The Peter Attia Drive - #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.

Episode Date: June 8, 2026

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter Tom Dayspring is a world-renowned lipidologist and one of the most thoughtful teachers in the field of lipid metabolism. In this episode, Tom returns to The Drive for a deep dive into the relationship between lipids and brain health, beginning with the fundamentals of cholesterol transport before exploring why the brain's cholesterol system operates almost entirely independently from the rest of the body. Tom examines the roles of apoB, apoA-I, and especially apoE in cholesterol homeostasis, discusses how APOE genotype influences Alzheimer's disease risk, and unpacks the complex links between cholesterol metabolism, amyloid, and tau pathology. He also reviews what is currently known—and still uncertain—about the effects of statins, ezetimibe, omega-3 fatty acids, and emerging CETP inhibitors on brain health and neurodegenerative disease risk. Although highly technical, this conversation provides an essential framework for understanding the nuanced relationship between lipid-lowering therapies, cardiovascular disease prevention, and neurodegenerative diseases in an area often clouded by misinformation. We discuss: The fundamentals of cholesterol transport in the body, and how peripheral cholesterol metabolism differs from cholesterol handling in the brain [2:45]; How cholesterol is transported through plasma and stored within cells, and why lowering LDL cholesterol does not deplete the body or brain of cholesterol [11:45]; How apoB particles drive atherosclerosis, why lowering lipids matters, and the factors that influence individual cardiovascular risk [20:00]; How the brain produces and transports its own cholesterol using apoE lipoproteins independently of circulating cholesterol and apoB-containing lipoproteins [29:00]; How apoB structure influences LDL receptor binding and LDL clearance [39:00]; How neurons acquire cholesterol from apoE-containing lipoproteins and why desmosterol serves as a unique marker of cholesterol synthesis in the brain [41:45]; The difference between the APOE gene and the apoE protein, the major APOE genotypes found in humans, and how APOE4 influences Alzheimer's disease risk [48:45]; HDL function beyond cholesterol: immune function, protein cargo, and communication with the brain [53:30]; How APOE4-associated defects in brain cholesterol transport may promote Alzheimer's disease: amyloid production, neuronal cholesterol homeostasis, and cholesterol clearance [58:00]; Statins and brain health: reviewing the evidence of the potential impact of statins on cognition and Alzheimer's disease risk [1:09:00]; Desmosterol and 24S-hydroxycholesterol as biomarkers of brain cholesterol metabolism and statin effects [1:17:15]; Possible cognitive benefits of ezetimibe beyond lowering apoB [1:19:30]; EPA, DHA, and the evidence for omega-3 fatty acids in brain health [1:23:15]; Obicetrapib: an emerging CETP inhibitor with potential implications for both cardiovascular and brain health [1:31:00]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive podcast. I'm your host, Peter Attia. 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 peteratia-md.com forward slash subscribe. My guest this week is Dr. Tom Dayspring, 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, you know, 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, and APO A1, and specifically APOE as it pertains to cholesterol. So we talk about how the APOE genotype relates to Alzheimer's disease risk, which is something we preferred to a lot. But then the link between APOE, cholesterol, homoeoeoeoeoeia,

amelostasis, amyloid, and tau. What we know and what we don't know about the effects of statins, Zetamide, 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, Dr. Tom, Dayspring.

Hey, Tom. Great to be with you again, as always. For sure, Peter. This has become a bit of a routine for us. We've done it. But I love the way we interact on this topic. Today we're going to talk about some different things, we're going to really focus on a topic that's really become an enormous passion of yours, and your curiosity drives so much of your learning, and then by extension, our learning in the practice. So I want to kind of go on a journey with you into this idea of cholesterol in the brain. It's obviously a very important topic for reasons that we'll get into. But I think before we do, it is worth making sure that everybody's starting from the same sort of knowledge

bass or singing from the same sheet of music, as some might say, as it pertains to lipids. So I know that you and I have discussed this in great detail elsewhere, and I realize that not everyone will have seen that. And even if they have, they might not recall. So let's start at the very beginning in a very short sort of five minute version. Let's talk through the idea of cells in the body making cholesterol and how they have to move that cholesterol around the body in the periphery, just the sort of the nuts and bolts of it. Yeah, as you've stated many times, cholesterol is essential for human life because it's used for making some critical things, but its most important function is it positions itself in the cell membranes in every cell in our body.

And cell membranes regulate the integrity, what gets in, what gets out of cell. So evolution is given every cell in the body the power to de novo synthesized cholesterol a little bit. Now, each cell needs, you know, a minor number of molecules or so. But if it does that, we got great cell membranes, and those cells are functioning happily or so. But we also know, and people sometimes don't understand this, like so many things, in excess of anything, can be harmful. So if any cell somehow has oversynthesized cholesterol, accumulated cholesterol, and has excess molecules, cholesterol has the ability to crystallize, which is toxic.

to a cell. It will kill the cell. So evolution 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 enwrapped 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 e-fluxes cholesterol out, it joins on a protein. The protein happens to be 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 what ever cell in the body is e-fluxing 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 the small intestine, and they belong to the APOB family of lipoproteins. And the difference between them and HGLs is their structural protein is this very large peptide called APA lipoprotein B. The intestine makes a full-size apobie, the intestine makes a truncated one, we call the, excuse me, the hepatic apobb 100, and the intestinal produced one because it has 48% of the molecular weight of 100 is APOB 48. So when the intestine makes a chylomicron to which traffics absorbed fatty acids, which become

triglycerides absorbed cholesterol into the bloodstream, it's in an APOB48 particle, a very transient post-pranial particle. The liver manufactures 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 to muscles and fat cells primarily and then returns to the liver. Some of the VLDLs is they lose the triglycerides, they shrink and they become something called either a VLDL remnant, a very transient particle called an intermediate density lipoprotein,

which rapidly becomes an low-density lipoprotein or LDL. But the liver also has the ability to de novo manufacture and secrete LDLs also. So our LDLs that are floating around have two sources. They're sort of like the sun of VLDL or they're, hey, a liver-produced one. Now, the APOB particles carry a lot of lipid, triglycerides primarily in the VLDL. The LDL is very interesting. It's pretty much a cholesterol carrying particle, X amount of triglycerides. glycerides. 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 once 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 traffics far more lipids because of their size. You know the volume of spear is a third power of the radius. So a couple of nanometer increase in diameter, boy, a lot more lipids can be

carried. But after the HDL has sucked out all of the cholesterol from whoever 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 cortisone or gonadal hormones. It can bring it to the adipocytes, the cholesterol storage organ, or of course it can return it to the liver. And even now the small intestine. But a lot of what an HDL does is it transfers its cholesterol mass into the APOB particles, the majority of which are LDLs because of its long plasma residence time. So if an HDL, we've always been taught, they do reverse cholesterol transport. And they can, they can bring it back to the liver of the gut. But interesting, if they send their cholesterol

to an LDL, the HDL becomes very small and it starts its journey all over again. And then the 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 direct where the HDL will bring it back. Total RCT is the sum of both. Most people are not aware that the primary function, why we have LDLs is return cholesterol to the liver. Everybody thinks it's delivering cholesterol to cells almost never, because every cell can make all the cholesterol it needs. Now, in an emergency, any cell can upregulate an LDL receptor and pull in the NLDL if it needs,

but just doesn't happen for the most part. And this is one reason, and we're going to talk about it because it's pertinent to the brain. If LDLs are bringing cholesterol back to the liver, if we can induce that with some of the drugs that we have that make LDL receptors express and stay expressed longer, we will drop LDL cholesterol levels in the plasma extremely low. And as we get deeper into the brain, you know, unfortunately a prevalent belief out there in the real world is I don't ever want to lower LDL cholesterol too much because I'll deprive the brain and I'll injure the brain. And soon we'll talk about why that is not true. So that is what you said. This is the

peripheral way that our body handles cholesterol. By peripheral, anytime we say peripheral, we mean anything that's not in the brain. So the brain lipid and lipoprotein system that we're going to talk about has almost nothing to do with the plasma, a transportation of lipids and lipoproteins. And that is such a crucial concept that must be understood. So what didn't I explain, Peter? I hope I've touched on that in a rapid fashion. Yep. Let me just maybe synthesize some of those points. So first off, maybe just even adding a little bit more context, the body does shuttle a lot of things around plasma.

Plasma is kind of the highway of the body, or at least the major highway of the body. Obviously, there's the lymphatic system. But, and plasma is, as you said, it's water. It has proteins in it, like hemoglobin and things like that within red blood cells, but it's essentially water. And therefore, things that are water soluble can transport easily. So glucose doesn't need a transporter.

We just have glucose floating around our bloodstream. 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 bind and 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 APOA family, the APOB family.

We always want to make sure people know that when we're talking about the APOA family, it has nothing to do with LPLLA. That'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 APOBs in absolute numbers, but because they're so much smaller, the total cholesterol carrying capacity is much greater in the APOB 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 deciliter,

you'll easily notice that the sum of your LDL and VLD cholesterol, it could easily be 140 of that 200 milligrams per deciliter, 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 at all is untrue. the LDLs do more by volume. I guess one question I would have for follow-up is for the person who says, but Tom, I 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, And if you really even look at your total cholesterol, it's going to go down too. So LDL's function is to bring cholesterol back to the liver. So if your LDL cholesterol is there's just not in need to get cholesterol back to the liver. The cells are not effluxing as much cholesterol because they're in cholesterol balance. The HDLs are transferring less cholesterol to the LDLs. And so the system is in, it's a very operational system. them 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 deciliter, I could calculate how much

cholesterol is in their blood because I know what they're 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 your liver, every organ you got, your skin. skin, membrane, in every cell in our body. So that's the mass of total cholesterol. And the brain has its own component because they don't interact. But in the plasma, it's interesting. Most of the, of course, you would think all of the circulating plasmas 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 they're of 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 ask the average person or even physician, even lipidologists, where's most of the cholesterol in the body or what organ has the most cholesterol and everybody says the liver and wrong? It's not even close. The brain of all the organs in the body has 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 onto cholesterol, like the bank holds onto its gold in the vault and everything. It does it. But whereas cholesterol, the liver is just sort of a handling station. Whatever cholesterol a liver has, it's senile or it's effluxed into the bio through bile

are 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. And this is another physiological point. We'll have to get into it. Yeah. The liver is more like, 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, 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 deciliter, it's, it's, you know, tempting to think, oh my gosh, my total body cholesterol has fallen by half. In reality, it's fallen by a couple of percent because it's a tiny, tiny. Between cellular cholesterol and circulating cholesterol. Yeah. So this is definitely one of the misconceptions people deal with. And again, although we're not going to focus on it, we'd be remiss to be sitting at this point in the game and not mention why one might want to have a total plasma cholesterol of 100

milligrams per deciliter as opposed to 200 cholesterol. 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 bodies pool have such an outsize 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, hey, the industrialized countries, it's all over. People are dying of heart attacks for variety of reasons. And I always like to say, if you have atherosclerosis, there's one sine qua non. You have cholesterol buildup 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, all right, Tom, well, how in the world does cholesterol get into that artery wall?

It's not like the artery is oversynthesizing cholesterol and building it up. That is not happening. So that means we've already described the cholesterol is floating in our highways in the plasma. So how does cholesterol get from the dump trucks? the lipoproteins that are carrying it into the artery wall. And this is why one of the reasons we talked about the APOB containing lipoproteins. By the way, henceforth, we may refer to beta lipoproteins. That's the APOB family.

The HDL family, 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 Ferrin slide, where every single trial it'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 lipoprote, an LDL or a VLDL, and because of its resin, time, the vast majority of those are LDLs, exceed a certain threshold number, they will enter the artery wall. It's a simple diffusion process. You could have endothelia dysfunction and they get pulled in. They get in a little easier, but they get in, even in healthy artery walls, once you exceed a certain concentration of APOB particles. So, and once they enter the artery wall, and this would be another whole podcast, all sorts of

things. They get trapped. they get aggregated, they get oxidized, and the immune system sends in white blood cells that engulfs them, and that creates a cholesterol-laden macrophage, the foam cells, they stick together creating plaque. So it's the particle number, and we can, there are assays that we can get LDO particle numbers or VLDO particle numbers if you want them, but since there is one APOB on every one of those particles, we simply measure APOB. One-A-B. One-A-B. One-A-B. One-A-B. One-E-L-A-B. APOB per particle. Once your APOB level starts to exceed certain thresholds, aphrosis is very likely

to occur. The main driver of your APOB concentration is two things. Of course, a little bit of production out of the liver. But most of the escalation becomes is due to defective clearance of the APOB particles from the plasma, meaning those LDL receptors, the liver for whatever reason is not expressing enough of them to clear to keep the APOB concentration physiologic in the bloodstream. So once APOB particles are not cleared, there's only one other option for them. They have to invade an artery wall. So it's the APOB concentration and they deliver cholesterol and that explains atherogenesis.

And in the old days, we still do. What are our ways of estimating APOB concentration? most of it is LDL particles. We look at LDL cholesterol. And for decades, that has been the poor man surrogate that you have too many APOB LDL particles floating around. We use VLDL cholesterol. Triglytherides divided by five is sort of an estimate.

Is there too much cholesterol in the VLDL particles? We don't have as great a test on that. But the vast majority of these dump trucks entering your audio wall are LDLs. So ultimately, this podcast is not. not directed at it, but if we can make the liver express more LDL receptors or let the LDL receptors recycle more, you will have increased clearance, you will lower the APOB, and every APOB particle goes into the liver is one less that's going into your artery wall. And that's basically the pathophysiology of atherogenesis. It's those APOB dump trucks.

Follow up on that point. Again, let's take two individuals whose APOB concentration and documented LDL cholesterol level is above that physiologic threshold, such that diffusion is going to favor entry of the LDL, the low-density lipoprotein into that subendothelial 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 deciliter. 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 apalb particles bringing them in. But that is not the only etiologic reason why one would have atheroscler. 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 2 diabetes, you have chronic inflammation in the body, you have endothelial cell damage in the body. So it's easier in those people for these particles to get in earlier in life and generate and plaque. We should make the point that this APOB entry into the artery wall is an incredibly slow process. It takes decades to develop. And this is why the concept now is not only lower is better, but the longer you keep things low with 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, collagen diseases, rheumatoid arthritis. They have lifelong inflammatory factors going on and other abnormalities that, weaken the arterial defense against atherosclerosis. Oxidative processes is a big part of atherogenesis. So if that is going on in the body. But sometimes we do see, like you said,

great grandma who smoked all her life and has high LDL cholesterol and why no plaque. And there are forces at play that we just do not understand. There's other protective whatever going on in their body that we have not been able to identify even genetically or we're testing this, test, 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. 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 rule less and think it's not going to bother me when for the vast majority of people it does create havoc in pathology? Yeah. So let's now talk about the brain. So we've got these APOB and APOA 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 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 will 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 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 your cell. So 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 sheath 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. It'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 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 that measured or LDL cholesterol, it might be 30 milligrams per decilator, 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's past, 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, they always will.

Microglyocytes, 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 anymore. 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. The neuron, of course, is the most active cell. 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. And then it falls on the astrosite.

So that's a little bit about cholesterol production in the brain. All of the cells can do it. But at a certain point, the neurons say, I don't want to do it anymore. Astrocytes, can you please make cholesterol and get it over to me? And this is where we get into the brain lipid transportation system. Because in the blood, as you've enumerated, lipids travel within the lipoproteins and 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 interstitual 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 in the neurons over there saying, hey, I need that, send it to me, we have to have a brain cholesterol transportation system or a brain lipid transportation system. And so what do the astrocytes do? Same thing that happens in the periphery. It makes a lipoprotein.

But there's going to be a big difference here. So the first thing the astrocytes are going to have to do is synthesize cholesterol. Very quickly, we won't elaborate in depth, but we've had podcasts on this before. One of the cholesterol synthesis pathways goes through the next to less sterile, penultimate sterol. And in the astrocytes, it's called desmosterol. And then desmosterol becomes cholesterol. So we'll probably talk about this is one way why we can measure desmastrol 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 we could shoot it out into the matrosome where it can travel, swim over, and get to the neuron. And here's the difference. In the periphery, we said, hey, the structural proteins are APOB and APOA.

In the brain, it's the famous APA lipoprotein 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. But let's just stick to the APOE protein. So the astrocytes synthesizes, it binds the cholesterol, and it becomes a little lipoprotein, which it secretes into the matrosome. But it's an apoe-e-containing lipoprotein. Now, if we could take out those apo-e-containing lipoproteins and put them in a centrifuge,

they would sink right to the bottom of the centerfuge. But what else would be sinking to the bottom of the centerfuge? 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. The 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 he 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 LD. receptor, so there have to be LDLs in the brain, no, because the LDL receptor has affinities of just a couple of apo proteins. In the periphery, the LDL receptor is looking for APOB 100, 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. That's what it recognizes. So Tom, I'm actually quite confused by this.

So there's a lot I want to back up on. I'll just start with that point. So let's back up to the liver for a moment. The liver's got this receptor, which we will continue to refer to as an LDL receptor. When an APOB particle, an LDL, a garden variety LDL makes its way to the liver, it has one and only one APOB around it. Can you briefly explain 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 certain amino acids that line up and they create, they have a surface charge, and here's the LDL receptor. Now, the LDL receptor has a certain segment that is called the APOB recognition domain. There's certain amino acids there that create 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. 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 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. 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 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 APO-E 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 APO-E and APO-B, which presumably must be the case or you wouldn't have the match. Yeah. The primary reason where APO-E gets involved with clearance of lipoproteins is on chylomicrons and V-LDLs. 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 colomicrons 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 VLDOs, and that's why they have such short plasma residence time. I'm going to mention it now. Sorry, but Tom, I was asking a different question, which maybe is, maybe I misunderstood something you said. I was asking about the neuron with its LDL receptor. How does the neuron with an LDL receptor tag and pull a tiny, tiny, tiny lipoprotein with an APOE on? it out of... And the real reason is 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 1, which is an APOE affinity clear.

Understood, understood. So yes, the LDL receptor can clear some of the APOE part, but it's the LRP that's doing most of it. The last receptor that the neuron explains, and we've talked about this is called the scavenger receptor B1. That binds to the HDL and it dilipidates it, but it's an APOE recognizing scavenger receptor also. So everything in the neuron is basically looking for 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. That's, although the LDL receptor can recognize it, it's a minor clearance pathway, APOE on an LDO. I want to go back to the synthesis.

You alluded to this briefly. We have two cholesterol synthetic pathways. I mean, one pathway that branches and, bifurcates into two pathways. And in each of those pathways, they make cholesterol, but the intermediaries are quite different. So different enzymes and different intermediaries. And we often refer to them thinking of what their penultimate molecule is. So you already referred to one, which is the path that turns desmosterol into cholesterol. And then the other one, of course, turns lithosterol 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 lithosterol pathway. Very little goes through the deismostral pathway. In fact, the primary cells that use the deismostril pathway in the periphery are our steroidogenic tissues. All of our other cells, I mean, a little bit will go through the dezmastro pathway, but most is lithostrol.

So if you are measuring sterols in the blood, lithosol 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. But 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 desmosterol that's winding up. If there's cholesterol molecules winding up in the neurons, it's through the astrocyte, the block pathway going through desmosterol.

Now, in a pinch, if there's a cholesterol deficiency in the brain, the neurons can start synthesizing cholesterol again, but in normal brain physiology, that doesn't happen. So lithostrol 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. Whereas if you measure desmastrol in the blood, the majority of it reflects, correlates extremely high with cerebral spinal fluid, desmosteral and brain tissue demotive. So that becomes a very cool marker that we can actually measure in the bloodstream because desmastrol in the plasma correlates

very highly with cerebral spinal fluid and brain cholesterol. Why is that, Tom? That's counterintuitive to me because they seem like completely independent pathways. Why should the desmastrol you measure in the blood tell us anything about the cholesterol synthesis of the brain? I think, and you're better at figuring out these 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 strogenic 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. 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

APO-E, and as you said, APO-E has a relationship to Alzheimer's disease. I just want to make sure people understand the difference between APO-E genes and APO-E the protein, because to date, through this discussion, we have only spoken about APO-Lipoprotein 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 3-4-4-4-2-2, 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 in shape and that will affect what it can bind to, which is the crucial function of apo proteins. So there are, the, you inherit the genes from mom and dad, and that means one gene from mom, one from dad. So you get one allele in your gene and the other allele from each. So was your mom in 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, E2, E3, E3, E3, E4, E3, E2, E2, E2, E2, E2, E2, E2, E2, E2, E2, E2, E4, E4, or E2, E2, E2, E2, E2, or E2, 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. And the main thing it's doing, it's serving as a ligand to what things are going to bind to or even what the APOE will bind to other than the lipoprotein. So the type of APOEU manufacturer 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 APO2 gene, and especially APOE2 homozygosity.

Peter, why don't you tell how many carry the E4 heterosygotes and the E4 homozygotes. You have those Yeah, I mean, you know, again, it depends on the series you look at, but it seems about 55% of the population are E3E3, the so-called wild type. 20 to 25% might be E3, E4, and one to two percent 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 E2E3 is probably on the order of two to three percent. E4 is also quite rare. So the two most common by far are E3E3 and E3E4. 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 three-four individuals,

the people that have one copy of three, one copy of four, they make a version of APOE, the protein that's not as good as the wild type. And their risk of Alzheimer's disease is about two times higher than someone who has a three three. And again, it depends on the series. Sometimes you'll see that at three times higher, but directionally, that's about the level. Conversely, if you have two copies of the four, that risk is significantly higher. There was a day, Tom, 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 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 going to have ramifications. We've done podcasts and Peter's 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 it here and there. And it almost tells us nothing. If you're measuring HDL cholesterol, tells us nothing about what the HDL particles. Remember, there are 90% of your lipoproteins out there.

So clearly what they're doing, cholesterol is not their major function. So that means HDLs do other things. And as we're learning, they do innumerable other things that regulate all aspects of human health. They're actually a part of the innate immune system. So they're involved with fighting inflammatory diseases, infectious diseases, chronic diseases, cancer. So what we wish we had is not HDL cholesterol, which tells us very little.

We wish we had tests that would tell us, are the HDLs in a given patient's body doing what they're supposed to be doing? Are they functional or not? But there's so many different functions that HDLs perform, it has. to do not with the cholesterol they're carrying, but yet the types of proteins they might be carrying. Well over 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 100 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 construct it 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. 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 HDLs carries the least amount of lipids compared to the APOB particles. That's why it sinks in the centerfuge tube. But the tiniest HDLs, the discoidyl H.D.Ls, 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? 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 APO-A-1 or an APO-A-1 that's bound to a couple of these other proteins. And maybe some of these proteins are very important, anti-oxidative 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. So all of a sudden, this astrosite 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 peopoA1. the blood-brain barrier.

It is believed that is receptor mediated, and it might be this good old scavenger receptor, again, expressed at the blood-brain barrier that facilitates entry of APO-A-1 or the really small, dense HDL, APOA-1s carrying accessory proteins. And the hope is, hey, number one, if they get in, great.

So now the brain HDLs, you have different subpopulation of brain HDLs. You might have only APOE containing brain HDLs. You might even have, 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. They would be dysfunctional HDLs. Don't I wish we had a blood test for that? And we do not. So in the brain, now you have these APOE particles, maybe can taring 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. Now all of a sudden the neuron is not getting the cholesterol it needs. And that will create havoc because the neuron puts it right into cell membranes. If you don't have the proper amount of cell membrane cholesterol, this is where something called amyloid precursor protein sits, and if you don't have the right cholesterol balance,

it's acted upon by certain enzyme called secretases. That's where you start producing beta amyloid and even tau, because you don't have the right amount of cholesterol in your 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 dispel. 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 ptow 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 thing that's the the relationship between amyloid tau and cholesterol. There must be a link, right? Definitely. We go way back, you can read the studies of autopsies on patients with Alzheimer's disease, and they're really cholesterol overloaded tissues, especially the neurons. So remember, the neuron, the main thing 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. So when there's too much cholesterol in the cell membrane of a neuron, there's something called beta and gamma secretase. they're enzymes that make the amyloid precursor protein cleave into the production of amyloid 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 APOB, and 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. The neuron is the one cell in the brain that has the ability to get rid of cholesterol.

We've spent a lot of time saying the brain makes cholesterol and it retains it. In fact, the half-life of cholesterol in the brain is five years as opposed to a few days in the periphery. So that tells you the brain is reserving cholesterol. But early, early, I told you too much cholesterol in any cell is toxic. 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 oxystero. 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 hydroxy cholesterol 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, 24S hydroxy cholesterol, that will make cholesterol change into 24S hydroxycholesterol, which is a water soluble, it 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 groups, so they separate, and it 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? Now, 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 oxysterile? It's the liver. And what does the liver do with oxysteroles? Well, the liver has cholesterol. You know, Pete, that the liver is our

major, our only manufacturer, bioacids, which are oxysterels. So cholesterol gets transformed into an oxysterole in the liver, same enzyme that the neurons express and the oxysterels, they 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 and send it to the liver where it could be fically excluded or so. So this 24S hydroxy cholesterol 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 24-S-hydroxycholesterol 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 and the plasma goes up. The liver doesn't secrete its oxysteroles 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. And that's one of the starryl biomarkers, as is the dezmastrol that we eluded. So we actually have two things that we can measure. Here's the bad thing. In the real world, we can get dezmastrol measurements fairly easily. There's no commercial laboratory that 24S 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 this 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 there is markedly decreased clearance of the E4 brain HDL, just when it touches the membrane, the cholesterol, 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 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 Bempidoic acid and is etymine and PCSK9 inhibitors or bile acid sequester or CPET inhibitors or C-TEP 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 statins do, if anything, in the brain. And I'll bracket the discussion by saying

maybe we can formulate it through the lens of the two types of statins, those that tend to be more hydrophobic and those that tend to be more hydrophilic. So maybe talk a little bit about that class of drugs. I don't think we have the time to go into the entire history of them so we can, We can even do it through the lens of the modern versions of those drugs as opposed to, you know, 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 in people 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.

It is the statin class. All of those other drugs mention 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, lipophobic, you know, a hydrophilic loves water, lipophilic loves lipids, hates water. And early on, there was lots of data showing just traversing a cell membrane border, the

lipophilic statins get through easier. Because the border itself has got a lot of lipids in, so they, all right, come right in. So it's a little for the hydrophilic statins to penetrate a barrier. Pretty 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 there for 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 resuvostatin, a hydrophilic statin is used more commonly. It certainly can get into the brain, maybe a little less slowly than lipotor, lipophilic statin, Tim, 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, is that size driven, Tom? Is it just that the size of a statin is such that it can get across the blood brain barrier, whereas the other classes can't? It's just the construction of the statin drug on how, you know, what converts a hydrophilic or a lipophilic property to that given statin. And, 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 hydrophilicity and other aspects of that alignment or construction of their molecules gives them the lipophilicity or lipophobicity. So anyway, since we, earlier, we just said, hey, Alzheimer's disease is too much cholesterol in the brain, too much cholesterol in the neurons. you could hypothesize that if statins did get into the brain, which they do, and all of them do, and in a steady state they all have the potential to 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. And this is why 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, 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. 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 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? 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. 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, and 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. 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 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 an E4 or you have a family history putting you at risk

for Alzheimer's disease. Again, a theory, but it would be supported by the trials you just said that tend to show here not much going on or benefit, and that could be the plausible reason. Now we go back to, you've went through the deismostrol and the phosphoryl pathways. There's a nice study published almost a decade ago where they were doing cerebral spinal fluid deismostrol levels and plasma dezmastrol levels and measuring it by aspect, and there was high correlation between the CSF desmastrol and the plasma desmastrol, saying that, wow, desmastrol in the plasma, it reflects desmastrol in the central nervous system.

And even more interesting, that study showed that the people with low dezmastrol 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, on the hope that we are going to help the lessen their incidence of Alzheimer's disease, maybe keeping an eye on plasma desmastrol sort of makes sense. And if you do oversuppress it with your statin therapy, maybe you can change the dose of that of 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. So it gets very interesting.

And the 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's 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 deismostril, because if that was low, ooh, I've maybe suppressed it a little bit too much. All wonderful hypothesis that has a lot. A lot of data can easily provide 20 references on dezmastrol in the brain, how critical it is.

So this is a very plausible theory right now. And don't expect the 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 azetamib. Again, is etymite is a drug that really works outside the body, so to speak, right? It works in the gut. It's a blocks that Neiman pixie one like one transporter. And in people who are not hyper absorbers, it's not even a particularly effective drug. Yet there is a kind of a suggestion that it might have some benefits in the brain, which is the furthest place from where we think of it working. What can

you say about that? You know, it's kind of amazing. Like you said, who would ever even hypothesize that 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 Kelly Niodas, who are very involved with these diseases. And is there anecdotal belief that is etymide, in addition to helping them control their APOB in their patients, there seems to be some cognitive in the people they deal with or so. So now there's actual plausible reason. Now, Zetamib 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 the Zetamide glucuronide that actually can pass through the blood-brain barrier in small amounts, but unlike a Zetamide that gets in. And there are animal studies showing that it interferes with hexokinineineate. 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. 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 patient, we use a lot of azetamide because we prefer to use low dose statins. And if we don't get to the

APOB goal, we're adding a Zetamide. We also, day one, check synthesis and absorption. So there are patients where we use a Zetamide day one because they're hyper absorbers. 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 Zetamide, but I think they might be a patient where you need a little bit of a statin

and a little bit of a Zetamide until somebody proves this. And I would not hold your breath waiting for a randomized control trial at a Zetamide, 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 a Zetamide does to P. or the amyloid ratios or so. I wish somebody should. You don't only maybe a small study. Well, I'm surprised you could probably pull it out of a bio bank for an existing study that was already done on a zetamib.

So it'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 azetamide trials. Don't we also have a monotherapy setia trial? Only in Japanese elderly people. And I don't think cognition was one of the thing. It was just, 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 petal. You definitely could. Yeah, AB 40240. Yeah. It's a great research project for some young PhD or 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. Without talking about specific products, let's talk about if in 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 us.

They're packaged in it 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, 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 my cells, gets absorbed by fatty acid absorbers, CD-36.

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 a diradal phospholipid, two fatty acid. But 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 makes three fatty acids or it could make lysophospholipids. But hey, if the remaining fatty acid on that lysophospholipid is in omega-3, it gets in. So once they're in the enterocite, what happens to them?

The enterosite 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 chylacron. It shoots them into the lymphatics, and they rapidly get into the plasma. They 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 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, 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. And once it gets into the brain, it's in the brain. It can be trafficked in these brain HDL particles, and it's part of the things they do too, or it can jump right into the cytosol or the first cell that it bumps into while it's in the matrosome. 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 relessening residual risk in people who have APOB controlled. The 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, you know, once they get into the brain, the brain has its omega-3 fatty acids. So I, and used to be all DHA, but I know the thought on that is changing EPA is required there to some people can convert EPA to DHA, but not everybody can. And that's how to get up into the brain. And there are 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. And 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, right, which is lipid homeostasis, good blood pressure, you know, sleep, exercise. I mean, things that just demonstrably matter when it comes to brain health, where in that pantheon would

you sort of put having a serum or EPA DHA level in the RBC membrane of 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. An academician would tell you, Tom, don't even talk to me. There's no level one randomized blinded controlled study doing what you say, so it's irrelevant to me. But if you look at all the observational data, just like we did with the statins where it's in

general pretty good. I think if you went through all of that data with omega-3s in the brain, you would find you. 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. We 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 controlled trials that changing that will reduce events other than that one trial of EPA and insulin-resistant high-risk people who had APOB 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 dysmastro 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 good. content at when you hit the 8 to 9% omega-3 index, you pretty much have the proper amount of omega-3s in the scenario you cell membranes of your body. There is no study you can allude to that,

hey, therefore, so it's so important in the brain, let's make it 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'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 C-TEP 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 Kastrelin. Probably got about four years ago. But since that time, we've had to be a lot of 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, Obesetrapib, and the Broadway trial specifically, and how we tie it into what we've talked about today. Yes, basically, CETP inhibitors of which Obesetrapib is the latest have been investigated to see what they do to atheroscotic heart disease and L.P. 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 Farmer recognize this. So they're actually putting a little money in. into clinical trials, perhaps investigating this hypothesis. And in that Broadway trial where you

administered Obesetriper, 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-tale, the amyloid 40-42 ratio, the other various ratio of these markers, the hibulatory 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 Obesetrapib 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 there 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 seen it. It's all on the HDL particles. So the liver actually starts overpriced. producing 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 Obesetripeed is increasing either APOA1 or the really tiny protein-lating 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 APOA-1 can jump on an E4, a brain APO-E 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 Obisetrapib. Yay, for its APOB 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 it's looking good, especially in the E4 carriers, I think there will 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 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 prediment. 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

of a Mediterranean diet to a low-fat diet, it was halted early. And again, I think that's just a great example of if you pick the right population, as I thought, you know, I thought of it as people who were just about to drive off the cliff, but weren't quite there. You could get an answer to a question in a few years. And I think that's 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 oligodendristites and neurons and the different pathways in APOE versus APOB? So again, I know that this podcast was a little technical, but I think you did a great job of explaining it, anthropomorphizing it when appropriate.

And obviously, this might be the podcast someone has to listen to or watch a couple of times and the show notes will be robust. So I want to thank you. And as always, Tom, it's been, gosh, it's been 15 years since you took me under your. your wing and helped me develop my understanding of this field of lipidology. So I can never, I can never waste an opportunity to thank you publicly for, for your generosity. You're personally with me. So, 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. 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, 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. 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 keeps changing and getting more and more and 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.

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