Washington University School of Medicine assistant professor of radiology, Brian Gordon talks about one gene that could possibly protect you from Alzheimer’s disease.
Interview conducted by Ivanhoe Broadcast News in 2023.
What’s the progression you see of Alzheimer’s?
Gordon: Alzheimer’s disease – we often think of it as the onset when people come in with memory complaints and dementia, but it’s actually a much longer disease we know from genetic forms and just longitudinal studies that can actually take a decade or more, a biological change before someone actually would present to a neurologist with impairment. And the first domino that falls is this protein called amyloid begins building up in the brain and this is a slow progression, again, it’ll take a decade or more. It starts in a couple areas of the brain that are very metabolically active and gets progressively higher and higher and higher. And again, that is first domino that falls in this cascade, which leads to changes in formation and eventually will lead to a formation of this second key protein in Alzheimer’s disease called tau. These neurofibrillary tangles that are accumulating within a cell. Those start to accumulate and build up right at that point when people become impaired, when they show the first signs of this early level of dementia and when that happens, we also tend to see lots of atrophy in the brain. So not always cell death, but more shrinking of cells, loss of dendrites and that primarily occurs in the temporal lobe. It’s a part of the brain and the key structure of the hippocampus and entorhinal cortex. These are areas of the brain that support memory and those areas start to become smaller and smaller and smaller. As you have more progressive dementia, then you’ll also start to see atrophy, which you can see just on an MRI scan and throughout the rest of the temporal lobe and the parietal lobe.
And once you start seeing this, you’re starting to see symptoms, right?
Gordon: You can have amyloid and remain cognitively normal for a decade or more but when you start to see that atrophy there on MRI, you start to see a buildup of tau using a PET scan that really is occurring though it’s fundamentally incompatible with being healthy and cognitively normal. Those two occur when people become demented.
And now, you’re saying that there’s even a more telltale sign about whether you’re going to be susceptible to Alzheimer’s.
Gordon: So, there’s a lot of different risk factors and probably the most salient one other than age is a polymorphism in a gene called apolipoproteins and there’s three different forms of this gene that you can inherit. The three is your base level of risk. It’s what’s most common in the population. If you happen to be lucky and get an E2 form of it, you have slightly protection against Alzheimer’s disease. If you have this one that’s an E4 polymorphism, your risk of developing Alzheimer’s disease goes up about four fold if you have one copy and about 12 fold if you have two copies of this gene. And so it’s been a real question of why, what is it about this gene that’s leading to this elevated risk? For the most part, what we think about this gene is that it just increases the odds of that first domino falling, that amyloid gene, that amyloid domino falling over and that’s true. So what you see is if you look at individuals that have an E3 versus an E4, is that individuals with an E4 are just much more likely to have amyloid starting to build up in the brain and this occurs at a much earlier age. That’s been the common view but then there’s also been a lot of emerging work from animal models about and that’s not all the APOE gene does that having this E4 allele can also lead to increased neurodegeneration and increased telepathy. And this has a lot of work coming out of the Boltzmann’s lab here at Washington University. After we saw his work in rodent models, we wanted to know, do you see the same thing in human data? That’s exactly what we see. You see this massive increase in the propensity to get amyloid but these individuals that also have the E4 for the same amount of amyloid, they have more tau pathology and they tend to have a little bit more neurodegeneration than those with a three, so it’s this double hit. The more likely to get amyloid, more likely to get amyloid at an earlier age and then you’re also more likely to get this this downstream pathology.
And does the APOE have anything to do with where the Alzheimer’s shows up in your brain and how it affects you?
Gordon: Yes. So, we tend to think of these proteins or biomarkers and it’s a binary plus-minus, you have it or you don’t. But the super powerful thing about imaging, it’s not about just do you have it, but it can tell us where. On the MRI I can see that you have atrophy specifically in the temporal lobe and then based upon what I know that region of the brain does, I can predict what cognitive deficits you will have. We’ve started to use data from the Allen human brain atlas where they went into post-mortem brains and they looked at mRNA expression. So it’s just a metric of how often are the specific proteins being synthesized in the brain. And what you’ll see is that APOE is not-even though your genes are constant across all your cells, their propensity the how commonly this APOE protein is actually being made varies. And it’s this mRNA expression is really high in the temporal lobes and so we then went and we said, okay, we can see from the PET imaging we’re having this genetic polymorphism increases tau pathology and then we compare the two. Where do we know the brain is actively making the protein? And there’s this really tight coupling and it’s important because it shows that having genetic risks, whether it be APOE, BDNF, something related to trim, you wouldn’t expect it to have an effect everywhere in the brain. There’s this tight coupling between where these proteins are made and where then polymorphisms in the genes that control the protein synthesis exist. And so we see this nice relationship where having this APOE E4 allele only leads to more tau in the same areas that have high APOE mRNA expression.
So, help me understand the difference between this person with Alzheimer’s is going to have memory problems and this person is going to have vision problems.
Gordon: So there’s different forms of Alzheimer’s disease. The most common one is just an amnestic presentation, so someone has memory problems. There’s also a form called posterior cortical atrophy, where people tend to have visual spatial problems, problem with vision. They might come in almost like you would think they have problems with their eyesight or maybe they’re going blind but that’s actually driven by Alzheimer’s pathology. There’s also a form that leads to problems with producing and understanding language and we don’t really understand. The amyloid for all of those individuals has the same pattern, but the tau pathology has a different pattern for the visual people. It has build up in visual cortex for the people who have language problems, it’s a language cortex and we don’t really understand what’s driving that and that’s because we don’t often think about the brain as being heterogeneous . Sometimes we just think of it as a black box. And when we start to dig down and start looking at these different patterns of mRNA expression for many different genes, what you’ll see is that there are these networks. You can see this with MRI, with a gene expression and having different patterns of gene expression, it’s leading to different regional vulnerabilities. So depending upon a person’s genetic profile and these functional networks we might expect that there be different regional vulnerabilities. And if we can figure out what’s driving those regional vulnerabilities, we can figure out why this person 1 get a visual presentation. Why this person 1 get a visual presentation and person 2 get an amnestic presentation and that’s important because if we can figure out what’s driving that, then we have a new avenue to intervene and it can guide us towards more advanced treatments or maybe perhaps more nuanced treatments, maybe for person 1 or person 2, depending upon their genetics, you might need slightly different tailored treatments or interventions.
Can you have Alzheimer’s and only have a vision problem and no memory problems? Can all the tiles be in that?
Gordon: Yeah, so what you’ll tend to get is that they will converge over time. It’s just what’s that first presentation? What’s that first symptom? Any of these. You have these people, There’s this really tight coupling. If tau shows up in visual cortex first, you will show up with a visual problem first, although you will also then get memory problems as well. And that tends to happen when the tau starts to show up in temporal lobes and memory areas as well.
So, patients who have vision problems might go misdiagnosed for a little bit?
Gordon: Yeah, so that’s that’s definitely a problem, they might not come to a neurologist first. That’s not going to be their first point of contact because they’re coming in they’re saying, “I can’t see, I’m having problems with visual neglect.” So they might take a little bit longer to end up in the clinic.
Is this similar to the genetic tests like actor Chris Hemsworth?
Gordon: So, we really actually don’t understand why people get the different forms at all. We do know that if you have an E4, you are less likely to have, and it’s probably due to the fact that this APOE gene is so over expressed in the temporal lobe that if you have an E4 and I’m showing here, that’s driving top pathology in the temporal lobe. That’s why those people are overwhelmingly getting this amnestic presentation because there’s this tight coupling. So for them it makes sense, yeah, they get an amnestic presentation because the E4 allele or APOE gene is being highly up and down regulated in these regions that we know are tied to memory. So what we hope to figure out in the future is with the people that see the PCA, the visual spatial or the linguistic predominant, can we figure out what is unique to those areas? Is it some gene that’s over expressed in those regions? Is it something about connectivity? Is it something about development? If we can figure out what’s driving something selective in those regions maybe we won’t be able to figure out and link it back to a genetic test or some other tests that can help a diagnosis.
Can you explain what you look at with these tests?
Gordon: Sure. So this is something that we might see on the research side looking at amyloid scans. That first domino that’s going to fall. Someone who came in. So this would be the front of their head, this is their nose, the back of their head. And this is using a PET scan. So we’re giving people a tracer and it’s going to bind to amyloid if they happen to have it in their brain. So this would be an example of a negative scan. You can see some binding that’s just background binding to white matter. But when we’re looking in the cortex, we see very low levels of binding. So this person came in. They’re in their late ’60s, early ’70s. It’s a typical older adult and they’re cognitively normal. So they would not meet criteria for being impaired or having any dementia. Then they came in about three years later. And here they have a scan still cognitively normal or at least cognitively unimpaired. They’re not meeting that criteria for dementia. But now we’re starting to see amyloid is building up in some radial parietal regions and some orbital frontal regions throughout the frontal cortex. And this would be a person that they had abnormal levels of amylase. So it’s this pre-clinical window. Then this person came back about three or four years later and you can see they have even more amyloid than they did here in this intermediate period. And now this person has become impaired. They’re meeting the criteria for dementia with one of our neurologists. And we know from the fact that when we added the Tau pathology in is that this person would be negative for Tau these two periods. And typically this moment they become impaired is when that nerve degeneration and when Tau pathology will build up.
Is there anything else you would like to add?
Gordon: Sure. We’re also thinking about disease. We also have to think about, not everyone’s the same and one of the biggest factors for that is actually sex. So this genetic factor, APOE, we know that going from your base level to three to an E4 where it increases your risk actually has a differential effect in men and women. And we don’t quite understand why that is. But because we knew that clinically, we looked at that both in where we’re looking at biologically in this effect on Tau pathology. And we did actually see an interaction with sex such that going from a three to a four, go into that risk of wheel increased Tau pathology in women more than it did with men. In men, we didn’t see a huge effect of going from a three to a four. But part of that is because men just had more pathology in general. So a male that had a 3-3 and a male that had a 3-4 or a 4-4 both had pretty high levels of Tau pathology versus a woman that had an E3 had relatively lower levels of pathology. And then if they had the E4, they have the same amount of pathology as the men did.
You said you scanned your brain. You are a 3-3. Will you always be a 3-3?
Gordon: Yeah. And we often tend to focus on later life. But there is emerging evidence that actually these have developmental consequences and the APOE gene is important in laying down myelin. Myelin is basically insulation on your neurons. And there’s emerging evidence that’s showing that having an E3 or versus having an E4. If you have an E4, you basically start to have abnormal insulation laid down on your neurons at a very young age. And this is something else, not only considering sex, race, and other factors, but also looking at, are these effects there forever? This is not something we don’t magically spring into existence when we’re 65. And really understanding the lifespan effect, particularly with these genetic factors.
When it comes to these women and men, what you’re saying is the men have lower levels, E3, E4, but more severe symptoms?
Gordon: So, that’s an excellent question. So, it’s unclear. We tend to think of minutes having perhaps more co-morbidities. They tend to be more obese. They tend to have more vascular impairment. We often think of them as having more non-AD primary contributions to perhaps some of their cognitive impairment. And maybe women are a little bit more resilient because they don’t have as many of these additional risk factors that are impacting cognition. But then sometimes once you hit that point of no return and you start to have rates of decline, perhaps women might decline faster or slower. It’s not always consistent.
The men are going to start declining sooner. Women are going to get hit like a brick and go downhill fast. That simple.
Gordon: It’s not always clear, because men tend to have worse health. The idea is that they basically will start to show impairment at a lower level of Alzheimer’s pathology because they have all these additional health complications. And women tend to maybe not show cognitive impairment until the pure AD pathology reaches the threshold. So it’s not always apples to apples. You can’t just say but you do have to just look holistic way. You have to incorporate, not just what do I know about their amyloid levels, but you also have to take into account their vascular factors or their obesity. And then that’s all riding on top of effects that we might see with sex, that a lot of these secondary pathologies are tracking sex. Also environmental exposures, sleep, lots of things are tracking. The sex effect is a very difficult story because here we’re showing a genetic sex effect. But when we look just epidemiologically, it is very difficult to disentangle. Is this a biological sex effect or is this lifestyle sex effects or exposure that’s tied to sex? But that’s important. So the most recent drug that just got the conditional approval, it basically didn’t show an effect in women. The effect is almost entirely driven by men, which we don’t really understand. But again, it just reinforces this idea that we really need to figure out how sex is interacting with genes and all these other risk factors.
Are there different levels of APOE in men and women?
Gordon: No. You’re just as likely to have an E3 being a man versus a woman.
For research, this is great to know your E3, E4, and E2. As a person, I don’t know if that’s healthy for you to know?
Gordon: For some tests, for example, there’s a test from C2N Diagnostics that they have an FDA approved. I can’t remember if it’s actually FDA approved or what the approval is, but their measure is precipitate test, is actually a combination of three measures. Your age, how much amyloids you have, and your APOE status. So I think clinically you have to take it into account. Now from a personal level, would you want to know? I wanted to know because it allows you to just take control and allows you to know more about it. And maybe that gives you that little bit orbit incentive to exercise or diet and just be proactive about your health. I think more information is always good. And then I also think personalized medicine is happening. Whole genome sequencing, all these things are becoming cheap. They’re going to be here and we need to be thinking about that mindset, that patient A and patient B might need to be approached differently based upon their genetics.
END OF INTERVIEW
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