Apolipoprotein E (APOE), a lipoprotein produced in the liver and the brain, plays a key role in fat metabolism. Approximately 25 percent of people living in the United States carry a genetic variant of this lipoprotein called APOE4, which is associated with higher circulating levels of LDL cholesterol and an increased risk for Alzheimer's disease. In this clip, Dr. Peter Attia discusses the role of the APOE4 gene variant and the associated risk for Alzheimer’s disease and cardiovascular disease.
Rhonda: Yeah, ApoE. I've actually got one ApoE4 allele, so I'm very interested in ApoE and I'm actually writing a paper on ApoE4 and its role in Alzheimer's right now.
Peter: Well, I'll tell you my take on that, which I'm sure you've seen the literature on it. But I actually think it's the phenotype that matters more than the genotype. So in other words, I think it's the amount of ApoE that's expressed that matters, not the ApoE, not the genotype. In other words, just as we measure ApoB as a surrogate for LDL particle number and VLDL and remnant VLDL particle, we can measure ApoE now. There's no clinically used or CLIA-approved assay for that yet, but there are labs that are doing it for experimental purposes. And there's a paper that I saw maybe six months, nine months ago that actually showed that if you take the ApoE 3/4s and 4/4s...so I'm sure better than I do, a 3/4 genotype just on a hazard ratio is about a 2x increase over the 3/3 in terms of Alzheimer's disease. A 4/4 of course, is anywhere from 10x to 20x depending on the series.
Okay, so if you're out there and you've got an ApoE 3/4, or especially if you've got a 4/4, you're worried, right? And I'm worried for my patients who are 4/4s. I have four patients who are 4/4s. But when I saw this paper what it showed was actually...and just so the listener would know, the majority of people with Alzheimer's are not 3/4 or 4/4, they're still 3/3. The difference is this...because remember, the 3/3 is the majority of the population. I mean the 3/4 is actually pretty big, it's about 20%. But the 3/3 is the largest one, so having a 3/3 doesn't protect you from Alzheimer's and having a 3/4 doesn't guarantee you're going to get it. And, by the way even a 4/4 doesn't guarantee you're going to get it.
So the key is there's something else that's more predictive, and I think it's the phenotype. So when they measured the serum level of ApoE it turned out to be more predictive of Alzheimer's disease than the genotype. So my hope is that we can get a clinically approved assay in a relatively short period of time that will allow us to actually do that, especially for the patients who are 3/4 and 4/4, which says, "Are you able to reduce your risk?"
So let's say I could measure you today and your ApoE level was here. And then we could say, "Well, look, there's some intervention. We believe that reducing or increasing insulin sensitivity of your brain, you know reducing the probability that pyruvate dehydrogenase is going to cause an energy shortage in your neuron is going to improve your odds for delaying or eliminating AD from the list." And then we could measure your ApoE at a point in time and it were lower, that would give me some confidence that we're moving in the right direction because...
Rhonda: Lower? So you're saying that the higher the...
Peter: The higher the expression, the higher the risk. That's what this...
Rhonda: Higher expression in the plasma.
Peter: In the plasma, the higher the risk.
Rhonda: Okay, So a couple of things, one is...
Peter: I'd be happy to show you the paper because that's...
Rhonda: Yeah, that's interesting because from my understanding, you make ApoE in the liver and you make it in the astrocytes. But one of the important things is that it plays an important role in bringing cholesterol...
Peter: Cholesterol. Yep, yep.
Rhonda: ...from the astrocytes to the neurons, but also in repairing damage that's done. So, you need to have neurite outgrowth to repair any sort of damage that's done, damage with normal brain aging or traumatic brain injury, which is like damage in real-time. I was under the impression that there's less...so there's less ApoE expression in ApoE4 and so there ends up being a problem because the LDL receptor is very important for bringing the cholesterol to the neurons, to getting it there and so... But the plasma, I don't know.
Peter: Yeah. And the other thing is I think the...and by the way, I could be wrong. It's been nine months since I read this paper, so I could have it backwards. But I think the more important thing is, I think there's two separate things going on, right? So the ApoE4 gene also plays a role in...because my real interest clinically is, of course, lipidology, that's my clinical obsession. And that's the place where I think we're becoming pretty clear now that the ApoE 4/4 or the 3/4 is not a death sentence in cardiac disease, especially the 4/4. The 4/4 was really viewed as, "Boy, you're guaranteed to have an MI before 60." And I think the evidence today suggests that once you normalize and correct for LDL particle number or ApoB, it stops mattering.
Rhonda: Yeah. Those are definitely probably more important.
Peter: Yeah. And so loosely speaking, this is an oversimplification, if you're a 3/4 or 4/4, in theory you should have a harder time clearing LDL particles from circulation. But I think that that's not entirely the issue that you're alluding to, right? I think there's two issues you're talking about. One is the clearance issue and then one is the cholesterol transport, the central part.
Rhonda: Yes. I mean, and there's also the different issues in the brain versus the liver. So, I mean, we're talking about, like, the astrocytes are almost like little livers in a way but not really. You know, I think looking at the effects on the brain and then looking at the effects on recycling LDL and all the other things going on in the periphery are different. But by the way, I did just want to mention that between 65% and 80% of all cases of Alzheimer's disease at least, you know...
Peter: At least 4?
Rhonda: At least one has a 4. Between 65% and 80% of all the Alzheimer's cases, so...
Peter: So the majority are 3/4s then?
Rhonda: The majority even have at least one allele. Yeah. 3/4s.
Peter: Yeah. But again, that's...
Rhonda: Having just one allele.
Peter: ...based on the hazard ratio, we know that that's just a numbers game because 20% to 25% of the population is 3/4.
Rhonda: Right, exactly. But the point is is that there's something...
Peter: But the 3/3 doesn't protect you from AD.
Rhonda: No, it doesn't.
Peter: So someone walking around with a 3/3 you shouldn't assume that, "Well I'm never going to get AD."
Rhonda: No, it does not protect you, but there is definitely something...
Peter: Does the 2/2 protect you?
Rhonda: The 2 does actually protect. Yes.
Peter: Yeah. I'm sure that some paper has the histogram of 2/2, 2/3...
Rhonda: It's protective. Yeah, it is. And so it's very...
Peter: Because in cardiac disease it does, and in cardiac disease the 2/4 is about the same as the 3/3. The 2 and the 4 cancel.
Rhonda: Wait, say that again? So the 2/4s is...?
Peter: The 2/4 is about the same as the 3/3.
Rhonda: Oh, good.
Peter: And again, just in hazard ratio.
Rhonda: I found that my mom was 2/4 and it was for the cardiac problem that I was kind of worried. Anyways, okay, that's very interesting. So we're totally going off on this ApoE tangent but it's something that...
Peter: No one is even watching at this point, it doesn't matter.
A neurodegenerative disorder characterized by progressive memory loss, spatial disorientation, cognitive dysfunction, and behavioral changes. The pathological hallmarks of Alzheimer's disease include amyloid-beta plaques, tau tangles, and reduced brain glucose uptake. Most cases of Alzheimer's disease do not run in families and are described as "sporadic." The primary risk factor for sporadic Alzheimer's disease is aging, with prevalence roughly doubling every five years after age 65. Roughly one-third of people aged 85 and older have Alzheimer's. The major genetic risk factor for Alzheimer's is a variant in the apolipoprotein E (APOE) gene called APOE4.
One of three common genetic variants of the APOE (apolipoprotein E) gene. The APOE4 allele, which is present in approximately 10-15% of people, increases the risk of developing Alzheimer's disease and lowers the age of onset. Having one copy of E4 increases risk 2- to 3-fold, while having two copies increases risk as much as 15-fold.
The primary apolipoprotein of chylomicrons, VLDL, IDL, and LDL particles. Apolipoprotein B is produced in the small intestine and the liver. It transports fat molecules (such as cholesterol) to all the body's cells and tissues. High levels of ApoB, especially when LDL particle concentrations are also high, are the primary driver of the formation of plaques that cause vascular disease.
A test used in laboratory medicine, pharmacology, environmental biology, and molecular biology to determine the content or quality of specific components.
Star-shaped cells found in the brain and spinal cord. Astrocytes facilitate neurotransmission, provide nutrients to neurons, maintain neuronal ion balance, and support the blood-brain barrier. Astrocytes also play a role in the repair and scarring process of the brain and spinal cord following traumatic injuries.
A waxy lipid produced primarily in the liver and intestines. Cholesterol can be synthesized endogenously and is present in all the body's cells, where it participates in many physiological functions, including fat metabolism, hormone production, vitamin D synthesis, and cell membrane integrity. Dietary sources of cholesterol include egg yolks, meat, and cheese.
The genetic constitution of an individual organism. The combination of genotype and environment determine an organism's physical characteristics – known as the phenotype.
A peptide hormone secreted by the beta cells of the pancreatic islets cells. Insulin maintains normal blood glucose levels by facilitating the uptake of glucose into cells; regulating carbohydrate, lipid, and protein metabolism; and promoting cell division and growth. Insulin resistance, a characteristic of type 2 diabetes, is a condition in which normal insulin levels do not produce a biological response, which can lead to high blood glucose levels.
A cell-surface receptor that mediates the endocytosis of cholesterol-rich LDL by recognizing ApoB, which is embedded in the outer phospholipid layer of LDL particles. The LDL receptor is found in almost all cells; however, LDL receptors are especially abundant in the liver, because this is where ~70% of LDL recycling occurs. This receptor also recognizes the ApoE protein.
The observable physical characteristics of an organism. Phenotype traits include height, weight, metabolic profile, and disease state. An individual’s phenotype is determined by both genetic and environmental factors.
One of the enzymes involved in the process of converting pyruvate, which is derived from glucose, into energy in the form of ATP inside of the mitochondria.
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