example of if you pick the right population, as 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 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 oligodendrous dites and neurons and the different pathways and apoe versus apoe? 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 thank you. And as always, Tom, it's been, gosh, it's been 15 years since you took me under your wing and helped me develop my understanding of this field of lipidology. So I can never waste an opportunity to thank you publicly for your generosity, 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. As I, 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 to the bud, 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 way 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 keep 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.com/shownotes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter, all with the handle peteratiamd.com. You can also leave us a review on Apple podcasts or whatever podcasts you want to make. and cast player you use. This podcast is for general informational purposes only, and does not constitute the practice of medicine, nursing, or other professional health care services, including the giving of medical advice. 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