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

Key Takeaway

The brain makes 100% of its own cholesterol and cannot extract any from the bloodstream. Even 2-year-olds with LDL cholesterol of just 30 mg/dL experience massive brain growth, proving the brain is completely independent of plasma cholesterol levels. This means lowering your blood cholesterol—even dramatically—will never harm your brain. The brain's cholesterol supply is separate, self-sufficient, and protected behind the blood-brain barrier.

Episode Overview

Dr. Tom Dayspring and Peter Attia discuss the critical distinction between peripheral cholesterol (in the bloodstream) and brain cholesterol. They explain how the brain independently produces all its cholesterol needs, dispelling the myth that lowering blood cholesterol harms cognitive function. The conversation covers cholesterol transport systems, lipoprotein mechanisms, and why the brain stores 20 times more cholesterol than the liver.

Full Transcript

Transcript of 395 – Brain lipidology: understanding APOE, cholesterol homeostasis, Alzheimer’s disease, & more from The Peter Attia Drive Podcast. Auto-generated from episode audio; may contain minor errors.

Hey everyone, welcome to the Drive podcast. I'm your host Peter Aia. Hey Tom, great to be with you again as always. always. always. 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. topic. topic. Today, we're going to talk about some different things. We're going to 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 want to kind of 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 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 fiveminute version. Let's talk through the idea of cells in the body making cholesterol and how they have to move that cholesterol around the body in the periphery just the sort of the nuts and bolts of it. Yeah, as you've stated many times, cholesterol is essential for human life because it 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 membranes are membranes are regulate the integrity what gets in what gets out of cell. So evolution has given every cell in the body the power to denovo synthesize cholesterol the little bit. Now each cell needs, you know, a minor number of molecules or so and uh but if it does that we got great cell membranes and those cells are functioning happily or so. But we also know and people sometimes don't understand this like so many things an excess of anything can be harmful.

So if any cell somehow has over synthesized cholesterol, accumulated cholesterol and has excess molecules, cholesterol has the ability to crystallize which is toxic to a cell. It will kill the cell. So evolution has also given cells the ability to export cholesterol out of its cytool into the plasma. But you know you've talked many times lipids are hydrophobic. they cannot circulate in plasma which is an aquous or or water solution. So again evolution said no problem. Evolution has given us proteins that can bind and adhere to lipids and en 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 fluxes cholesterol out, it joins on a protein. The protein happens to be called APO A1, which is sort of the structural protein of our high density lipoproteins. density lipoproteins. density lipoproteins. So that's how HDLs are created. They accept cholesterol from whatever cell in the body is eluxing 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 apo B family of lipoproteins and the difference between them and HCLs is their structural protein is this very large peptide called apal lipoprotein B.

The intestine makes a full-size apo. The intestine makes a truncated one. We call the excuse me the hippatic uh apo apo 100 and the intestinal produced one because it has 48% of the molecular weight of 100 is apo B48. So when the intestine makes a kyomicron to intro which traffics absorbed fatty acids which become triglycerides absorb cholesterol into the bloodstream. It's in an apo48 particle, a very transient postprandial particle. The liver manufactures apo particles. Uh one is a very low density lipoprotein. It's quite big because it's packing the triglycerides which like the kyomicrons it transports to muscles and fat cells primarily and then returns to the liver.

Some of the VLDLDLs as they lose the triglycerides they shrink and they become something called either a VLDLDL 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 denovo manufacture and secrete LDLs also so our LDLs that are floating around have two sources they're sort of like the son of VLDDL or they're hey a liver produced one. Now the apo particles carry a lot of lipidage triglycerides primarily in the VLDLDL.

The LDL is very interesting. It's got it's pretty much a cholesterol carrying particle. X amount of triglycerides, but it has the longest plasma resonance time of anything in the APOB family. It can last three to four, even five days in some circumstances. Ultimately, just like the VLDLDL, it gets cleared by the liver expressing and sticking into the plasma something called an LDL receptor, which binds to these apo 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.

Uh the LDLs hang around for that amount of time and this is not well recognized because they interact with the HDLs. something totally not well known if we look at all the lipoproteins in the body 90% of them are HDLs and the rest of the apo family now the apo B family traffics far more lipids because of their size you know the volume of a spear is a third power of the radius so couple nanometer increase in diameter boy a lot more lipids can be carried but after the HDL has sucked out all of the cholesterol from whoever it has it becomes a big fat mature HDL.

Now, it has to do things with that cholesterol. It has the option of delivering it to steroidogenic tissue that make cortisone or gonatal hormones. It can bring it to the atypuses, the cholesterol storage organ, or of course it can return it to the liver and even now the small intestine. But a lot of what an HDL does is it transfers its cholesterol mass into the apo particles, the majority of which are LDLs because of its long plasma resonance 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 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 bring 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 in an LDL receptor and pull in the NLDL if it needs it but just doesn't happen for the most part.

And this is one reason and we're going to talk about it because it's pertinent to the brain. 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 you know a unfortunately a prevalent uh belief out there in the real world is I don't ever want to lower LDL cholesterol too much because I'll deprive the brain and I'll injure the brain and soon we'll talk about why that is not true.

So that is what you said. This is the peripheral way that uh our body handles cholesterol. By peripheral anytime we say peripheral we mean anything that's not in the brain. So the brain lipid and lipoprotein system that we're going to talk about has almost nothing to do with the plasma transportation of lipids and lipoproteins. And that is such a crucial concept that must be understood. So what didn't I explain, Peter? I hope I've touched on that in a rapid fashion. Yep. Let me just maybe 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 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 binding globbulin 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 or is soluble within water. And then again, you mentioned the two families, the apoa family, the apo 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 little A. That's a totally different uh apo lipoprotein, which we're not going to talk about today, although we've got lots of content on that.

Um, you also mentioned how much the APOA's the APOA's the APOA's outnumber the apo's 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 200 mg per deciliter, you'll easily notice that the sum of your LDL and VLDL cholesterol it could easily be 140 of that 200 milligrams per deciliter whereas the HDL cholesterol might only be 60 of that.

So again, many more in number but much less in cholesterol carrying capacity. And then of course you talked about this idea of reverse cholesterol transport. We have the indirect and the direct. 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 followup is for the person who says but Tom I buy I understand everything you're saying but if LDL is so important for reverse cholesterol transport in the periphery what happens as LDL goes down is that a bad thing?

Am I losing the ability to return cholesterol to the liver? No, that just means that if LDL cholesterol goes down, if you really even look at your total cholesterol, it's going to go down too. So there's less less less 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 eluxing as much cholesterol because they're in cholesterol balance. the HDLs are uh sending transferring less cholesterol to the LDLs and so the system is in it's a very operational system and they all talk to one another the nuclear transcription factors that regulate all of the some of the mechanisms I spoke to are imbalance.

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 because all it's in balance in all the other cells. Tom, another question that might be worth addressing here is what is the amount of total cholesterol in the body that is in the plasma, i.e. that which we measure versus not in the plasma. I mean cholesterol is this essential molecule for life. We've talked about how it makes up cell membranes.

It forms the basis of 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? Well, it's much smaller. I mean most of the cholesterol in the body is within the cells of our body and we've already divided it.

Hey the body is the peripheral system and the brain system and if you look at total amount of cholesterol most of it in in some is in all of the periphery that means your liver every organ you got your skin where every membrane and every cell in our body. So that's the mass of total cholesterol and the uh then the brain has its own component because they they don't interact. But in the plasma uh it's interesting it's interesting it's interesting most of the of course all uh you would think all of the circulating plasma is within lipoproteins but it's not.

There's a and this comes to a surprise to many people too. The biggest carrier of cholesterol in our bloodstream is in our red blood. Red blood cells. Yeah. Yeah. Because they're cells. They have cell membranes and they're big. They're vastly larger than a lipoprotein. So they actually carry more milligrams of cholesterol than do our everybody thinks it's the lipoproteins. It's not. So that's how it's distributed in the blood. There is no free cholesterol. I mean there's a minuscule amount on albamin. Not much, but that's it.

it's in a lipoprotein or it's in a red blood cell membrane. Then we have the organs of the body and it's another question that you can trick up people because if you tell ask the average person or even physician even lipidologist uh what's where's most of the cholesterol in the body or what organ has the most cholesterol and everybody says the liver and wrong. It's not even close. The brain o of all the organs in the body has 20 times more cholesterol than does the liver.

The liver I 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 3 to five grams. Now one reason is and we're going to get into this. The brain holds on to cholesterol like the bank holds on to its gold in the vault and everything. It doesn't. But whereas cholesterol, the liver is just sort of a handling station. Whatever cholesterol a liver has, it's sent out or it's eluxed into the bile through bile acids or free cholesterol.

So the liver is like a transfer station. So it stores a little bit of liver because it always has to have a pool of cholesterol to do what it does. Whereas the brain holds on to its cholesterol. And this is another physiologic point we'll have to get into or so. No, it's the brain. Pardon me. The liver is more like a bank with money which is it's got a high flux. It takes a lot it takes a lot of deposits in but then of course the only way it makes money is by loaning out or distributing that capital and putting it to work.

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 it's tiny tiny amount. Yeah. Between cellular cholesterol and circulating cholesterol. circulating cholesterol. circulating cholesterol. Yeah. So, this is this is definitely one of the misconceptions people deal with. Um and again, although we're not going to focus on 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 just lowering that tiny fraction of the total body's pool have such an outsiz effect on atherosclerosis? on atherosclerosis? on atherosclerosis? Yes. So now we're into the pathology associated with cholesterol and we know the leading global killer is atheroscerotic disease. It's not hey 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 aththeroscerosis there's one sineuinonan 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 atheroscerosis and you can't suffer the consequences thereof so the next question is all right Tom well how in the world does cholesterol get into that artery wall.

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

alpha lipoproteins. alpha lipoproteins. But we now know, and this is really not even up for discussion. You've done podcasts on this and the references on it. It's you have that great slide, the ference slide, where every single trial that's ever been done, every Mandelian analysis of lipids and lipoproteins shows the the more you lower cholesterol, the less atheroscerotic events happen. So we now know, we've already told you it's the beta lipoproteins that are carrying most of the cholesterol in the bloodstream. So if a beta lipoprotein an LDL or a VLDLDL and because of its resonance time 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. 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 they immune system sends in white blood cells that engulfs them and that creates a cholesterol-lated uh laden macroofage 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 LVL particle numbers or VLOO particle numbers if you want them.

But since there is one apo on every one of those particles, we simply measure apo. One apo per particle. Once your apo level starts to exceed certain thresholds, thresholds, thresholds, atheroscerosis is very likely to occur. The main driver of your apo concentration is two things. of course a little bit of production out of the liver but the most of the escalation becomes is due to defective clearance of the apo particles from the plasma meaning those LDL receptors the liver for whatever reason is not expressing enough of them to clear to keep the apo concentration physiologic in the bloodstream so once apo particles are not cleared there's only one other option for them they have to invade an artery wall.

So it's the Apo B concentration and they deliver cholesterol and that explains aogenesis and in the old days we used 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 VLDLDL cholesterol all triglycerides divided by five is sort of an estimate. Is there too much cholesterol in the VLDL particles? We don't have as great a test on that, but the vast majority of these dump trucks entering your artery wall are LDLs.

So, uh ultimately, 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 apo and that every apo 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 apo dump trucks. Follow up on that point. Um again let's take two individuals whose APOB concentration concentration concentration or and documented LDL cholesterol level is above that physiologic threshold uh such that diffusion is going to favor entry of the LDL the lowdensity 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 and 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 sure well as I mentioned if cholesterol gets in your artery wall you have the disease and it's the apo particles bringing them in but that is not the only ideologic uh reason why one would have atherosceros there a number of other factors that go into play and it's the rest of your health your metabolic health is a major concern if you are insulin resistant up to type 2 diabetes, you have chronic inflammation in the body, you have endothelial cell damage in the body.

So, it's easier in those people for these uh particles to get in earlier in life and generating plaque. We should make the um point that uh this apo 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 April B is better. So your blood pressure would be a factor. Your uh smoking as you said if you have some autoimmune disease that's contributing to inflammation.

We know uh people who have chronic inflammation uh get have increased atheroscerosis increased atheroscerosis increased atheroscerosis uh collagen diseases, rheumatoid arthritis, they have lifelong uh inflammatory factors going on and uh other abnormalities that weaken the arterial defense arterial defense arterial defense against atherosclerosis. against atherosclerosis. against atherosclerosis. Uh oxidative processes is a big part of atherogenesis. So if that is going on in the body, but sometimes we do see like you said great grandma who smoked all her life and has high LDL cholesterol and why no plaque and there are forces at play that we just do not understand.

There's other protective whatever going on in their body that we have not been able to identify even genetically or we're testing this test. Oh, they got some elevation of molecule Z. It's protecting them something's going on. But and one day we'll ascertain that. You know, as the polygenic risk scores come into if we do them early in life, it can sort of predict who is going to make it to 80 and never have a heart attack and who is not because they're looking at a multitude of genetic things that you are never looking at one at a time in an individual patient.

So, look, genes control everything. they are genetically blessed. Those but important thing to make is don't ever think because your LDL cholesterol is 200 that I'm one of them because there's no way to know that. Why play Russian roulette and think it's not going to bother me when for the vast majority of people it does create havoc and pathology. So let's now um talk about the brain. Um, so we've got these um, apo and apoa lipoproteins, the HDLs and the LDLs predominantly. predominantly. 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 peripheries cholesterol? Um, and if so, can apo B and Apoa A lipoproteins get in there and deliver cholesterol as needed? Well, the quick answer to that and then I'm going to elaborate is the what's going on with cholesterol in the brain, how much cholesterol is 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 apo 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 bloodb brain barrier which is actually a barrier that separates the brain from the periphery as we've talked but I like to start to give you an idea about why has the brain got so much more cholesterol why is it storing it so much more than say the liver or any other organ in the body.

Well, as uh we are in uterero with mom in the second and the third trimester, the fetal brain is already starting to denovo synthesize its cholesterol because it evolution knows it's going to 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 or so. So every brain cell starts producing cholesterol in uterero very quickly.

Brain cells it's very easy. You have neurons, the ones I allude, but any cell that is not a neuron in the brain is called the gal cell. And there's only three of them. You have astroytes which in the adults produce a lot of the cholesterol. We have aligodendrites. 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 glyo cell in the brain is a micro glyioite uh and they are the brain immune uh cells. So they are uh the last remaining cell. So uh in uterero the day we're born you there's no more mom contributing cholesterol to the brain. It's the brain making it itself. And every cell I just mentioned is overproducing cholesterol because the brain knows as I as it grows and grows, it's going to need more and more cholesterol for all these cell membranes.

So everybody that can produce cholesterol has to do it. Knowing that the brain cannot extract any cholesterol from what's circulating in the plasma. You've mentioned it many times on your podcast. If you take a a 2-year-old and measure their LDL cholesterol, it might be 30 milligrams per deciliter. Yet, that is the time when the brain is growing more than it ever will. Between birth and age of 10, the brain is expanding to its adult size and it's has it can't do that without cholesterol. So, it's supermanufacturing cholesterol, but it's doing it in people who little children who have very low detectable LDL cholesterol.

So that tells you basically physiologic 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. Oodendrites keep making it. They always will. The the microgle they don't have to make that much. Aststerytes continue to produce it at a high form. But there's one cell that stops producing cholesterol. It's the neurons. At when the brain is full adult size, the neuron says, "No, no, no.

I'm not going to make anymore. I want the astroytes 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 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 want to waste ATPs making cholesterol if it can get it elsewhere. The neuron starts using ATP for its functioning. So and then it falls on the astroite. So that's a little bit about cholesterol production in the brain. All of the cells can do it, but at a certain point the neurons say, "I don't want to do it anymore. Astroytes, 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 uh enumerated lipids travel within the lipoproteins in the plasma.

Well in the brain the cholesterol that's going back and forth between cells doesn't use the blood. It uses the brain interstitual s uh tissue which is called the matrosome. So if we take the brain, it's it's this connective tissue and there are zillions of these cells in them, the glyo cells and the neurons. Now they're very close together, but they're not contiguous. They're not binding to each other. So if an astroite produces cholesterol molecules and the neurons over there saying, "Hey, I need that. Send it to me." We have to have a brain cholesterol transportation system or a brain lipid transportation system.

And so what do the aststerytes do? Same thing that happens in the periphery. It makes a lipoprotein. lipoprotein. lipoprotein. But there's going to be a big difference here. So what the first thing the aststerytes are going to have to do is synthesize cholesterol. Very quickly, we won't elaborate in depth, but we've had podcasts on this before. One of the cholesterol synthesis pathways goes through the next to last sterile, penultimate sterile, and in the brain astroytes it's called deserol. And then desosterol becomes cholesterol. So we'll probably talk about this is one way why we can measure desol in the cerebral spinal fluid.

Nah, that's kind of hard to do. But in the plasma it correlates with brain uh cholesterol production. So the astroy makes cholesterol. It's now going to obviously have to wrap it with a protein, an apoin, so it could shoot it out into the mattress where it can travel, swim over and get to the neuron. And here's the difference. In the periphery, we said, hey, the structural proteins are apo B and apo A. In the brain, it's the famous apal lipoprotein E. And APOE, many people know, oh, that has something to do with the brain because we know there are types of APOE that are associated with cognitive disorders and Alzheimer's disease.

But let's just stick to the APOE protein. So the astroite synthesizes, it binds to cholesterol and it becomes a little lipoprotein lipoprotein lipoprotein uh which it secretes into the matriome but it's an APOE containing lipoprotein. Now if we could take out those APOE containing lipoproteins and put them in a centuge they would sink right to the bottom of the centuge. But what else would be sinking to the bottom of the centuge? Highdensity lipoproteins in the plasma. So the brain lipoproteins are referred to as HDLs because they have the buoyancy and density of a plasma HDL but they're very different because the plasma HDL will have two three four copies of APO A1.

The brain HDL will have a couple of three copies of APOE and that is the big difference. Now once it's in the matriosome this particle it continues to mature cholesterol becomes cholesterolster cholesterolster cholesterolster goes to the center of the particle and it becomes a big fat particle but remember its mission is to deliver cholesterol to the neuron. So the neuron's going to have to grab that apo containing particle and internalize it or grab it and delipid 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 the neurons have LDL receptors, so there have to be LDLs in the brain." No, because the LDL receptor has affinities for ex of just a couple of apop proteins. In the periphery, the LDL receptor is looking for apo B 100. But in the periphery, even APOE can bind to an LDL receptor. But in the brain, the LDL receptor only binds to APOE containing lipoproteins because there are no APOB containing lipoproteins. So it's the same darn receptor.

And this is why I think we should stop calling it the LDL receptor. We call it we should call it the APOB APOE receptor because that's what it recognizes. 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 confirmationally how that LDL interacts with the LDL receptor? What is it about the APOB protein that enables the key to fit into the lock? the lock? the lock? There's a very small segment of the APOB receptor that's called the LDL receptor binding domain. Excuse me. on the APO B there are ex certain amino acids that line up and they create they have a surface charge and here's the LDL receptor. Now the LDL receptor has a certain segment that is called the apo recognition domain.

There's certain amino acids there that create certain electrostatic forces. And if the domain on apo and what determines is that sticking out properly is the confirmation of apo that explains the difference clearance rates between big LDLs and small LDLs as opposed to normally constructed in size LDLs that have a normal apo confirmation. They have much higher clearance. the small LDL where that domain may not be exposed as readily or the big LDL where it's not where it should be. The LDL receptors don't as easily recognize big LDLs or small LDLs and that's why people with small LDLs or even big LDLs often have very high LDL particle counts because clearances decrease.

So there are certain just small areas on the LDL receptor and the APOE B that if they align properly you have great clearance. New news is just discovered and published last year from our friends at the NIH the NIH 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, but that's sort of irrelevant to just understanding the LDL receptor clearance process.

So, that explains part of the extended uh plasma resonance times of LDLs. How is the apo be conformed? So, so Tom, given that the size of the LDL within a variation of normal, right, um, can impact clearance, it really surprises me that that same LDL receptor can easily find somewhere on the APOE wrapping a very, very, very small lipoprotein in the brain, enough of a confirmational 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 apo 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 apo which presumably must be the case or you wouldn't have the match the primary very uh reason where APOE gets involved with clearance of lipoproteins is on kyomicrons and VLDL's they carry several copies of APOE per particle unlike the apo which is one copy per particle so when they are fully full of triglycerides they're very big big apo is distorted in a certain way now the receptor in the liver that's going to clear VLDL's and komicrons is called the LDL uh re related receptor 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 kyos and the VLDL's and that's why they have such short plasma resonance time. I'm going to mention it now. now. now. Sorry, 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 of of and the real reason and this is why I'm explaining to you how the liver clears VLDLDLs and kyomicrons because the LRP only recognizes APOE and the brain not only expresses LDL receptors but they express a lot of the LDL receptor related protein one.

Okay. Okay. Okay. Which is an APOE affinity clearing. Understood. Understood. the LDL receptor can clear some of the APOE part, but it's the LRP that's doing most of it. The last receptor that the neuron expresses, and we've talked about this, is called the scavenger receptor B1 that binds to the HDL and it delidates it, but it's an APOE recognizing scavenger receptor also. So everything in the neuron is basically looking for APOE and it gets it through especially the LRP which is only an APOE recognizing receptor and the scavenger receptor recognizes APOA1 recognizes APOA1 recognizes APOA1 typically not in the brain but it can be and we'll get to that also but APOE works well with the scavenger receptor too and uh so very few LDLs in the uh periphery uh I mean maybe 2% of your LDLs have an AP OE 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. 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 descol into cholesterol and then the other one of course turns lethostol into cholesterol.

What is the relative balance of cholesterol synthesis in the brain between those two pathways? Very interesting. In the periphery the vast majority goes through the lethostal pathway. very little goes through the dismal pathway. In fact, the primary cells that use the desmosal pathway in the periphery are our steroidenic tissues. All of our other cells, I mean a little bit will go through the desmosal pathway, but most is lithostal. So, if you are measuring steriles in the blood, lethost 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 lifoststerol but at the age of 10 when the neuron decides I don't want to make cholesterol anymore it there's no lithostol being produced by the neurons it's all dismasteral that's winding up if there's cholesterol molecules winding up in the neurons it's through the astroite uh the block pathway going through deserol. 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 lethostol is not used as a marker of uh brain cholesterol synthesis for the big reason even though there is some lethostal pathway going on in the brain. If you measured it in the blood 95% of it is your other cells making it. Whereas if you measure desostrol in the blood the majority of it reflects correlates extremely high with cerebral spinal fluid desostrol and brain tissue de desmos. So that becomes a very cool marker that we can actually measure in the bloodstream because desmos in the plasma re correlates very highly with cerebral spinal fluid and brain cholesterol.

cholesterol. cholesterol. And why is that Tom? That's that's counterintuitive to me because they seem like completely independent pathways. Why should the desol you measure in the blood uh tell us anything about the the cholesterol synthesis of the brain? I think uh and you're better at figuring out these teologic reasons than I that uh evolution decided there's one pathway that we're going to do in very critical areas. The brain which only makes its own cholesterol and stores it in the steroidenic tissue. Uh we 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. reflects. reflects. All right. We'll come back to that because 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 that 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 different lipoprotein 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 oligodendrites and presumably to some extent aststerytes.

I do want to just make one point clear for the listener um which we we haven't really explicitly stated but um the astute listener of course has already picked up on the fact that we've talked about APOE and as you said APOE has a relationship to Alzheimer's disease. 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 apo lipoprotein e a protein and this is denoted with a small a small a small p small o big e and that's when we're talking about apo 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 33 or 3 444 23 etc.

Um do you want to just explain the relationship between those different six combinations of genotypes? Everything from a 22 to a 44. Um and how the different genes make different proteins and then we should talk about why that's relevant. relevant. relevant. 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 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 apoproteins.

So we do there are the you inherit the genes from mom and dad and that means one gene from mom one from dad. So you get one al in your gene and the other alo from each. So was your mom an apo2 three or four and likewise with dad and you're going to inherit there's several potentials. You can be an E2, E2, E2, E3, E3, E4, E3, E2, E, uh, E2, E4, E4, or E double homozygote for E4. So depending which of those genes you attack, your APOE protein is going to be constructed a little bit differently, which is going to affect its ability to function, whatever APOE is doing when it's stuck to a lipoprotein.

And the main thing it's doing, it's serving as a lian to what things are going to bind to or even what the APOE will bind to other than the lipoprotein. the lipoprotein. 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 twothirds of people that have that. Far less people carry the APO2 gene, especially APOE2 homozygosity. APOE2 homozygosity. APOE2 homozygosity. Peter, why don't you tell how many carry the E4 hetererozygot and the E4 homozygot?

you have those percentages then? then? then? Yeah, I mean I you know again it depends on the series you look at but it seems about 55% of the population are E3 E3 that the so-called wild type um 20 to 25% might be E3 E4. Um and 1 to 2% 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 3%.

Uh E2E4 is also quite rare. Um so the two most common by far are E3 E3 and E3E E4. Um, and as we've talked about many times on the podcast, um, the risk associated with Alzheimer's disease between 33, which is always the reference case, and 34 and 44, those go up nonlinearly. So the three four individuals, the people that have one copy of three, one copy of four, they make a version of APOE, the protein that's not as good as the wild type, and their risk of Alzheimer's disease is about two times higher that than someone who has a 33.

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, u that risk is significantly higher. Uh there was a day Tom 15 years ago the literature was calling that 20 to 25 times higher. That number has come down considerably and I think most most series would talk about that as being an 8 to 12fold 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.

effective. effective. Yes. And this is going to have ramifications. ramifications. ramifications. We've done podcasts and Peter's had Dan Rder on here. The most important thing about the peripheral HDLs is not the amount of cholesterol they traffic. It's kind of trivial and it gets transferred here and there and it almost tells us nothing if you're measuring HDL cholesterol. Tells us nothing about what the HDL particles remember they're 90% of your lipoproteins out there. So clearly they're what they're doing to cholesterol is not their major function. So that means HDLs do other things and as we're learning they do innumerable other things that regulate all aspects of human health.

They're actually a part of the innate immune system. So they're involved with fighting inflammatory diseases, infectious diseases, chronic diseases, cancer. 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 200 proteins have been described in the periphery as being found on HDL particles. Now, that doesn't mean there's an HDL particle carrying a 100 peptides on it. Impossible. They're too small. But each HDL might carry one or two peptides. And each of those peptides might have some function that it's hard to even know what they are. Are they helping the immune system or or are they involved with coagulation or or what? So uh we have actually numerous armies of HDLs each constructed with one or two of those peptides in addition to APO A1 and APO A2 some of the lipolippid related APO proteins uh and so there's no way to know uh for us to measure these HDL subopuls.

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 centifuge 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 centuge tube. But the tiniest HDLs, the discoidal HDLs, APO A1 by itself, they're sitting right at the bottom because 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, gez, don't you wish we could measure them? But here's where it gets interesting. I we've hinted earlier in this podcast that there is a lipoprotein that can traverse that bloodb brain barrier and get into the brain and it's these extremely small HDL particles either free apoa1 or an apoa1 that's bound to a couple of these other proteins and maybe some of these proteins are very important antioxidative proteins anti-inflammatory proteins so if those tiny HDLs that we cannot measure jump into the bloodb brain barrier or through it and they're now in the mattress.

mattress. mattress. 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 astroite APOE constructed brain HDL particle is also carrying a copy or two of H APO A1 that actually originated from the plasma. The brains can't synthesize Apoa AA1 the brain cells. So if it's in the brain and we know it is it it they do pass the bloodb brain barrier. It is believed that is receptor mediated. It might be this good old scavenger receptor again expressed at the bloodb brain barrier that facilitates entry of apo1 or the really small dense HDL uh apo1s carrying accessory proteins.

And the hope is, hey, number one, if they get in, great. So now the brain HDLs, you have different subopul of brain HDLs. You might have only APOE containing brain HDLs. You might even have some APO A1 brain HDLs, but most of them are going to be APOE plus APO A1 brain HDLs. And those other proteins that came with the APO A1 maybe can do start doing some good things in the brain. and where this might be really good. So in the periphery we have brain functionality.

functionality. functionality. I did not introduce it but it's easily you can deduce that wait a minute if there are functional HDLs in the periphery I'll bet there are circumstances where there are dysfunctional HDLs in the periphery that are not equipped with the proper protein or they're carrying proteins they shouldn't be carrying proteins that can do harmful things to tissues they would be dysfunctional HDLs don't I wish we had a blood test for that and we do not so in the brain Now you have these uh APOE particles maybe can carrying APO A1 but now if you're an APOE E4 producer when your astroite produces APOE it's going to be an APO E4 type of 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 aststerite 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 disrupted cholesterol transport into the neuron. Now all of a sudden the neuron is not getting the cholesterol it needs and that will create havoc because the neuron puts it right in the cell membranes if you don't have the proper amount of cell membrane cholesterol.

This is where something called amaloid precursor protein sits and if you don't have the right cholesterol balance it's acted upon by certain enzyme called secretases. That's where you start producing beta amalloid and even tow 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 maybe describe some of the other things that APOE4 brain HDLs don't do that an APOE3 or an APOE2 HDL would.

Well, I actually want to take us backwards for a second, Tom, because one thing that we've danced around, but I don't think we've explicitly addressed is what is the relationship between brain cholesterol movement and something that people are very familiar with if they've listened to this podcast, which is amaloid. Uh so people are obviously familiar with the accumulation of beta amaloid and ptow 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, as you talk about all of this dysfunctional uh movement of cholesterol in the brain uh uh 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 amaloid tow and cholesterol? There must be a link, right? Definitely. We go way back. You can read the studies of autopsies on patients with Alzheimer's disease and they're really cholesterol overloaded brah tissues especially the neurons.

So remember the neuron the main thing determining its function is its cell membrane integrity and if you have the proper cell main construction signaling occurs properly the synapses fire properly or so. Now what will happen if you have too much cholesterol in that cell membrane and this is what happens I in the Alzheimer's patients Alzheimer's patients Alzheimer's patients what I just alluded to a few seconds ago also located in the cell membrane is amaloid precursor protein that's a protein that is going to evolve into the production of beta amalloid so uh and whether it produces there's two types of that amaloid 40 and 42 with 40 uh uh being uh 42 being the more injurious type of uh amaloid beta and the 40 being a less toxic type of amaloid 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 amaloid precursor protein cleave into the production of amaloid 42. If there is the proper amount of cholesterol in the neuron cell membrane, it's uh the a secretase alpha secretase that sort of slows the cleavage of amaloid precursor protein into apob and you wind up producing more of the apo amaloid beta amalloid 40 which is the less toxic form. So obviously it's the cholesterol content in your cell membrane that is a major major factor.

There's one other aspect of cholesterol homeostasis that we might as well introduce now because too much cholesterol in the cell membranes is a danger to the neuron because the membrane isn't going to function. The neuron is the one uh cell in the brain that has the ability to get rid of cholesterol. We've spent a lot of time saying the brain makes cholesterol and it retains it. In fact, the halflife of cholesterol in the brain is five years as opposed to a few days in the periphery.

So that tells you the brain is reserving cholesterol. But early early I told you too much cholesterol in any cell is toxic in the neurons. Not only will it disrupt membrane function, but it crystallizes in the cytool of the neuron and it kills neurons. You don't want to kill neurons. You're going to 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 oxyol. And the one it produces is called 24S hydroxy cholesterol.

hydroxy cholesterol. hydroxy cholesterol. Uh people who un know what cholesterol looks like biochemistry-wise, it has one oxygen molecule at the third position of the first ring. 24s hydroxy cholesterol not only has that one cholesterol molecule, it has a second one at carbon 24. So now you have a hydroxy group on both ends of the cholesterol molecule. That makes it a little bit more water soluble. So when the neuron says I got to get rid of cholesterol, it has an enzyme 24S hydroxy cholesterolase that will make cholesterol change into 24S hydroxy cholesterol which is water soluble.

It it comes out of the neuron. It floats right through the mattress to the bloodb brain barrier where it can pass right through it because it's sort of a hydrophilic lipid with an oxygen hydroxy group on each end. when it hits the uh bloodb brain barrier, the fatty acids and the phospholipids hate the hydroxy groups so they separate and it's just creates a little tunnel through which the 24S hydroxy cholesterol can jump into plasma. Now wait a minute, it's a lipid. It can't jump into free plasma.

But what's floating in the RA in the plasma that rapidly binds to the excreted 24S hydroxy cholesterol? either albamin or any brain lipoprotein that floats by. Now it's part of a protein. It's either on albamin or it's on a lipoprotein. They bring it back to the liver. Now here's the cool thing. What's the only other tissue in the body beside the bra brain that can produce an oxy? It's the liver. And what does the liver do with oxy? Well, the liver has cholesterol. You know Pete that the liver is our major our only manufacturer of bile acids which are oxysterols.

So cholesterol gets transformed into an oxysterol in the liver. Same enzyme that the neurons express and the oxysterols they go through several steps but they become your bile acids down to your gut. Goodbye fecally. So the brain actually has this cool way of getting rid of excess cholesterol by that transformation. and you send it to the liver where it could be feally excluded or so. So this 24S hydroxy cholesterol gets very important. But if again you start to build up too much cholesterol in your neuron cell membrane, it's in the cell membrane now.

So there's less cholesterol in the cytool of the neuron. The neuron stops making 24S hydroxy cholesterol. brain is not uh it's not escaping into the plasma anymore. This is why researchers use 24S hydroxy cholesterol in the plasma as a biioarker of brain health. It shouldn't be there because the brain is retaining all its cholesterol. The neuron's not trying to excrete any cholesterol. But if it does, the chole concentration of that in the plasma goes up. the only uh the liver doesn't secrete its oxysterols into the plasma but the brain does.

So it's a great biioarker 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 hydroxy cholesterol because they think if their drug is helping the brain prevent Alzheimer's disease, you won't find 24S hydroxy cholesterol in the bloodstream. And that's one of the sterile biioarkers as is the desol that we eluded. So we actually have two things that we can measure. Here's the bad thing. In the real world, we can get desostro measurements fairly easily.

there's no commercial laboratory that 24S hydroxy cholesterol is become available. Uh so we don't uh outside of research studies I wish we could measure that in our patients because it would just be another of the many biomarkers that are starting to emerge on brain health. So finally back up it's this disruptive this apoE4 this apoE4 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 marketkedly 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 cytool. So it's very complex these lipid mechanics that are going on in the E4 patient. And I'll I'll let you ask about that before we get into other attributes of what apo E4 might not be doing well in the brain. Well, I kind of want to ask a a question 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 pharmarmacology.

So, I want to sort of make that bridge. Now, um obviously we're not going to get into all the reasons why one would lower APOB pharmacologically. It's implied in so much of what we already discussed in the periphery. Um and when you talk about that the thing that comes to most people's minds I mean most people aren't thinking of bmpidoic acid and isetto and PCSK9 inhibitors or bile acid sequesterance or CPET inhibitors or CEP inhibitors rather when 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 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. And of course, statins are the number one drug to lower apo in the periphery because that no doubt about it reduces atheroscotic heart disease. But of all, and Peter rattled off the classes of Apring drugs that are primarily used nowadays. Of all of those, there's only one that can penetrate the bloodb brain barrier and get into the brain and it is the statin class. All of those other drugs mentioned either whack work solely in the liver or no way they could penetrate the bloodb brain barrier.

It didn't do anything to brain cholesterol homeostasis. homeostasis. homeostasis. So if a statin gets into the brain now a little bit Peter mentioned what we call hydrophilic hydrophobic hydrophilic hydrophobic hydrophilic hydrophobic statins lipophilic lipophobic and you know a hydrophilic loves water uh lipohilic loves lipids hates water and uh early on there was lots of data showing just traversing a cell membrane border the uh lipohilic statins get through easier they because the border itself has got a lot of lipids in. So they all right come right in.

So it's a little for an the lipid hydrophilic statins to penetrate a barrier pretty much there has there are receptors that pull them into even the liver the uh hydrophilic statins there are receptors that pull them into the liver and they get in quickly. So tactically the lipophilic statin should get into the brain a little easier than the hydrophilic statins. But more modern studies have shown that really doesn't matter as much because once you're in a steady state, meaning you're on a statin, you have your blood level of the statin, ultimately they're all in the brain.

Yes, the lipophilic ones may get in a little easier, but there the hydrophilic ones get in also. And they all have the ability therefore to various degrees inhibit cholesterol synthesis in the brain. So I don't think you necessarily have to pick a statin based on its lipohalicity or hydrophalicity worrying about the brain. I think because in real world practice uh rua statin a hydrophilic statin is used more more commonly uh it certainly can get into the brain maybe a little less slowly than lipur lipophilic statin can but if you're in a steady state they're all in they all have the ability to reduce cholesterol synthesis in the brain so is that is that size driven Tom is it just that the size of a statin is such that it can get across the bloodb brain barrier as the other classes can't.

It's just the construction uh uh of the uh the statin drug on how uh uh you know what converts a hydrophilic or a lipohil lipohilic 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's certain aspects of that construction that gives them hydrophalicity and other aspects of that alignment or construction of their molecules gives them the lipo uh felicity or or lipophobicity. So anyway, since we earlier we just said, hey, Alzheimer's disease is too much cholesterol in the brain, too much cholesterol in the neurons, you could hypothesize that if statins did get into the brain, which they do, and all of them do, and in a steady state, they all have the potential to affect cholesterol synthesis in the brain, it might actually be good in a lot of people to slow down a little bit of the cholesterol synthesis in the brain because too much cholesterol results results in uh pathology of the the neurons and tissues.

And this is why and we're not going to review them here. If you look at all the statin trials, the metaanalyses, metaanalyses, metaanalyses, 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. brain. brain. 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 metaanalyses and yeah, the the TLDDR 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 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? problematic? problematic? Yes. And this is more in the hypothetical range right now because nobody's going to do these studies to prove it one way or the other. But because as Peter just says, cholesterol is so important, you would never want to oversuppress 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. No, you know, my addition isn't as good as it used to be. And we stop the statin and rather quickly that goes away. So one hypothesis would be that is the person that the statin is oversuppressing cholesterol synthesis rather rapidly and uh severely and that's why they got neurologic symptoms and they stop it obviously you've stopped the statin you're what you're restoring whatever synthesis was going on in the brain or so. So, um, that becomes a plausible hypothesis.

Uh, and I said, nobody's ever going to 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 stat and you don't get that acute brain fog, it's probably safe to oversuppress cholesterol a little bit over time. and maybe especially so if you're an 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 here not much going on or benefit and that could be the plausible reason.

Now, we go back to you've uh went through the desol and the phosphol pathways. There's a nice study published almost a decade ago where they were doing cerebral spinal fluid desmos levels and plasma desmostral levels and measuring it by mass spec and there was high correlation between the CSF desostrol and the plasma desmostrol desmostrol desmostrol saying that wow desmos in the plasma it reflects desostrol in the central nervous system. And even more interesting that study showed that the people with low desol 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 going to help the lessen their incidence of Alzheimer disease, maybe keeping an eye on plasma desmosol sort of makes sense. And if you do oversuppress it with your statin therapy, maybe you can change the dose of that statin therapy or maybe you can just abandon statin therapy and lower APOB to reduce heart attacks with the several other drugs that you ran through very quickly there.

So, so it gets very interesting. And last thing to tie it into that 24 s hydroxy cholesterol. Remember, if you're on the way to Alzheimer's disease, that's increased in the plasma. There's studies showing that if you prescribe a statin, the 24 s hydroxy cholesterol 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 because you don't want to see that. But then you would back it up with the dismal because if that was low I've maybe suppressed it a little bit too much.

All wonderful hypothesis that has a lot a lot of data. I I can easily provide 20 references on desmos in the brain how critical it is. So this is a very plausible theory right now and don't expect a clinical trial to prove or disprove this hypothesis right now. We'll we'll link to those um sources Tom in the in the show notes. Um, one other drug I just want to talk about really quickly is. Um, again, is a, you know, a drug that really works outside the body, so to speak, right?

It works in the gut. It's a blocks that Neiman picks C1 like1 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? 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 know we have a couple of neurologic colleagues Richard Isacson and Kelly Otis who are very involved with these diseases and is there anecdotal belief that a zettoi in addition to helping them control their April B 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 Zetto is one of those drugs that just cannot cross the bloodb brain barrier. So, how in the world could it be helping dementia or so?

But it has a metabolite called a zettoide glucaronide that actually can pass through the bloodb brain barrier in small amounts. But unlike a zettoide, it gets in and there are animal studies showing that it interferes with hexocinase and the glycosillation of brain proteins to a if you reduce that there's some benefit less inflammation in the brain or so. So there is that and again it's a study I will definitely give you the reference to that people can read that there's some plausibility to it and there's an anecdotal belief among neurologists who live in this field that it's a helper so wouldn't that be cool you know Peter in as we control apo aggressively in your patients we use a lot of aettoide because we prefer to use lowd dose statins and if we don't get to the apo goal we're adding a zettomide.

We also day one check synthesis and absorption. So there are patients where we use a zettoide day one because they're hyperabsorbers and that's where you get the most efficacious apo lowering. So in the future as we have people who carry the apoE4 alles and they have apo B issues, issues, issues, you know, we might pick a statin first, we might pick a zetto, but I think they might be a patient where you need a little bit of a statin and a little bit of a zetto until somebody proves this.

And I would not hold your breath waiting for a randomized control trial that is edetto what it's doing to even some of the uh uh uh Alzheimer's biomarkers in the blood. Uh because uh only emerging drugs are they starting to do those type of studies on that. Nobody's going to go back and look what is edetto pow or amaloid ratios or so. I wish somebody should you only maybe a small study. Well, I'm surprised you could probably pull it out of a bio bank for an existing uh study that was already done on aibbe.

So, that's not we could at least get the suggestion of that from from such a study because we do have at least one. least one. least one. Well, I know we have statin versus statin plus a zettobe trials. Don't we also have a monotherapy zedia trial? uh only in Japanese elderly people and I don't think cognition was one of the thing it was just and it was not a r a blinded trial so it was an open label trial yeah trial yeah trial yeah just to show it was efficacious in lowering apo in a primary prevention setting setting setting but they certainly didn't look at cognition or biomarkers in that stud but if they still have serum banked you could at least look at pre and post levels of pal you definitely could 424 yeah be a great research project for some young PhD or uh budding lipidologist uh hopefully listening right now.

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 there 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 do we know about EPA and DHA and brain health? Without talking about specific products, let's talk about if an EPA and DHA are both important to the brain. There's far more DHA, but we're finding out that even EPA is important for the brain now also. So, uh, 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 from krill oil. Uh so now once you ingest a triglyceride or a phospholipid remember the only thing that can really be absorbed free fatty acids. So pancreatic enzymes lipaces 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 my cells gets absorbed by a fatty acid absorber CD36.

Interestingly not only can a free fatty acid be absorbed but a lysofphospholipid can be absorbed. A phospholipid has a phosphorus moy and a head group and two fatty acids attached to it. That's called a diradal 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, and the lipaces either makes free fatty acids or it could make lysofphospholippids. But hey, if the remaining fatty acid on that lysophospholipid is an omega-3, it gets in.

So once they're in the entrite, what happens to them? The the entrite immediately reynthesizes them to a full phospholipid uh or attaches them to a triglyceride molecule which goes in the core of the kyomicron. The phospholipid goes on the surface of the kyomicron. It shoots them into the lymphatics and they rapidly get into the plasma. They undergo rapid hydraysis at the fatty at the muscles and fat cells by lipaces and that frees up these phospholipids. Uhhuh. 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 bloodb brain barrier and there's a specific receptor in the bloodb brain barrier that will internalize the lysophospholipid lysophospholipid lysophospholipid form of DHA or EPA and once it gets into the brain it's in the brain it uh you know it can be trafficked in these brain HDL particles and it's part of the things they do too it can jump right into the cytool or the first cell that it bumps into while it's in the mattress.

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 has the amount of omega-3s they say they do. Uh don't trust the labels of every supplement you may may buy. and they get in. Now in the periphery there's a lot on and there's a big trial it shows perhaps for preventing lessening residual risk in people who have a B control the EPA is a little bit more important and 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 and used to be all DHA but I know the thought on that is changing EPA is required or two.

Some people can convert EPA to DHA but not everybody can and that's how they get up into the brain and there 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 because where do omega-3s go in the cell membranes and that's everything cell membrane health in the brain cells. I hope I explain that. Maybe you could I'll have rid of them more. more. more. 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 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 demonstrabably matter when it comes to brain health. Where where in that uh pantheon would you sort of put um having 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? Well, the data is all going to 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 uh 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 level one randomized blinded controlled study doing what you say so it's irrelevant to me. But if you look at all the observational data, just like we did with the statins, where it's in general pretty good, I think if you went through all of that data with omega-3s in the brain, you would find you Bill Harris has studies relating it to brain size or at least certain sections of the brain size and omega-3 context, I believe in the hypothalamus or other areas of the brain.

So again, it's this plausible stuff, but there's no level one evidence. We certainly have evidence in the blood that low levels of omega-3 index are certainly associated with sudden death and increased atheroscerotic heart disease. Again, we lack the randomized control trials that changing that will reduce events other than that one trial of EPA and insulin resistant high-risisk people who had a B well controlled. So, uh, you're in that gray zone area with the clinical trials on this and they're not the type of trials that in a guideline is going to tell you this is what you have to do.

But again, it's just like our dismal hypothesis. Again, excuse me. This is plausibility there. I see little downside to using omega-3s. Bill Harris, who you've interviewed, has looked at his trials, and he's pretty content that when you hit the eight to 9% omega-3 index, you pretty much have the proper amount of omega-3s in the area 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. 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 new drug in a new class. Um, I alluded to this class very briefly a few moments ago, the CEP inhibitors. You and I have spoken about these drugs in the past on a podcast. We've got several podcasts on this topic, including most recently one with John Casterlin 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 obese and the Broadway trial specifically and how we tie it into what we've talked about today. Yes. basically uh CP inhibitors of which obeseetropib is the latest uh uh have been investigated to see what they do to atheroscotic heart disease and uh LP little A and maybe brain functioners we there's a signal that if you have CP loss of function genetically those people have less Alzheimer's disease or cognitive impairment so that makes it plausible well if we inhibited CP phac ologically we almost convert you into the genetic status maybe there would be less Alzheimer's disease and now in that Broadway trial uh look the people at New Amsterdam Farmer recognized this so they're actually putting a little money into clinical trials perhaps investigating this hypothesis and in that Broadway trial where you administered obese remember it was given to them primarily to reduce apo B and ultimately reduce mace in those people but They actually looked at some of the biomarkers of Alzheimer's disease.

Uh the phosphorolated pal, the amaloid 4042 ratio, the other various ratio of these markers, the fibrillatory markers, all things you can measure and they saw some very interesting movement in the right direction of those Alzheimer's associated biomarkers. associated biomarkers. associated biomarkers. Now, the next step would have to be in a clinical trial, continue to monitor them and and that was a very quick study. You would monitor it over time, but maybe you'd throw in some cognitive function in some of the studies to see, geez, could obtib could obtib could obtib 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 APO A1 in the plasma. But when the HDLs are big on a CP inhibitor, the liver senses, oh, we have a deficiency of ApoA1 because they're not seeing it. It's all on the HDL particles. So the liver actually starts overproducing APO AA1. So Apoa AA1 goes up in the plasma but and 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 obeseetropid is increasing either apoa1 or the really tiny protein laden uh HDL species that can cross the bloodb brain barrier. They believe the potential would be that hey some protective proteins are getting into the brain. They've looked at some anti-inflammatory, antioxidative aspects of those proteins and they believe the apo1 can jump on an E4 apo a brain APOE HDL particle and rescue it and maybe turn dysfunctional brain HDL particles into functional brain particles.

So boy, it's a wonderful story on paper right now, but the fact that the biomarkers are moving in the right direction, I think gives us all great hope. And I believe the company is going to put money into investigating this with further cognitive studies and more advanced studies and perhaps even some imaging studies, PET things like that. Although these biomarkers really, 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 obese.

Yay for its April B ability. we're all going to certainly be using for that. That'll be its FDA indication. But if we get more and more information like this that it's looking good, especially in the E4 carriers, I think there will people would look at any downside. So far, not any or they would have had arrest at their trials, but it's not FDA approved yet. So, they have more data to collect yet. And we will see, but the hope is high. Yeah, I I remain very optimistic um based on the data so far.

And I think the key is going to be doing the right clinical trial. Um, again, I think a lot of these things, um, if you if you 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, um, and duration. Um, you you've got to be able to select people who are high enough risk, E4 carriers, um, 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 um uh at a minimum mace, but also I believe it even looked at all cause mortality or maybe it was cardiac mortality.

And um again, it was primary prevention, which I always thought was I I I thought the study I 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." Um, and not only did the trial succeed in demonstrating the superiority of a of a Mediterranean diet to a low-fat diet, it it was halted early. Um, and again, I I I think it'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 but weren't quite there.

Um, you you could you could get an answer to a question in a few years. And and I think that's that's that's the way to think about doing this and I and I hope they can do that. Yeah. Look, I'll just say, you know, Michael Davidson, your friend, and John Castelline, your friend, they are really driving all of these studies, and they are well experienced trialists. So, they will do the right studies. Uh Tom, this has been an amazing tour of of a topic that is is is sort of new to the podcast.

We haven't done sort of a deep dive into brain cholesterol. Um but I think it's been such an important discussion because um I think there's a lot of uh confusion out there on this topic. I think that the the 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 oligodendraites and neurons and the different pathways and APOE versus apo?

So, so again, I I know that this this podcast was a little technical, but I think I think you did a great job of explaining it, uh, anthropomorphizing it when appropriate. Um, 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. Um, so I want to thank you and as want to 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.

um and and helped me uh develop my understanding of this field of of lipidology. So I can never uh I can never waste an opportunity to to thank you publicly for uh for your generosity your personally with me. So so thank you very much Tom. And look I'll wrap this up by saying yes I was your lipid mentor for a while but over the time we've known each other a long time and I've got to experience your immense knowledge on things I had never even considered before.

So, you've taught me just as much about so many things if I I think it's a great partnership that we thank God we bumped into each other and we've evolved into this role and I'm still going and have the honor of still working uh within your practice not as a prescriber to 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, I it's just been a phenomenal wonderful way for me to continue my career.

So, uh, I love you eternally. You know that. And, uh, 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. it. it. 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.

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