395 – Brain lipidology: understanding APOE, cholesterol homeostasis, Alzheimer’s disease, & more

1. 0:00 – 0:11

   Intro

   1. PAPeter Attia0:00

      [intro music] Hey, everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia.

2. 0:11 – 9:27

   The fundamentals of cholesterol transport in the body, and how peripheral cholesterol metabolism differs from cholesterol handling in the brain

   1. PAPeter Attia0:11

      Hey, Tom. Great to, uh, be with you again as always.

   2. TDTom Dayspring0:15

      For sure, Peter. This has become a bit of a routine for us. We've done it, but, uh, I love, uh, the way we interact on this topic.

   3. PAPeter Attia0:23

      Today, we're gonna talk about some different things. We're gonna really focus on, um, a topic that's really become an enormous passion of yours, and your, your curiosity drives so much of your learning and then by extension, our learning in the practice. So, um, I wanna kinda go on a, on a journey with you into this idea of cholesterol in the brain. Um, it's, it's obviously a very important topic for, for reasons that we'll get into. But, um, I think before we do, it is worth making sure that everybody's starting from the same sort of, uh, knowledge base or, or, or, or, uh, 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, 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, you know, 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.

   4. TDTom Dayspring1:31

      Yeah. As you've stated many times, cholesterol is essential for human life because it, it's used for making some critical things, but its most important function is it, uh, positions itself in the cell membranes in every cell in our body, and cell membranes are, re- regulate the integrity, what gets in, what gets out a cell. So evolution has given every cell in the body the power to de novo synthesize cholesterol, but a little bit. Now, each cell needs, uh, you know, a, a minor number of molecules or so. And, uh, but if it does that, we got great cell membranes, and those cells are, uh, functioning happily or so. But we also know, and people sometimes don't understand this, like so many things, an excess of anything can be harmful. So if any cell somehow has over-synthesized cholesterol or, uh, accumulated cholesterol and has excess molecules, cholesterol has the ability to crystallize, which is toxic to a cell. It will kill the cell. So evolution has also given cells the ability to export cholesterol out of its cytosol into the plasma, but you know, we've, uh, talked many times, lipids are hydrophobic. They cannot circulate in plasma, which is an aqueous or, or water solution. So again, evolution said, "No problem." Evolution has given us proteins that can bind and adhere to lipids and then wrap them into particles that are the lipoproteins. And that's how, uh, lipids, cholesterol, triglycerides, and numerous other lipids that we don't have to mention circulate in our bloodstream. So if a cell effluxes cholesterol out, it joins on a protein. The protein happens to be called apoA-I, which is sort of, uh, the structural protein of our high-density lipoproteins. So that's how HDLs are created. They accept cholesterol from whatever cell in the body is effluxing it or so. We have another family of lipoproteins that are much bigger than the HDLs, and those are produced in the liver. One, uh, type is produced in the small intestine, and they belong to the apoB family of lipoproteins. And the difference between them and HDLs is their structural protein is this very large peptide called apolipoprotein B. The intestine makes a full-size apoB. The intestine makes a truncated one we call the in-- uh, excuse me, the hepatic, uh, apoB, apoB 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 intra-- uh, which traffics absorbed fatty acids, which become triglycerides, absorb cholesterol into the bloodstream, it's in an apoB 48 particle, a very transient postprandial particle. The liver manufactures apoB particles. Uh, one is a very low-density lipoprotein. It's quite big because it's packing the triglycerides, which like the chylomicrons, it transports to muscles and fat cells primarily and then returns to the liver. Some of the VLDLs, as they lose the triglycerides, they shrink, and they become something called either a VLDL remnant, a very transient particle called an intermediate density lipoprotein, which rapidly becomes 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 son of VLDL, or they're a, a liver-produced one. Now, the apoB particles carry a lot of lipids, triglycerides primarily in the VLDL. The LDL is very interesting. It's got c- it's pretty much a cholesterol-carrying particle, X amount of triglycerides, but it has the longest plasma residence time of anything in the apoB family. It can last three to four, even five days in some circumstances. Ultimately, just like the VLDL, it gets cleared by the liver expressing and sticking into the plasma something called an LDL receptor, which binds to these apoB particles and pulls them into the liver, and then the liver digests them and does whatever it wants with the component parts of the lipoprotein. Um, the LDLs hang around for that amount of time, and this is not well-recognized, 'cause 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 are the apoB family. Now, the apoB family traffics far more lipids because of their size. You know the volume of a sphere is a third power of the radius, so a couple of nanometer increase in diameter, boy, a lot more lipids can be carried. But after the HDL has sucked out all of the cholesterol from wherever it has, it becomes a big, fat, mature HDL. Now, it has to do things with that cholesterol. It has the option of j- 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 w- 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 or the gut. But to, uh, 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 a direct, where the HDL will bring it back. Total RCT is the sum of both. Most people are not aware that the primary function why we have LDLs is to return cholesterol to the liver. Everybody thinks it's delivering cholesterol to cells. Almost never, because every cell can make all the cholesterol it needs. Now, in an emergency, a cell, any cell can upregulate an, an LDL receptor and pull in the nLDL if it needs it, but just doesn't happen for the most part. And this is one reason, and we're gonna talk about it 'cause it's pertinent to the brain, uh, if LDLs are bringing cholesterol back to the liver or if we can induce that with some of the drugs that we have that make LDL receptors express and stay expressed longer, we will drop LDL cholesterol levels in the plasma extremely low, and we're, as we get deeper into the brain, y- you know, a, unfortunately a prevalent, uh, belief out there in the real world is, "I don't ever want to lower chole- LDL cholesterol too much 'cause 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, uh, our body handles cholesterol. And by peripheral, anytime we say peripheral, we mean anything that's not in the brain. So the brain lipid and lipoprotein system that we're gonna talk about has almost nothing to do with the plasma, uh, 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.

   5. PAPeter Attia9:26

      Yep.

3. 9:27 – 17:57

   How cholesterol is transported through plasma and stored within cells, and why lowering LDL cholesterol does not deplete the body or brain of cholesterol

   1. PAPeter Attia9:27

      Let me just maybe, uh, synthesize some of those points. So first off, um, maybe just even adding a little bit more context, the body does shuttle a lot of things around plasma. Uh, 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, um, [clears throat] and, and plasma is, as you said, it's water. Um, it has proteins in it, like hemoglobin and things like that within red blood cells, but, but it's, it's, 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. Uh, ions, sodium, potassium, chloride, they don't need to be bound to anything to move around. Conversely, uh, steroidal hormones like testosterone or cortisol, they actually are virtually all bound. There's a slight amount that's free, but they're bound to albumin or sex hormone binding globulin, uh, 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, uh, 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 Lp (a) . That's a totally different, uh, apolipoprotein which we're not gonna talk about today, although we've got lots of content on that. Um, you also mentioned how much the apoAs outnumber the apoBs in absolute numbers, but because they're so much smaller, the total cholesterol carrying capacity is much greater in the apoB family. And a way for the, for a person to appreciate that is to look at their lipid panel. If you see that your total cholesterol is two hundred milligrams per deciliter, you'll easily notice that the sum of your LDL and VLDL cholesterol, it could easily be a hundred and forty of that two hundred milligrams per deciliter, whereas the HDL cholesterol might only be sixty of that. So again, many more in number, but much less in cholesterol carrying capacity. And then of course, you talked about this idea of reverse cholesterol transport. We have the indirect and the direct. Um, we've talked about those in the past, but again, I think the most important takeaway that I get from what you said is, um, the old version of that, which is that it's HDLs that do it all, is untrue. The LDLs do more by volume. Um, I, I guess one question I would have for follow-up is for the person who says, "But Tom, I buy, I understand everything you're saying, but If LDL is so important for reverse cholesterol transport in the periphery, what happens as LDL goes down? Is that a bad thing? Am I losing the ability to return cholesterol to the liver?

   2. TDTom Dayspring12:27

      No, that just means that if LDL cholesterol goes down, if you really even look at your total cholesterol, it's gonna go down too. So there's less, uh... LDL's function is to bring cholesterol back to the liver. So if your LDL cholesterol is, there's just not, not a need to get cholesterol back to the liver. The cells are not effluxing as much cholesterol 'cause they're in cholesterol balance. The HDLs are, uh, sending, transferring less cholesterol to the LDLs. And so the system is in, uh, it's a very operational system, and they all talk to one another. The nuclear transcription factors that regulate all of the, some of the mechanisms I spoke to are in balance. So lower 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 'cause all, it's in balance in all the other cells.

   3. PAPeter Attia13:23

      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, of, uh, producing many hormones. But if, if, if I were to measure somebody's serum cholesterol and I measured, you know, again, total cholesterol of 200 milligrams per deciliter, um, I could calculate how much cholesterol is in their blood because I know what their circulating blood volume is. And, you know, presumably I could do the math and it would be a few grams of cholesterol. How does that compare to the total body store of cholesterol?

   4. TDTom Dayspring14:07

      Well, it's much smaller. I mean, most of the cholesterol in the body is within the cells of our body. And y- 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 i- in, in sum is in all of the periphery. That means your liver, every organ you got, your skin, y- where every, in membrane in every cell in our body. So that's the mass of total cholesterol. And the, uh, and the brain has its own component 'cause they, they don't interact. But in the plasma, uh, it's interesting, uh, most of the... Of course, uh, all, uh, you would think all of the circulating plasma is within lipoproteins, but it's not. There's a, a... And this comes to a surprise to many people, too. The biggest carrier of cholesterol in our bloodstream is in our red blood cells.

   5. PAPeter Attia15:05

      Red blood cells, yeah.

   6. TDTom Dayspring15:06

      Yeah. 'Cause they're cells. They have cell membranes, and they're big. They're vastly larger than a lipoprotein. So they actually carry more milligrams of cholesterol than do our... Everybody thinks it's the lipoproteins. It's not. So that's how it's distributed in the blood. There is no free cholesterol. I mean, there's a minuscule amount on albumin, not much, but that's it. It's in a lipoprotein or it's in a red blood cell membrane. Then we have the organs of the body, and, uh, it's another question that you can trick up people, 'cause if you te- tell, ask the average person or even physician, even lipidologist, uh, "What's, uh, where's most of the cholesterol in the body?" Or, "What organ has the most cholesterol?" And everybody says the liver, and they're wrong. It's not even close. The brain, o- of all the organs in the body, has 20 times more cholesterol than does the liver. The liver, uh, 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 gonna get into this, the brain holds onto cholesterol like [chuckles] the bank holds onto its gold in the vault and everything. It doesn't... But whereas cholesterol, the liver is just sort of a handling station. Whatever cholesterol the liver has, it's sent out or it's effluxed into the bile through bile acids or free cholesterol. So the liver's like a transfer station. So it stores a little bit of liver 'cause it always has to have a pool of cholesterol to do what it does, whereas the brain holds onto its cholesterol, and this is another physiologic point we'll have to get into ourselves. No, it's the brain.

   7. PAPeter Attia16:51

      Uh, pardon me. The liver is more like a bank with money, which is it's got a high flux.

   8. TDTom Dayspring16:56

      Comes and goes.

   9. PAPeter Attia16:57

      It takes a lots of, it takes a lot of deposits in, but then, of course, the only way it makes money is by loaning out or distributing that capital and putting it to work. Um, 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, the transfer through the organ. Um, so going back to finish the swing on that point, of course, I, I just want the listener to be, to be cognizant of the idea that if your peripheral cholesterol goes down by 50%, 75%, right? If you, if you, 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-

   10. TDTom Dayspring17:46

       Yeah. So almost no relationship-

   11. PAPeter Attia17:46

       ... it's a tiny, tiny amount. Yeah

   12. TDTom Dayspring17:48

       ... between cellular cholesterol and circulating cholesterol.

   13. PAPeter Attia17:52

       Yeah. So this is, this is definitely one of the misconceptions people deal with. Um,

4. 17:57 – 27:27

   How apoB particles drive atherosclerosis, why lowering lipids matters, and the factors that influence individual cardiovascular risk

   1. PAPeter Attia17:57

      and again, although we're not gonna focus on it, it- we'd be remiss to be sitting at this point, uh, in the game and not mention why one might want to have a total, uh, plasma cholesterol of 100 milligrams per deciliter as opposed to 200 cholesterol. He's like, "Why, why are we in the business of lipid lowering if we're trying to help people avoid certain diseases? And how does the just lowering that tiny fraction of the total body's pool have such an outsize effect on atherosclerosis?

   2. TDTom Dayspring18:28

      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, it, the industrialized countries, it's all over. People are dying of heart attacks for a variety of reasons. And I always like to say, if you have atherosclerosis, there's one sine qua non, you have cholesterol buildup in your artery wall. If we do not have cholesterol, uh, buildup in our artery wall, you do not have the disease called atherosclerosis, and you can't suffer the consequences thereof. So the next question is, "All right, Tom, well, how in the world does cholesterol get into that artery wall?" It's not like the artery is over-synthesizing cholesterol and building it up. That is not happening. So that means we've already described the cholesterol is floating in our highways in the plasma. So how does cholesterol get from the dump trucks, the lipoproteins that are carrying it, into the artery wall? And this is where w- 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 [chuckles] done podcasts on this and the references on it. It's, uh, you have that great slide, the Ference slide, where every single trial that's ever been done, every Mendelian analysis of, uh, lipids and lipoproteins shows the, the more you lower cholesterol, the less atherosclerotic events happen. So we now know, g- uh, we've already told you it's the beta lipoproteins that are carrying most of the cholesterol in the bloodstream. So if a beta lipoprotein, an LDL or a VLDL, and because of its resin stein, the vast majority of those are LDLs, exceed a certain threshold number, it... they will enter the artery wall. It's a simple diffusion process. Y- you could have endothelial 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, uh, aggregated, they get oxidized, and the immune system sends in white blood cells that engulfs them, and that creates a cholesterolated, uh, laden macrophage, the foam cells, they stick together creating plaque. So, uh, it's the particle number, and we can... There are assays that we can get LDL particle numbers or VLDL particle numbers if you want them. But since there is one apoB on every one of those particles, we simply measure apoB. One apoB per particle. Once your apoB level starts to exceed certain thresholds, atherosclerosis 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 the most of the escalation becomes, is due to defective clearance of the apoB particles from the plasma, meaning those LDL receptors, the liver, for whatever reason, is not expressing enough of them to clear, to keep the apoB concentration physiologic in the bloodstream. So once 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 used to, and still do, uh, 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's surrogate that you have too many apoB LDL particles floating around. Uh, we use VLDL cholesterol, triglycerides divided by five as sort of an estimate. Is there too much cholesterol in the VLDL particles? We don't have as great a test on that, but the vast majority of these dump trucks entering your artery wall are LDLs. So, uh, ultimately, and, and this podcast is not directed at it, but if we can make the liver express, uh, more LDL receptors or let the LDL receptors recycle more, you will have increased clearance, you will lower the apoB, and that every apoB particle that goes into the liver is one less that's going into your artery wall. Uh, and, and that's basically the pathophysiology of atherogenesis. It's those apoB dump trucks.

   3. PAPeter Attia23:18

      Follow-up on that point. Um, again, let's take two individuals whose apoB concentration or, and documented LDL cholesterol level is above that physiologic threshold, uh, such that diffusion is gonna favor entry of the LDL, the low-density lipoprotein, into that subendothelial space to begin that cascade that we talked about. Um, 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. Um, whereas you can see another person with that same lipid profile that's having their first heart attack at 51. Um, I, I mean, I don't expect you to have an answer for this because I just think there are certain things we, 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, what do you think are the most compelling explanations for why we don't have complete and total homogeneity of, um, risk factor and disease, uh, uh, and w- when we confine it to this disease. I mean, we don't have it for any disease, but, but what do you think is the best explanation for a disease in which we so well understand the physiologic steps?

   4. TDTom Dayspring24:41

      Sure. Well, as I mentioned, if cholesterol gets in your artery wall, you have the disease, and it's the apoB particles bringing them in. But, uh, that is not the only etiologic, uh, reason why one would have atherosclerosis. There are a number of other factors that go i- 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, uh, particles to get in earlier in life and generating plaque. We should make the, um, point that, uh, 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. Your, um, uh, smoking, as you said, if you have some autoimmune disease that's contributing to inflammation. We know, uh, uh, w- uh, people who have chronic inflammation, uh, g- have increased atherosclerosis. R- uh, the collagen diseases, rheumatoid arthritis, they have lifelong, uh, inflammatory factors going on and, uh, other abnormalities that weaken the arterial defense ag- uh, uh, against atherosclerosis. Uh, oxidative processes is a big part of atherogenesis, so if that is going on in a body. But sometimes we do see, like you said, 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, um, we're testing this test, "Ah, they got some elevation of molecule Z. It's protecting them." Something's going on, but-- and one day we'll, uh, ascertain that. Y- y- you know, as the polygenic risk scores come into, if we do them early in life, it can sort of predict who is gonna make it to 80 and never have a heart attack and who is not, because they're looking at a multitude of genetic things that y- you are never looking at one at a time in an individual patient. So look, genes control everything. They are genetically blessed, those. Uh, but important thing to make is don't ever think 'cause your LDL cholesterol is 200 that I'm one of them, [chuckles] 'cause there's no way to know that. Why play Russian roulette and think it's not gonna bother me, when for the vast majority of people, it does create havoc and pathology?

5. 27:27 – 37:44

   How the brain produces and transports its own cholesterol using apoE lipoproteins independently of circulating cholesterol and apoB-containing lipoproteins

   1. PAPeter Attia27:27

      So let's now, um, talk about the brain. Um, so we've got these, um, apoB and apoA lipoproteins, the HDLs and the LDLs predominantly. Um, you mentioned, though, that the brain has the greatest source of cholesterol in the body, greatest storage source of cholesterol in the body. Um, does the brain need to rely on any of the periphery's cholesterol? Um, and if so, can apoB and apoA lipoproteins get in there and deliver cholesterol as needed?

   2. TDTom Dayspring28:03

      Well, the quick answer to that, and then I'm gonna elaborate, is the, uh, what's going on with cholesterol in the brain, how much cholesterol is, uh, uh, stored in the brain, has zero to do with what is floating in the plasma. So there are certain lipoproteins that we'll talk about that can work their way into the brain, but the apoB-containing particles, the vast-- which carry the vast majority of cholesterol, cannot. They're much too big to pass through that, what we call the blood-brain barrier, which is actually a barrier that separates the brain from the periphery, as we've talked. But I'd like to start, uh, to give you an idea about why has the brain got so much more cholesterol, why is it storing it so much more than, say, the liver or any other organ in the body. Well, as, uh, we are in utero with mom, in the second and the third trimester, the fetal brain is already starting to de novo synthesize its cholesterol, 'cause it, evolution knows it's gonna need cholesterol because the brain probably has more cell membranes than any other tissue put together, and, uh, especially our neurons, those cell membranes are kind of critical on do our neurons work or not, and whether the neurons work or not is do we work or not normally ourself. 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 a glial cell, and there's only three of them. You have astrocytes, which in the adults produce a lot of the cholesterol. We have oligodendrocytes, it's a big word, and they produce about 70% of the brain cholesterol, because one of the mega things the brain does with cholesterol is create myelin, which sheaths every axon and dendrite, uh, the nerve endings that are in our body. So that is, uh, a big, big reason why the brain stores and has so much cholesterol. It's in myelin. The other cell, glial cell in the brain is a microgliocyte, uh, and they are the brain immune, uh, cells. So, uh, they are, uh, the last remaining cell. So, uh- In the utero, the day we're born, you-- we-- there's no more mom contributing cholesterol to the brain. It's the brain making it itself. And every cell I just mentioned is overproducing cholesterol because the brain knows as I g- as it grows and grows, it's gonna 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, a two-year-old and measure their LDL cholesterol, [chuckles] it might be 30 milligrams per deciliter. Yet that is the time when the brain is growing more than it ever will. Between birth and age of 10, the brain is expanding to its adult size, and it's-- has-- 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 [chuckles] 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, pretty much the adult brain size is formed, so at that point, there's a readjustment of cholesterol synthesis in the brain. Um, oligodendrocytes keep making it. They always will. The, the gl- um, microgliocytes, they don't have to make that much. Astrocytes c-continue to produce it a-at a high form, but there's one cell that stops producing cholesterol, and it's the neurons. At d- when the brain is full adult size, the neuron says, "No, no, no, I'm not gonna make any more. I want the astrocytes to make it and send it to me." And there's a simple reason it does that. We've, in our earlier podcast, discussed the very complex cholesterol synthesis pathways. It's actually 37 steps. Every step is a different enzyme. Every step requires ATP. So to f- to syn- any cell to synthesize one molecule of cholesterol, it consumes over 30 molecules of ATP. The neuron, of course, is the most active cell in the brain because it's firing off all these action potential in their synapses all day long, and that requires ATP. So the neuron does not wanna waste ATPs making cholesterol if it can get it elsewhere. The neuron starts using ATP for its functioning. So, and then it falls on the astrocyte. So that's a little bit about cholesterol production in the brain. All of the cells can do it, but at a certain point, the neurons say, "I don't wanna do it anymore. Astrocytes, can you please make cholesterol and get it over to me?" And this is where we get into the brain lipid transportation system. Because in the blood, as you, we've delubr- uh, enumerated, uh, lipids travel within the lipoproteins in the plasma. Well, in the brain, the cholesterol that's going back and forth between cells doesn't use the blood. It uses the brain interstitial sys- uh, tissue, which is called the matrisome. So if w-we take the brain, it's, it's this connective tissue, and there are zillions of these cells in them, the glial cells and the neurons. Now, they're very close together, but they're not, uh, contiguous. They're not binding to each other. So if an astrocyte produces cholesterol molecules, and the neuron's over there saying, "Hey, I need that. Send it to me," we have to have a brain tran- uh, 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, uh, gonna be a big difference here. So w- the first thing the astrocytes are gonna have to do is synthesize cholesterol. Very quickly, we won't elaborate in depth, but we've had podcasts on this before. One of the cholesterol synthesis pathways goes through the next to last sterol, penultimate sterol, and in the bra- astrocytes, it's called desmosterol. And then desmosterol becomes cholesterol. So we'll probably talk about this is one way where we can measure desmosterol in the cerebral spinal fluid. Nah, that's t- [chuckles] kind of hard to do. But in the plasma, it correlates with brain, uh, cholesterol production. So, uh, the astrocyte makes cholesterol. It's now gonna obviously have to wrap it with a protein, an apoprotein, so we can shoot it out into the matrisome, where it can travel, swim over, and w- get to the neuron. And here's the difference. In the periphery, we said, hey, the structural proteins are apoB and apoA. In the brain, it's the famous apolipoprotein E. And apoE, many people know, oh, that has something to do with the brain because we know there are types of apoE that are associated with cognitive disorders and Alzheimer's disease. But let's just stick to the apoE protein. So the astrocyte synthesizes, it binds the cholesterol, and it becomes a little lipoprotein, uh, which it secretes into the matrisome. Uh, but it's an apoE-containing lipoprotein. Now, if we could take out those apoE-containing lipoproteins and put them in a centrifuge, they would sink right to the bottom of the centrifuge. But what else would be sinking to the bottom of the centrifuge? High-density lipoproteins in the plasma. So the brain lipoproteins are referred to as HDLs because they have the buoyancy and density of a plasma HDL. But they're very different because the plasma HDL will have s- 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 matrisome, this particle, it continues to mature. Cholesterol becomes cholesterol ester, goes to the center of the particle, and it becomes a big, fat particle. But remember, its mission is to deliver cholesterol to the- A neuron. So the neuron's gonna have to grab that apoB-containing particle and internalize it or grab it and delipivate it. So guess what the neuron expresses? Low-density lipoprotein receptors. And that creates confusion because if you-- somebody says, "Oh, I know the brain and neurons have LDL receptors, so there have to be LDLs in the brain." No, because the LDL receptor, uh, has affinities for X of just a couple of apoproteins. 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 and we call it... We should call it the apoB, apoE receptor because that's what it recognizes.

6. 37:44 – 40:37

   How apoB structure influences LDL receptor binding and LDL clearance

   1. PAPeter Attia37:44

      So Tom, I'm, I'm actually quite confused by this. So, um, there, there's a lot I want to back up on. I'll just start with that point. So let's, let's back up to the liver for a moment. Um, 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 conformationally how that LDL interacts with the LDL receptor? What is it about the apoB protein that enables the key to fit into the lock?

   2. TDTom Dayspring38:32

      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 ex- certain amino acids that line up and they create... They, 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 are certain amino acids there that create certain electrostatic forces, and if the domain on apoB, and what determines is that sticking out properly is the conformation 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 conformation. 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, uh, where it should be, the LDL receptors don't as easily recognize big LDLs or small LDLs, and that's why people with small LDLs or even big LDLs often have very high LDL particle counts, because clearances decrease. So there are certain just small areas on the LDL receptor and the 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, uh, 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 th-that's sort of irrelevant to just understanding the LDL receptor clearance process. So that explains s- part of the extended, uh, plasma residence times of LDLs, how is the apoB conformed.

   3. PAPeter Attia40:26

      So, so Tom, given that the size of the LDL within a variation of normal, right, um, can impact clearance,

7. 40:37 – 47:50

   How neurons acquire cholesterol from apoE-containing lipoproteins and why desmosterol serves as a unique marker of cholesterol synthesis in the brain

   1. PAPeter Attia40:37

      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. That... So that is new- not only news to me, but very difficult to wrap my little cholesterol-rich brain around, because I would think that the apoE lipoprotein being so much smaller than an LDL and being much closer to an HDL would never be able to find it, even with complete homology between that section of apoE and apoB, which presumably must be the case or you wouldn't have the match.

   2. TDTom Dayspring41:24

      The primary re- uh, uh, reason where apoE gets involved with clearance of lipoproteins is on chylomicrons and VLDLs. They carry several copies of apoE per particle, unlike the apoB, which is one copy per particle. So when they are fully f-full of triglycerides, they're very b-big. The apoB is distorted in a certain way. Now, the receptor in the liver that's gonna clear VLDLs and chylomicrons is called the LDL re- uh, re- uh, related receptor one. So... And it's only has an affinity for apoE. So it's the LRP that clears most of the, uh, apoE-containing particles, the chylos and the VLDLs, and that's why they have such short plasma residence time. I'm gonna mention it now 'cause it's gonna-

   3. PAPeter Attia42:13

      Oh, sorry. But, but, 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

   4. TDTom Dayspring42:31

      And the real reason, and this is why I'm explaining to you how the liver clears VLDLs and chylomicrons, 'cause the LRP only recognizes apoE. And the brain not only expresses LDL receptors, but they express a lot of the LDL receptor-related protein one-

   5. PAPeter Attia42:47

      I see. Okay. Okay. Got it

   6. TDTom Dayspring42:48

      ... which is an apoE affinity clearer.

   7. PAPeter Attia42:51

      Understood. Understood.

   8. TDTom Dayspring42:52

      Unless the LDL receptor can clear some of the-

   9. PAPeter Attia42:55

      Yep

   10. TDTom Dayspring42:55

       ... apoE part, but it's the LRP that's doing most of it. The last receptor that the neuron expresses, and we've talked about this, is called the scavenger receptor B1. That binds to the HDL and it delipidades 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 r-recognizes apoA-I, 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. And, uh, so very few, uh, LDLs in the, uh, periphery. Uh, I mean, maybe 2% of your LDLs have an apoE on them. Mostly there's no apoE. That's... Although the LDL receptor can recognize it, it's, it's a minor clearance pathway, apoE on an LDL.

   11. PAPeter Attia43:54

       I want to go back to the synthesis. You, you alluded to this briefly. Um, 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, uh, 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 lathosterol into cholesterol. What is the relative balance of cholesterol synthesis in the brain between those two pathways?

   12. TDTom Dayspring44:32

       Very interesting. In the periphery, the vast majority goes through the lathosterol pathway. Very little goes through the desmosterol pathway. In fact, the primary cells that use the desmosterol pathway in the periphery are our steroidogenic tissues. All of our other cells, I mean, a little bit will go through the desmosterol pathway, but most is lathosterol. So if you are measuring sterols in the blood and lathosterol 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 lathosterol.

   13. PAPeter Attia45:14

       Huh.

   14. TDTom Dayspring45:14

       But at the age of 10, when the neuron decides, "I don't want to make cholesterol anymore," it, there's no lathosterol 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, uh, the block pathway going through desmosterol. Uh, 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 lathosterol is not used as a marker of, uh, brain cholesterol synthesis for the big reason, even though there is some lathosterol pathway going on in the brain, if you measured it in the blood, n- [chuckles] 95% of it is your other cells making it. Whereas if you measured desmosterol in the blood, the majority of it reflects, correlates extremely high with cerebrospinal fluid desmosterol and brain tissue demo-de-desmosterol. So that becomes a very cool marker that we can actually measure in the bloodstream 'cause desmosterol in the plasma ref- correlates very highly with cerebrospinal fluid and brain cholesterol. So it is-

   15. PAPeter Attia46:26

       Why, and why is that, Tom? Uh, that's c- that's counterintuitive to me because they seem like completely independent pathways. Why should the desmosterol you measure in the blood, uh, tell us anything about the, the cholesterol synthesis of the brain?

   16. TDTom Dayspring46:38

       I think, uh, and you're better at figuring out these teleologic reasons than I, that, uh, evolution decided there's one pathway that we're gonna do in very critical t- areas. The brain, which only makes its own cholesterol and stores it in the steroidogenic tissue, uh, we d- we want them to be dependent on that pathway. Why? I, I don't have an answer for you on that, but that's what that pathway, uh, reflects.

   17. PAPeter Attia47:07

       All right. We'll come back to that 'cause I know there's a, there's a clinically relevant reason that we, we might want to think about that. Um, okay. So we've established that the, the, the neurons, um, 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. Um, and we've also established that you have a different lipoprotein, um, that is transporting cholesterol in the brain so that the neurons can still acquire plenty of it from their, their, their neighboring, uh, oligodendrocytes and presumably to some extent astrocytes.

8. 47:50 – 52:49

   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

   1. PAPeter Attia47:50

      I do want to just make one point clear for the listener, um, which we, we haven't really explicitly stated, but, um, [lip smack] the astute listener of course has already picked up on the fact that we've talked about apoE and as you've said, apoE has a relationship to Alzheimer's disease. Um, I just want to make sure people understand the difference between apoE genes and apoE the protein, because to date, through this discussion, we have only spoken about apolipoprotein E, a protein, and this is denoted with a small A. Small A, small P, small O, big E, and that's when we're talking about apoE the protein. But if you were to write all caps A-P-O-E, you'd be referring to the genotype. And of course, you have two of these, so you could be a three-three or three-four, four-four, two-three, et cetera. Um, do you wanna just explain the relationship between those different six combinations of genotypes, everything from a two-two to a four-four, um, and how the different genes make different proteins? And then we should talk about why that's relevant.

   2. TDTom Dayspring48:56

      Yeah, and it's a big part of this discussion. So the ApoE protein comes in different shapes. They're, they're called isoforms. Peter has explained this many times. It's, uh, really only one different amino acid in the darn protein that separates these. But just removing or replacing or putting the wrong amino acid in the entire peptide changes its ability to bend and shape, and that will affect what it can bind to, which is the crucial function of, uh, uh, apoproteins. So we u- uh, there are the, uh, y- you inherit the genes from mom and dad, and that means one gene from mom, one from dad. So you get one allele in your gene and the other allele from each. So was your mom an ApoE two, three, or four? Well, and likewise with dad. And you're gonna inherit... There's several potentials. You can be an E-two-E-two, E-two-E-three, E-three-E-four, E-three-E-two, uh, E, uh, E-two-E-four, E-four, or E double, uh, uh, ho- uh, homozygote for E-four. So depending which of those genes you attack, your ApoE protein is gonna be constructed a little bit differently, which is gonna affect its ability to s- 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 gonna bind to or even what the ApoE will bind to other than the lipoprotein. So the type of ApoE you manufacture is critical to certain disease pathologies. Peter can give you the exact indices. The average person has an ApoE3-E3 genotype. I believe it's about two-thirds of people that have that. Far less people carry the ApoE2, uh, gene, and especially ApoE2 homozygosity. Peter, why don't you ex- tell how many carry the E4 heterozygotes and the E4 homozygotes? You have those percentages down.

   3. PAPeter Attia51:01

      Yeah, I mean, I, you know, again, it depends on the series you look at, but, uh, it seems about fifty-five percent of the population are E3-E3, the, the so-called wild type. Um, twenty to twenty-five percent might be E3-E4. Um, and one to two percent would be E4-E4. Um, as you pointed out, E2-E2 is the most rare phenotype by far. That's significantly less than half a percent. Um, and I think E2-E3 is probably on the order of two to three percent. Uh, E2-E4 is also quite rare. Um, so the two most common by far are E3-E3 and E3-E4. Um, and as we've talked about many times on the podcast, um, the risk associated with Alzheimer's disease between three-three, which is always the reference case, and three-four and four-four, 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 that, than someone who has a three-three. Uh, and again, it depends on the series. Sometimes you'll see that at three times higher, but directionally, that's about the level. Uh, conversely, if you have two copies of the four, um, that risk is significantly higher. Uh, there was a day, Tom, fifteen years ago, the literature was calling that twenty to twenty-five times higher. That number has come down considerably, and I think most, most series would talk about that as being an eight to twelve-fold increase. Um, 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.

   4. TDTom Dayspring52:48

      Yes,

9. 52:49 – 57:44

   HDL function beyond cholesterol: immune function, protein cargo, and communication with the brain

   1. TDTom Dayspring52:49

      and this is gonna have ramifications. Uh, 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 here and there. And it, uh, almost tells us nothing, uh, if you're measuring HDL cholesterol, tells us nothing about what the HDL particles. Remember, they're ninety percent of your lipoproteins out there, so, uh, clearly they're, uh, what they're doing to cholesterol is not their major function. So that means HDLs do other things. And w- 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. Uh, so what we wish we had is not HDL cholesterol, which tells us very little. We wish we had tests that would tell us, are the HDLs in a given patient's body doing what they're supposed to be doing? Are they functional or not? But there's so many different functions that HDLs perform. It has to do not with the cholesterol they're carrying, but yet the types of proteins they might be carrying. Well over two hundred proteins have been described in the periphery as being found on HDL particles. Now, that doesn't mean there's an HDL particle carrying a hundred peptides on it. Impossible. They're too small. But each HDL might carry one or two peptides, and each of those peptides might have some function that It's hard to even know what they are. Are they helping the immune system or, or are they involved with coagulation or, or what? So, uh, we have actually s- numerous armies of HDLs, each constructed with one or two of those peptides in addition to apoA-I and apoA-II, some of the lipo- lipid-related, uh, apoproteins. Uh, and so there's no way to know, uh, 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 centrifuge tube. But the tiniest HDLs, the discoidal HDLs, apoA-I by itself, they're sitting right at the bottom 'cause there's zero buoyancy to them. So, um, if we have this whole army of very tiny, high-density HDL particles that are packing probably critical proteins, jeez, don't you wish we could measure them? But here's where it gets interesting. I-- We've hinted, uh, 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 apoA-I or an, an apoA-I that's bound to a couple of these other proteins, and maybe some of these proteins are very important antioxidative proteins-

   2. PAPeter Attia56:16

      Mm

   3. TDTom Dayspring56:16

      ... 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 matrisome, what do-- where do they go? They immediately bind to the first apoE-containing brain HDL that they bump into. So all of a sudden, this astrocyte apoE-constructed brain HDL particle is also carrying a copy or two of H- apoA-I that actually originated from the plasma. The brains can't synthesize apoA-I, the brain cells, so if it's in the brain, and we know it is, uh, it, it, it-- they do pass the blood-brain barrier. It is believed that is receptor-mediated and might be this good old scavenger receptor, again, expressed at the blood-brain barrier that facilitates entry of apoA-I or the really small, dense HDL, uh, apoA-Is carrying accessory proteins. And the hope is, hey, number one, if they get in, great. So now the brain HDLs, you have different p- subpopulation of brain HDLs. You might have only apoE-containing brain HDLs. You might even have s- some apoA-I brain HDLs, but most of them are gonna be apoE plus apoA-I brain HDLs. And those other proteins that came with the apoA-I maybe can do, start doing some good things in the brain. And where

10. 57:44 – 1:09:13

    How APOE4-associated defects in brain cholesterol transport may promote Alzheimer’s disease: amyloid production, neuronal cholesterol homeostasis, and cholesterol clearance

    1. TDTom Dayspring57:44

       this might be really good, so in the periphery, we have brain functionality. I did not introduce it, but i- it's easily, you can de-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 [chuckles] 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.

    2. PAPeter Attia58:17

       Hmm.

    3. TDTom Dayspring58:18

       So, uh, in the brain, now you have these, uh, apoE particles, maybe containing apoA-I. But now, if you're an apoE4 producer, when your astrocyte produces apoE, it's gonna be an apoF- E4 type of, uh, and that tends, just like in the periphery, it's a dysfunctional type of apoE. So if you're 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 a, an E3 or an E2 might to those receptors, and therefore you have d-disrupted cholesterol transport into the neuron. Now all of a sudden, the neuron is not getting the cholesterol it needs, and that will create havoc because the neuron puts it right in the cell membranes. If you don't have the proper amount of cell membr- um, brain cholesterol, this is where something called amyloid precursor protein sits, and if you don't have the right cholesterol balance, it's acted upon by a certain enzyme called secretases. That's where you start producing beta amyloid and even tau, uh, uh, 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 des- maybe describe some of the other things that apoE4 brain HDLs don't do that an apoE3 or an apoE2 HDL would.

    4. PAPeter Attia1:00:04

       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? Uh, so people are obviously familiar with the accumulation of beta amyloid and p-tau in the brain, and people are now really starting to understand that we, we actually have great biomarkers where we can start to track those things. Is there any relationship between those? Uh, in other words-

    5. TDTom Dayspring1:00:37

       Oh, yeah. Yeah

    6. PAPeter Attia1:00:37

       ... as you talk about all of this dysfunctional, uh, movement of cholesterol in the brain, uh- And, and we know that that is highly associated with your ApoE genotype, and we also know that your ApoE genotype is highly associated with Alzheimer's disease. So the one thing we haven't put together is what's the relationship between amyloid tau and cholesterol? There must be a link, right?

    7. TDTom Dayspring1:01:00

       Definitely. We go way back, you can, uh, read the studies of autopsies on, uh, patients with Alzheimer's disease, and they're really cholesterol-overloaded brain, uh, tissues, especially the neurons. So remember, the neuron, it-- the main thing determining its function is its cell membrane integ-integrity. And if you have the proper cell membrane 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 i-i-in the Alzheimer's patients, uh, 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 gonna evolve into the production of, uh, beta amyloid. So, uh, and whether it produces... There's two types of that amyloid, 40 and 42, with 40, uh, uh, being, uh, uh, 42 being the more injurious type of, uh, a-amyloid beta and the 40 being a less toxic type of amyloid beta. So, uh, 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, uh, the, a secretase, alpha secretase, that sort of slows the cleavage of amyloid precursor protein into apoB, and you wind up producing more of the apo-, uh, or the be- uh, amyloid f- uh, beta amyloid 40, which is the less toxic form. So, uh, 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, uh, because the, the membrane isn't gonna function, the neuron is the one, uh, cell in the brain that has the ability to get rid of cholesterol. We've, uh, s-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 w- early, early I told you too much cholesterol in any cell is toxic. In the neurons, not only will it disrupt membrane function, but it crystallizes in the cytosol of the neuron, and it kills neurons. [chuckles] You don't wanna kill neurons. You're gonna have some sort of, uh, chronic brain disease if that happens over time. So evolution has given the neurons the ability, um, to change cholesterol into something called an oxyesterol, and the one it produces is called 24S-hydroxycholesterol. Uh, people who, um, know what cholesterol looks like biochemistry-wise, it has one oxygen molecule a- at the third position of the first ring. 24S-hydroxycholesterol not only has that one cholesterol molecule, it has a second one at carbon 24. So now you have a hydroxy group on both ends of the cholesterol molecule. That makes it a little bit more water-soluble. So when the neuron says, "I've gotta get rid of cholesterol," it has an enzyme, 24S-hydroxycholesterolase, that will make cholesterol change into 24S-hydroxycholesterol, which is water-soluble. It, it, it comes out of the neuron, it floats right through the matrisome to the blood-brain barrier, where it can pass right through it, 'cause it's sort of a hydrophilic lipid with an oxygen hydroxy group on each end. When it hits the, uh, 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 ra- 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 either on 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 besides the bra- brain that can produce an oxyesterol? It's the liver. And what does the liver do with oxysterols? Well, the liver has cholesterol. You know, Pete, that the liver is our major, our only manufacturer of bile acids, which are oxysterols. So cholesterol gets transformed into an oxyesterol in the liver, same enzyme that the neurons express. And the oxysterols, they go through several steps, but they become your bile acids down to your gut, goodbye fecally. So the brain actually has this cool way of getting rid of excess cholesterol by that transformation. You send it to the liver, where it could be fecally, uh, excluded or so. So this 24S-hydroxycholesterol gets very important. But if, again, you start to build up too much cholesterol in your neuron cell membrane It's in the cell membrane now, so there's less cholesterol in the cytosol of the neuron. The neuron stops making 24S-hydroxycholesterol. Brain is not, uh, it's not escaping into the plasma anymore. This is why researchers use 24S-hydroxycholesterol in the plasma as a mar- biomarker of brain health. It shouldn't be there, 'cause the brain is retaining all its cholesterol. The neuron's not trying to excrete any cholesterol. But if it does, the chole- the concentration of that in the plasma goes up. The only, uh, the, the liver doesn't secrete its, uh, oxysterols into the plasma, but the brain does. So it's a great biomarker on brain health. So too much tells you the brain is in danger. This is why people who are developing drugs for the brain to try and prevent dementia, they monitor 24S-hydroxycholesterol, 'cause 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 sterol biomarkers, as is the desmosterol that we alluded. So we actually have two things that we can measure. Here's the bad thing. In the real world, we can get desmosterol measurements fairly easily. There's no commercial laboratory that 24S-hydroxycholesterol is become available. Uh, so we d- uh, outside of research studies, I wish we could measure that in our patients, 'cause 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, uh, going to the receptors that should be internalizing the ApoE HDL in the brain into the lysosomes in the neuron, which will generate cholesterol for the neuron to use. But since they, there is markedly decreased clearance of the E4 brain HDL, just when it touches the membrane, the cholesterol can jump into the cell membrane of the neuron, but it doesn't get to the cytosol. So it's very complex, these lipid mechanics that are going on in the E4 patient. And, uh, I'll, I'll let you ask about that before we get into other attributes of what ApoE4 might not be doing well in the brain.

    8. PAPeter Attia1:09:10

       Well, I kinda wanna ask a, a question

11. 1:09:13 – 1:17:35

    Statins and brain health: reviewing the evidence of the potential impact of statins on cognition and Alzheimer’s disease risk

    1. PAPeter Attia1:09:13

       that brings it even further to something clinical, which is we've, we've come this far in the discussion without really talking about the impact of pharmacology, so I wanna, I wanna sort of, uh, make that bridge now. Um, obviously we're not gonna 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. Um, and when you talk about that, the thing that comes to most people's minds, I mean, most people aren't thinking of bempedoic acid and ezetimibe and PCSK9 inhibitors or bile acid sequestrants or C- CPET inhibitors or CETP inhibitors, rather. When a- 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, 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, so maybe talk a little bit about that class of drugs. Um, I don't think we have the time to go into the entire history of them, um, so we can-

    2. TDTom Dayspring1:10:23

       Correct

    3. PAPeter Attia1:10:23

       ... 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, but talk a little bit about how those drugs work in the brain specifically.

    4. TDTom Dayspring1:10:32

       And of course, statins are the number one drug to l- lower ApoB in the periphery because that, no doubt about it, reduces atherosclerotic heart disease. But of all, and Peter rattled off s- uh, the classes of ApoB-lowering drugs that are primarily used nowadays, of all of those, there's only one that can penetrate the blood-brain barrier and get into the brain, and it is the statin class. All of those other drugs mentioned either w- work solely in the liver or no way they could penetrate the blood-brain barrier, 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, um, uh, statins, lipophilic, lipophobic, and ha- you know, a hydrophilic loves water, uh, lipophilic, uh, loves lipids, hates water. And, uh, early on, there was lots of data showing just traversing a cell membrane border, the, uh, lipophilic statins get through easier. They, 'cause the border itself has got a lot of lipids in, so they, all right, come right in. So it's a little, for an, uh, the, um, a, uh, lipo- uh, the hydrophilic statins to penetrate a barrier, pretty much there has, there are receptors that, uh, pull them into... Even the liver, uh, the, uh, hydrophilic statins, there are, uh, receptors that pull them into the liver, and they get in quickly. So tactically, the, uh, 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 they're, the hydrophilic ones get in also. And they all have the ability, therefore, to various degrees inhibit cholesterol synthesis in the brain. So I don't think you necessarily have to pick a statin b- based on its lipophilicity or hydrophilicity worrying about the brain. I think because i- in real world practice, uh, rosuvastatin, a hydrophilic statin, is used more, more commonly, uh, it- Certainly can get into the brain, maybe a little less slowly than Lipitor, a 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.

    5. PAPeter Attia1:13:04

       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?

    6. TDTom Dayspring1:13:11

       No, it-it-it-it's just the construction, uh, uh, o-o-of the, uh, the statin drug on how, uh, uh, you know, what converts a hydrophilic or a lipophil- a lipophilic property to that given statin. You know, if you look at-- We put up a slide here showing all the different statins. They're all a little bit different, and there are certain aspects of that construction that gives them, uh, hydrophilicity and other aspects of that alignment or construction of their molecules gives them the lipophilicity or, or lipophobicity. So anyway, uh, since we earlier we just said, "Hey, uh, 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, uh, pathology of the, the neurons and tissues. And this is why, and we're not gonna 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 injure the brain.

    7. PAPeter Attia1:14:41

       Yeah, well, just, 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, the TLDR is that every study we looked at for either MCI or Alzheimer's disease or dementia otherwise not specified showed either neutrality or improvement. Um, and these are all RCTs, of course, um, 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 we-- if, 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?

    8. TDTom Dayspring1:15:48

       Yes, and this is more in the hypothetical range right now because nobody's gonna do these studies to prove it one way or the other. But because, as Peter just says, cholesterol is so important, you would never wanna 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. Uh, "Hey, I'm on the statin. I'm not thinking right. N-n-not-- 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 o-o-one hypothesis would be that is the person that the statin is over-suppressing cholesterol synthesis rather rapidly and, uh, severely, and that's why they got neurologic symptoms. And they stop it. Obviously, uh, you've stopped the statin. You're, well, you're restoring whatever synthesis was going on in the brain or so. So, um, that becomes a plausible hypothesis. Uh, and as I said, nobody's ever gonna do a study to prove that or disprove it. But you could also say, you know, Alzheimer's disease takes decades to develop. So again, if you're-- I give you a statin and you don't get that acute brain fog, it's probably safe to 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, uh, trials you just said that tend to show either not much going on or a benefit, and that could be the plausible reason. Now we

12. 1:17:35 – 1:19:49

    Desmosterol and 24S-hydroxycholesterol as biomarkers of brain cholesterol metabolism and statin effects

    1. TDTom Dayspring1:17:35

       go back to you've, uh, went through the desmosterol and the phos- the phospherol, uh, pathways. There's a nice study published almost a decade ago where they were doing cerebral spinal fluid desmosterol levels and plasma desmosterol levels and measuring it by mass spec, and there was high correlation between the CSF desmosterol and the plasma desmosterol, saying that, wow, desmosterol in the plasma, it reflects desmosterol in the central nervous system. And even more interesting, that study showed that the people with low desmosterol have, uh, the higher incidence of cognitive impairment in Alzheimer's disease. So if, and we- you've talked about this many times on the podcast too, if we are administering statins to our patients, even the E4 patients, on the hope that we are gonna help the, lessen their incidence of Alzheimer disease, maybe keeping an eye on plasma desmosterol sort of makes sense. And if you do over-suppress it with your statin therapy, maybe you can change the dose of that statin therapy, or maybe you can just abandon statin therapy and lower apoB to reduce heart attacks with the several other drugs that you ran through very quickly there. So, so it gets very interesting. And last thing to tie it into that 24S-hydroxycholesterol, remember, if you're on the way to Alzheimer's disease, that's increased in the plasma. There are studies showing that if you prescribe a statin, the 24S-hydroxycholesterol disappears. That would s- again be proof that the statins are lessening cholesterol synthesis in the brain and maybe to a level that's really desirable, 'cause you don't want to see that. But then you would back it up with the desmosterol, 'cause if that was low, ooh, I've maybe suppressed it a little bit too much. All wonderful hypothesis. It has a lo- a lot of data. I, I can easily provide 20 references on desmosterol in the brain, how critical it is. So this is a very plausible theory right now, and don't expect a clinical trial to prove or disprove this hypothesis right now.

    2. PAPeter Attia1:19:45

       We'll, we'll link to those, um, sources, Tom, in the, in the show notes. Um,

13. 1:19:49 – 1:23:57

    Possible cognitive benefits of ezetimibe beyond lowering apoB

    1. PAPeter Attia1:19:49

       one other drug I just want to talk about really quickly is, is ezetimibe. Um, again, ezetimibe is a, you know, a drug that really works outside the body, so to speak, right? It works in the gut. It's, uh, blocks the Niemann-Pick C1-like one transporter. Um, and, you know, in people who are not hyperabsorbers, it's not even a particularly effective drug. Yet there is a kind of, uh, a suggestion that it might have some benefits in the brain, which is the furthest place from where we think of it working. What, what can you say about that?

    2. TDTom Dayspring1:20:21

       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, you, y- you know, we h- have a couple of neurologic colleagues, Richard Isaacson and Kelly Andiotis, who are very involved with these diseases, and it is their anecdotal belief that ezetimibe, in addition to helping them control their apoB in their patients, there is seems to be some cognitive benefit in the, in the people they deal with or so. So now there's some actual plausible reason. Now, ezetimibe is one of those drugs that just cannot cross the blood-brain barrier, so how on earth could it be helping dementia or so? But it has a metabolite called a ezetimibe glucuronide that'll, actually can pass through the blood-brain barrier in small amounts, but unlike ezetimibe, it gets in. And there are animal studies showing that it interferes with hexokinase and the glycosylation of brain proteins to ab- if you reduce that, there's some benefit, less inflammation in the brain or so. So there is that w- and w- 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 i- it's a helper. So wouldn't that be cool? You know, Peter, in, as we control apoB aggressively in your patients, we use a lot of ezetimibe because we prefer to use low-dose statins, and if we don't get to the apoB goal, we're adding ezetimibe. We also day one check synthesis and absorption, so there are patients where we use ezetimibe day one because they're hyperabsorbers, and that's where you get the most efficacious apoB lowering. So in the future, as we have people who carry the ApoE4 alleles and they have apoB issues, you know, we might pick a statin first, we might pick ezetimibe, but I think they might be a patient where you need a little bit of a statin and a little bit of ezetimibe un- until somebody proves this. And I would not hold your breath waiting for a randomized control trial that ezetimibe, what it's doing to even some of the, uh, uh, uh, Alzheimer's biomarkers in the blood, uh, 'cause, uh, only emerging drugs are they starting to do those type of studies on. Th- nobody's gonna go back and look what ezetimibe does to p-tau or the amyloid ratios or so. I wish somebody should. You'd only need maybe a small, small study.

    3. PAPeter Attia1:23:00

       Well, I'm surprised. You could probably pull it out of a biobank for an existing, uh, study that was already done on ezetimibe. So that's not-- We could at least get the suggestion of that from, from such a study, 'cause we do have at least one... Well, I know we have statin versus statin plus ezetimibe trials. Don't we also have a monotherapy CETIA trial?

    4. TDTom Dayspring1:23:21

       Uh, only in Japanese elderly people, and I don't n- think cognition was one of the things. It was just... And it was not a r- uh, a blinded trial, so it was an open label trial.

    5. PAPeter Attia1:23:31

       Open label trial, yeah.

    6. TDTom Dayspring1:23:32

       Just to show it was efficacious in lowering apoB in a primary prevention setting. But, uh, they certainly didn't look at cognition or biomarkers in that study.

    7. PAPeter Attia1:23:40

       But if they still have serum banked, you could at least look at pre and post levels of p-tau-

    8. TDTom Dayspring1:23:46

       You definitely could

    9. PAPeter Attia1:23:47

       ... and, yeah, AB42/40.

    10. TDTom Dayspring1:23:49

        Yeah, and look-

    11. PAPeter Attia1:23:50

        Yeah

    12. TDTom Dayspring1:23:50

        ... be a great research project for some young PhD or a, a budding lipidologist, uh, to maybe-

    13. PAPeter Attia1:23:56

        Hopefully listening right

14. 1:23:57 – 1:32:11

    EPA, DHA, and the evidence for omega-3 fatty acids in brain health

    1. PAPeter Attia1:23:57

       now

    2. TDTom Dayspring1:23:57

       ... do, do. [laughs]

    3. PAPeter Attia1:23:57

       Um, let's, 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. Um, again, they're readily available as supplements over the counter, and there are certainly some brands out there that are, that are, uh, legitimate, which is to say you're, you're getting what they, the label says you're getting, and they're free of contaminants. Um, but they're, they also make pharmacologic variants of both of these, um, fatty acids. Um- So, so yeah, take that in whichever way you'd like, but let's... What, what do we know about EPA and DHA and brain health?

    4. TDTom Dayspring1:24:30

       Without talking of, of specific products, let's talk about if an EPA and DHA are both important to the brain. There's far more DHA, but we're finding out that even EPA is important for the brain now also. So, uh, w- and 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 as a triglyceride. Typically, one of the fatty acids on a synthesized triglyceride would be an omega-3, and there is a product that delivers omega-3s as a phospholipid, uh, from krill oil. Uh, 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, cleave off the fatty acids from the triglyceride or phospholipid vehicle, and then the free EPA or free DHA, which joins with other lipids in the biliary micelles, gets absorbed by a fatty acid absorber, CD36. Interestingly, not only can a free fatty acid be absorbed, but a lysophospholipid can be absorbed. A phospholipid, uh, it has a phosphorus moiety and a head group and two fatty acids attached to it. That's called a diradyl phospholipid, two fatty acids. But if I took one fatty acid off of a phospholipid, it's called a lysophospholipid. It's actually a smaller molecule, and they're easily absorbed. So, uh, [clears throat] the lipases either makes free fatty acids or it could make lysophospholipids. But hey, if the remaining fatty acid on that lysophospholipid is an omega-3, it gets in. So once they're in the enterocyte, what happens to them? The, the enterocyte immediately resynthesizes them to a full phospholipid, uh, or attaches them to a triglyceride molecule, which goes in the core of the chylomicron. The phospholipid goes on the surface of the chylomicron. It shoots them into the lymphatics, and they rapidly get into the plasma. They undergo rapid hydrolysis at the fatty... at the, uh, muscles and fat cells by lipases, and that frees up these phospholipids. Uh-huh. Now, phospholipids are a lipid. They can't circulate in the bloodstream. They immediately bind to something called a phospholipid transfer protein, and the phospholipid transfer protein will bind to either a full phospholipid or a lysophospholipid, and it's that little delivery truck of an omega-3 phospholipid transfer protein which goes up, butts into the blood-brain barrier, and there's a specific receptor in the blood-brain barrier that will internalize the lysophospholipid form of DHA or EPA. And once it gets into the brain, it's in the brain. It, uh, uh, y- you know, it can be trafficked in these brain HDL particles, and it's part of the things they do too, or it can jump right into the cytosol of the first cell that it bumps into while it's in the matrisome. So that's the journey. So, uh, look, it almost doesn't matter the vehicle you're ingesting, uh, an omega-3 with. We would prefer that you've established that a supplement is actually con- has the amount of omega-3s they say they do. Uh, don't trust the labels of every, uh, supplement you, uh, may, may buy. And they get in. Now, in the periphery, there's a lot on... And there's a big trial that shows perhaps for preventing or lessening residual risk in people who have apoB controlled, the EPA is a little bit more important, and, uh, the DHA, uh, 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, uh, and used to be all DHA, but I know the thought on that is changing. EPA is required there too. Some people can convert EPA to DHA, but not everybody can. And that's how they get up into the brain. And they're, uh, 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? 'Cause where do omega-3s go? In the cell membranes, and that's everything. Cell membrane health in the brain cells. I hope I explained that. Maybe you can elaborate a little more. [chuckles]

    5. PAPeter Attia1:29:10

       And, 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, um, you know, sleep, exercise. I mean, things that just demonstrably matter when it comes to brain health. Where, where in that, uh, pantheon would you sort of put, um, having a, a, a, you know, a serum or EPA, DHA level in the RBC membrane of 10% versus 6%? How, how... What's your level of confidence?

    6. TDTom Dayspring1:29:55

       Well, the data is all gonna come from observational trials for the most part. Uh, so... And in those trials, there are ones that specifically looked at certain brain, uh, functions and correlated omega-3 index with the, uh- uh, 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 r- uh, 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 it. Bill Harris has studies relating it to brain size or at least certain sections of the brain size in omega-3 context, uh, uh, 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 in insulin-resistant, high-risk people who had ApoB well controlled.

    7. PAPeter Attia1:31:16

       Mm-hmm.

    8. TDTom Dayspring1:31:17

       So, uh, you're in that gray zone area with the clinical trials on this, and they're not the type of trials that any guideline is gonna tell you this is what you have to do. But again, it's just like our desmosterol hypothesis. Again, excuse me. Th- there's a plausibility there. I see little downside to using omega-3s. Bill Harris, who you've interviewed, has looked at his trials, and he's pretty content that when you hit the 8% to 9% omega-3 index, you pretty much have the proper amount of omega-3s in the cell-- various cell membranes of your body. Uh, you know, 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.

15. 1:32:11 – 1:44:02

    Obicetrapib: an emerging CETP inhibitor with potential implications for both cardiovascular and brain health

    1. PAPeter Attia1:32:11

       Well, Tom, I want to close with something that's-- you and I are very excited about. Um, I did a brief podcast on it, uh, a little while ago, which is a, a, a new drug in a new class. Uh, I alluded to this class very briefly a few moments ago, the CETP inhibitors. Uh, 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 Caserlynd, uh, probably, God, about, uh, four years ago. Um, but since that time, we've had some exciting data, which I talked about in, in, in my podcast. But maybe just we could remind people about that drug, obicetrapib, and the BROADWAY trial specifically, and how we tie it into what we've talked about today.

    2. TDTom Dayspring1:32:55

       Yes. Basically, uh, CETP inhibitors, of which obicetrapib is the latest, uh, uh, have been investigated to see what they do to atherosclerotic heart disease and, uh, Lp (a) and maybe brain function as well. We-- 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, uh, y- look, the people at New Amsterdam Pharma recognize this, so they're actually putting a little money into clinical trials, perhaps investigating this hypothesis. And in that BROADWAY trial where you administered obicetrapib, 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, uh, uh, the phosphorylated p-tau, the, uh, amyloid, uh, 40/42 ratio, the other various ratio of these markers, the fibrillary 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, and that was a, 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 obicetrapib actually, because it's improving these biomarkers, really affect what we want to do, better brain function? And the plausibility is because they make your HDLs very big and they're-- 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 s- uh, senses, oh, we have a deficiency of ApoA1, 'cause they're not seeing it. It's all on the HDL particles. So the liver actually, uh, starts overproducing ApoA1, so ApoA1 goes up in the plasma. But in o- uh, once ApoA1 goes up, what does it start doing? It starts binding to some of these potentially protective proteins we've talked about. And, uh, guess what? So if you're increasing, if obicetrapib is increasing either ApoA1 or the really tiny protein-laden, uh, 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. It, uh, they've looked at some anti-inflammatory, anti-oxidative aspects of those proteins, and they believe the ApoA1 can jump on an E4 Apo, a brain ApoE HDL particle and rescue it and maybe turn dysfunctional brain HDL particles into functional brain particles. So boy, it's a wonderful story on paper right now, but the fact that the biomarkers are moving in the right direction, I think gives us all great hope, and I believe the company is gonna put money into investigating this with further cognitive studies and m- uh, more advanced studies and perhaps even some imaging studies, PET, things like that. Although these biomarkers really You know, 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 Obicetrapib. 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 are people who 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.

    3. PAPeter Attia1:37:07

       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 Predimed study. This is more than 10 years ago, which was a primary prevention trial of dietary therapy for at a minimum MACE, but also I believe it even looked at all-cause mortality, or maybe it was cardiac mortality. And again, it was primary prevention, which I always thought was, I thought the study would fail. I really did. I was like, you're not going to do a dietary primary prevention study. Come on. And not only did the trial succeed in demonstrating the superiority of a Mediterranean diet to a low-fat diet, it was halted early. And again, I think that's just a great example of if you pick the right population, as I thought, you know, I thought of it as people who were just about to drive off the cliff but weren't quite there, you could get an answer to a question in a few years. And I think that's the way to think about doing this, and I hope they can do that.

    4. TDTom Dayspring1:38:37

       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.

    5. PAPeter Attia1:38:49

       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 oligodendrocytes and neurons and the different pathways and ApoE versus ApoB? So again, I know that this podcast was a little technical, but I think you did a great job of explaining it, anthropomorphizing it when appropriate. And obviously, this might be the podcast someone has to listen to or watch a couple of times, and the show notes will be robust. So I want to thank you. And as always, Tom, it's been, gosh, it's been 15 years since you took me under your wing and helped me develop my understanding of this field of lipidology. So I can never waste an opportunity to thank you publicly for your generosity personally with me. So thank you very much, Tom.

    6. TDTom Dayspring1:40:08

       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, but just to keep the staff educated. And you know I'm shipping you out. Here's the newest, latest, and greatest stuff all the time. So it's just been a phenomenal, wonderful way for me to continue my career. So I love you eternally. You know that. And hey, sooner or later it'll be another topic we're going to have to expound on again because lipids keeps changing and getting more and more and exciting. So I love doing it.

    7. PAPeter Attia1:41:03

       Thank you, Tom. Thank you very much. Thank you for listening to this week's episode of The Drive. It's 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. So 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. Premium membership includes several benefits. First, comprehensive podcast show notes that detail every topic, paper, person, and thing that we discuss in each episode. And the word on the street is nobody's show notes rival ours. Second, monthly Ask Me Anything or AMA episodes. These episodes are comprised of detailed responses to subscriber questions, typically focused on a single topic and are designed to offer a great deal of clarity and detail on topics of special interest to our members. You'll also get access to the show notes for these episodes, of course. Third, delivery of our premium newsletter, which is put together by our dedicated team of research analysts. This newsletter covers a wide range of topics related to longevity and provides much more detail than our free weekly newsletter. Fourth, access to our private podcast feed that provides you with access to every episode, including AMAs, sans the spiel you're listening to now, and in your regular podcast feed. Fifth, The Qualies, an additional member-only podcast we put together that serves as a highlight reel featuring the best excerpts from previous episodes of The Drive. This is a great way to catch up on previous episodes without having to go back and listen to each one of them. And finally, other benefits that are added along the way. If you want to learn more and access these member-only benefits, you can head over to peterattiamd.com/subscribe. You can also find me on YouTube, Instagram, and Twitter, all with the handle PeterAttiaMD. You can also leave us a review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com/about where I keep an up-to-date and active list of all disclosures.

Episode duration: 1:44:09