[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.