#395 - Brain lipidology: understanding APOE, cholesterol homeostasis, Alzheimer's disease risk, and the effects of lipid-lowering therapies on brain health | Tom Dayspring, M.D.

28:35Because 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. But important thing to make is don't ever think because your LDL cholesterol is 200 that I'm one of them because there's no way to know that. Why play Russian roulette 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.

29:23Does the brain need to rely on any of the periphery's 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 talked.

30:09But I 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 novo synthesize 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 or so.

30:48So every brain cell starts producing cholesterol in utero. Very quickly, brain cells, it's very easy. You have neurons, the ones I allude, 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 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.

31:35It's in myelin. The other glial cell in the brain is a microgliocyte and they are the brain immune cells. So they are the last remaining cell. So in the 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 i as it grows and grows it's going to need more and more cholesterol for all these 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 measure their LDL cholesterol, it might be 30 milligrams per deciliter.

32:27Yet 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 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 10, really 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.

33:11They always will. Microgliocytes, 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 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've, in our earlier podcast, discussed the very complex cholesterol synthesis pathways. It's actually 37 steps. Every step is a different enzyme. Every step requires ATP. So any cell to synthesize one molecule of cholesterol consumes over 30 molecules of ATP.

33:58The 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. 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 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.

34:41Because in the blood, as we've enumerated, lipids 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 this connective tissue and there are zillions 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 and the neurons over there saying, hey, I need that, send it to me.

35:21We 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 last sterol, penultimate sterol, and in the astrocytes, it's called desmostrol. And then desmostrol becomes cholesterol. So we'll probably talk about, this is one way why we can measure desmostrol in the cerebral spinal fluid.

36:06Nah, 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 we can 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 apolipoprotein E. And ApoE, many people know, oh, 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.

36:50But let's just stick to the ApoE protein. So the astrocyte synthesizes, it binds the cholesterol, and it becomes a little lipoprotein, which it secretes into the matrosome. But it's an ApoE-containing lipoprotein. Now, if we could take out those ApoE-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 APOA1.

37:38The brain HDL will have a couple of three copies of ApoE, 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, the neurons have LDL receptors, so there have to be LDLs in the brain.

38:23No, because the LDL receptor has affinities for just a couple of apoproteins. In the periphery, the LDL receptor is looking for ApoB100. But in the periphery, even ApoE can bind to an LDL 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 darn receptor. And this is why I think we should stop calling it the LDL receptor. We should call it the ApoB-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.

39:09So 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 confirmationally 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 X certain amino acids that line up and they create, They have a surface charge.

39:58And here's the LDL receptor. Now, the LDL receptor has a certain segment that is called the APOB recognition domain. There are 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's not where it should be, the LDL receptors don't as easily recognize big LDLs or small LDLs.

40:48And 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 ApoB that if they align properly, you have great clearance. New 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 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 resonance times of LDLs.

41:33How is the APOB conformed? 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 lipoprotein 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.

42:31Yeah. 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 APOB, which is one copy per particle. So when they are fully full of triglycerides, they're very big. The APOB is distorted in a certain way. Now, the receptor in the liver that's going to clear VLDLs and chylomicrons 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 chylos and the VLDLs. And that's why they have such short plasma residence time.

43:17I'm going to mention it now. Oh, 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 - And the 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 they express a lot of the LDL receptor related protein one, which is an APOE affinity clear. So yes, the LDL receptor can clear some of the APOE part, but it's the LRP that's doing most of it.

44:03The 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 ApoA1. 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.

44:49Although 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 desmostrol into cholesterol. And then the other one, of course, turns lithosterol into cholesterol.

45:29What 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 lithosterol pathway. Very little goes through the desmostral pathway. In fact, the primary cells that use the desmostral pathway in the periphery are our steroidogenic tissues. All of our other cells, I mean, a little bit will go through the desmostral pathway, but most is lithosterol. So if you are measuring sterols in the blood, lithosterol 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 10, all of the cells are producing cholesterol, including the neurons, the neuron synthesis pathway actually does go through lithosterol.

46:16But at the age of 10, when the neuron decides I don't want to make cholesterol anymore, there's no lithosterol being produced by the neurons. It's all desmostrol that's winding up. If there's cholesterol molecules winding up in the neurons, it's through the astrocyte, the block pathway going through desmostrol. 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, 95 % of it is your other cells making it.

47:03Whereas 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 desmostrol you measure in the blood tell us anything about the cholesterol synthesis of the I think, and you're 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.

47:50The brain, which only makes its own cholesterol in stores and in the steroidogenic 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 oligodendrocytes and presumably to some extent astrocytes.

48:43I 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 apolipoprotein 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, A-P-O-E, you'd be referring to the genotype.

49:24And of course, you have two of these. So you could be a 3-3 or 3-4-4-4-2-3, et cetera. 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. 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 and shape, and that will affect what it can bind to, which is the crucial function of apoproteins.

50:15So 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 Eugene and the other allele from each. So was your mom an APO E2, three or four? And likewise with dad, and you're going to inherit, there's several potentials. You can be an E2, E2, E2, E3, E3, E4, E3, E2, E2, E4, E4, or E double 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.

51:05And 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 ApoE you manufacture is critical to certain disease pathologies. Peter can give you the exact indices. The average person has an ApoE3, E3 genotype. I believe it's about two-thirds of people that have that. Far less people carry the ApoE2 gene, and especially ApoE2 homozygosity. Peter, why don't you tell how many carry the E4 heterozygotes and the E4 homozygotes? You have those percentages. Yeah. I mean, again, it depends on the series you look at, but it seems about 55 % of the population are E3, E3, the so-called wild type.

51:5220 % 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 two to 3%. 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, one copy of 4, they make a version of ApoE, the protein that's not as good as the wild type.

52:43And 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 4, 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 series would talk about that as being an eight to 12 fold increase. So 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.

53:22Yes. 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, it tells us nothing about what the HDL particles, remember they're 90 % 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.

54:03They'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 200 proteins have been described in the periphery as being found on HDL particles.

54:48Now 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 armies of HDLs, each constructed with one or two of those peptides, in addition to APOA1 and APOA2, some of the lipid-related apoproteins. 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.

55:37So 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. Now, HDLs carries the least amount of lipids compared to the ApoB particles. That's why it sinks in the centrifuge tube. But the tiniest HDLs, the discoidal HDLs, 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, geez, don't you wish we could measure them?

56:21But here's where it gets interesting. We've hinted earlier in this podcast if 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, 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 matrosome, where do they go? They immediately bind to the first ApoE-containing brain HDL that they bump into.

57:06So all of a sudden, this astrocyte ApoE-constructed brain HDL particle is also carrying a copy or two of ApoA1 that actually originated from the plasma. The brains can't 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, expressed at the blood-brain barrier that facilitates entry of APOA1 or the really small, dense HDL, APOA1s 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.

57:52You might have only APOE containing brain HDLs. You might even have some APOA1 brain HDLs, but most of them are going to be APOE plus APOA1 brain HDLs. 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, 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.

58:38They 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 contrarian 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 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 E3 or an E2 might to those receptors, and therefore you have disrupted cholesterol transport into the neuron.

59:36Now, 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 amyloid precursor protein sits. And if you don't have the right cholesterol balance, it's acted upon by a 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 neuron cell membranes. And this is how E4, one of the many reasons why it's associated with Alzheimer's.

1:00:17I'll stop there perhaps for you to jump in before Or 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 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 where we can start to track those things.

1:00:58Is 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.

1:01:32So remember, the neuron, the main thing determined in 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 amyloid 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 that add amyloid, 40 and 42, with 42 being the more injurious type of amyloid beta and the 40 being a less toxic type of amyloid beta.

1:02:26So 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 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 amyloid precursor protein into apobine. You wind up producing more of the beta amyloid 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 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.

1:03:27The 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.

1:04:06So evolution has given the neurons the ability to change cholesterol into something called an oxysterol. And the one it produces is called 24S hydroxycholesterol. People who know what cholesterol looks like biochemistry wise, it has one oxygen molecule at the third position of the first ring. 24S hydroxycholesterol 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 got to get rid of cholesterol, it has an enzyme, 24S hydroxycholesterolase, that will make cholesterol change into 24S hydroxycholesterol, which is water soluble.

1:05:01It comes out of the neuron. It floats right through the matrosome 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 and the phospholipids hate the hydroxy group. So they separate and it's just creates a little tunnel through which the 24S hydroxycholesterol 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 24S hydroxycholesterol, either albumin or any brain lipoprotein that floats by.

1:05:43Now it's part of a 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 does the liver do with oxysterols? Well, the liver has cholesterol. You know, Pete, that the liver is our major, our only manufacturer of 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 steps, but they become your bile acids down to your gut.

1:06:24Goodbye, fecally. So the brain actually has this cool way of getting rid of excess cholesterol by that transformation and send it to the liver where it could be fecally excluded or so. So this 24S 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 24-S hydroxycholesterol. Brain is not escaping into the plasma anymore. This is why researchers use 24S hydroxycholesterol in the plasma as a biomarker of brain health.

1:07:13It 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 24S hydroxycholesterol because they think if their drug is helping the brain prevent Alzheimer's disease, you won't find 24S hydroxycholesterol in the bloodstream.

1:07:53And that's one of the sterol biomarkers, as is the desmostrol 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 desmostrol measurements fairly easily. There's no commercial laboratory that 24-S hydroxycholesterol 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 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.

1:08:43But since there is markedly decreased clearance of the E4 brain HDL, just when it touches is 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.

1:09:27Obviously, 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 benpedoic acid and azetamide and PCSK9 inhibitors or bile acid sequesterants or CPET inhibitors or CTEP 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.

1:10:15So 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 APOB in the periphery because that, no doubt about it, reduces atheroscronic heart disease. But of all, Peter rattled off the classes of ApoB-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, and it is the statin class.

1:10:53All of those other drugs mentioned either 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. 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, All right, come right in. So it's a little for the hydrophilic statins to penetrate a barrier.

1:11:41Pretty much 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 tactically, the lipophilic statin 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, therefore, to various degrees inhibit cholesterol synthesis in the brain.

1:12:28So 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, resuvastatin, a hydrophilic statin is used more commonly, it certainly can get into the brain, maybe a little less slowly than lipophilic statin can, 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 statin drug on how, you know, what converts a hydrophilic or a lipophilic property to that given statin.

1:13:16You 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 hydrophilicity and other aspects of that alignment or construction of their molecules gives them the lipophobicity. So anyway, since 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 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 and tissues.

1:14:09And this is why, and we're not going to review them here, if you look at all the statin trials, 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. Well, 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.

1:14:54And 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 counterintuitive, 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?

1:15:34Yes. 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. 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 the statin is over suppressing cholesterol synthesis rather rapidly and severely.

1:16:25And that's why they got neurologic symptoms and they stop it. Obviously you've stopped the statin. 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 Alzheimer's disease takes decades to develop. So again, if I give you a statin 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 an E4 or you have a family history putting you at risk for Alzheimer's disease.

1:17:07Again, a theory, but it would 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 desmostrol and the thosterol pathways. There's a nice study published almost a decade ago where they were doing cerebral spinal fluid desmostrol levels and plasma desmostrol levels and measuring it by mass spec. And there was high correlation between the CSF desmostrol and the plasma desmostrol saying that, wow, desmostrol in the plasma, it reflects desmostrol in the central nervous system.

1:17:51And even more interesting, that study showed that the people with low desmostrol have the higher incidence of cognitive impairment in 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 E4 patients, I'm a hope that we are going to help the lessen their incidence of Alzheimer's disease. Maybe keeping an eye on plasma desmostrol sort of makes sense. And if you do oversuppress 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 ApoB to reduce heart attacks with the several other drugs that you ran through very quickly there.

1:18:36So it gets very interesting. And last thing to tie it into that 24-S-hydroxycholesterol. Remember, if you're on the way to Alzheimer's disease, that's increased in the plasma. There are studies showing that if you prescribe a statin, the 24-S-hydroxycholesterol 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 desmostrol, because if that was low, ooh, I've maybe suppressed it a little bit too much. All wonderful hypothesis.

1:19:12It has a lot of data. I can easily provide 20 references on desmostrol 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 ezetimibe. Again, ezetimibe is a drug that really works outside the body, so to speak, right? It works in the gut. It's a block that Neiman picks C1-like-one transporter. And in people who are not hyper absorbers, it's not even a particularly effective drug.

1:19:50Yet 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, that this drug that acts in the intestine might have beneficial effects in the brain or so? And I think, you know, we 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 azetimibe, in addition to helping them control their APL-B in their patients, there seems to be some cognitive benefit in the people they deal with or so.

1:20:31So now there's some actual plausible reason. Now, azetimibe 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 azetamide glucuronide that actually can pass through the blood-brain barrier in small amounts, but unlike azetamide, it gets in. And there are animal studies showing that it interferes with hexokinase and the glycosylation 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.

1:21:15And 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 ezetimibe because we prefer to use low-dose statins. And if we don't get to the ApoB goal, we're adding ezetimibe. We also, day one, check synthesis and absorption. So there are patients where we use ezetimibe 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 APO-B issues, we might pick a statin first.

1:22:01We might pick azetimibe, but I think they might be a patient where you need a little bit of a statin and a little bit of ezetimibe until somebody proves this. And I would not hold your breath waiting for a randomized control trial that ezetimibe, 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 ezetimibe does, the P-Tower, the amyloid ratios or so. I wish somebody should. You'd only need maybe a small study. Well, I'm surprised you could probably pull it out of a biobank for an existing study that was already done on ezetimibe.

1:22:37So 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 ezetimibe trials. Don't we also have a monotherapy CETIA trial? only in Japanese elderly people. And I don't think cognition was one of the things. And it was not a blinded trial, so it was an open-label trial. Just to show it was efficacious in lowering APOB 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 P-TAL.

1:23:15You definitely could. Yeah, AB4240. Be a great research project for some young PhD or a budding 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 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?

1:23:54Without 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 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 us. They're packaged in it as a triglyceride. Typically, one of the fatty acids on a synthesized triglyceride would be an omega-3. And there is a product that delivers omega-3s as a phospholipid from krill oil.

1:24:37So 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 and the biliary micelles, gets absorbed by a fatty acid absorber, CD36. Interestingly, not only can a free fatty acid be absorbed, but a lysophospholipid can be absorbed. A phospholipid has a phosphorus moiety in a head group and two fatty acids attached to it. That's called the diuretol phospholipid, two fatty acids.

1:25:24But if I took one fatty acid off of a phospholipid, it's called a lysophospholipid. It's actually a smaller molecule and they're easily absorbed. So the lipases either make three fatty acids or it 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 resynthesizes them to a full phospholipid or attaches them to a triglyceride molecule, which goes in the core of the chylomicron. The phospholipid goes on the surface of the chylomicron. It shoots them into the lymphatics and they rapidly get into the plasma.

1:26:06They undergo rapid hydrolysis at the muscles and fat cells by lipases. 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 a 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, butts 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.

1:26:50and 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 of the first cell that it bumps into while it's in the matrosome. So that's the journey. So look, it almost doesn't matter the vehicle you're ingesting an omega-3 with. 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 that shows perhaps for preventing or lessening residual risk in people who have ApoB controlled.

1:27:36The EPA 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 once they get into the brain, the brain has its omega-3 fatty acids. And used to be all DHA, but I know the thought on that is changing. EPA is required there too. Some people can convert EPA to DHA, but not everybody 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 omega-3s go? In the cell membranes. And that's everything, cell membrane health in the brain cells.

1:28:21And I guess, where do you stack this in terms of evidence, right? 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, things that just demonstrably matter when it comes to brain health. Where in that pantheon would you 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 all going to come from observational trials for the most part. And 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.

1:29:22An 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 threes 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-3 context, 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.

1:29:57We certainly have evidence in the blood that low levels of omega-3 index are certainly associated with sudden death and increased 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 APL-B 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 dysmoscral hypothesis. This is a plausibility there.

1:30:35I 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 8, the 9 % omega-3 index, you pretty much have the proper amount of omega-3s in the scenario. you sell 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 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 want to close with something that you and I are very excited about.

1:31:16I 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, 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, Obisetrapib and the Broadway trial specifically, and how we tie it into what we've talked about today. Yes.

1:31:54Basically, CETP inhibitors of which Obisetrapib is the latest have been investigated to see what they do to atherosclerotic 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 recognize this. So they're actually putting a little money into clinical trials, perhaps investigating this hypothesis.

1:32:40And in that Broadway trial where you administered Obisetriprin, And remember, 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 P-tau, the amyloid 40-42 ratio, the other various ratio of these markers, the fibrillatory 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.

1:33:22You would monitor it over time, but maybe you'd throw in some cognitive function in some of the studies to see, geez, could Obisetrapib 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 CETP inhibitor, the liver senses, oh, 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.

1:34:08So 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 obisetrapid is increasing either APOA1 or the really tiny protein-laden 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, anti-oxidative aspects of those proteins. And they believe the APOA1 can jump on an E4, a brain APOE HDL particle and rescue it and maybe turn dysfunctional brain HDL particles into functional brain particles.

1:35:00So, 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 obesity or PIB. Yay for its APOB ability. We're all going to certainly be using for that.

1:35:37That'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.

1:36:16you'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 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 predimed 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.

1:36:52Come 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 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.

1:37:29So 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 oligodendrostites and neurons and the different pathways and ApoE versus ApoB?

1:38:04So 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.

1:38:54So you've taught me just as much about so many things. 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 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.

1:39:35So 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 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 AtiyahMD. You can also leave us a review on Apple Podcasts or whatever podcast. 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.

1:40:14The use of this information and the materials linked to this podcast is 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 advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peteratiamd.com forward slash about where I keep an up-to-date and active list of all disclosures.