How One Gene Affects Alzheimer’s Risk

Today on the podcast, trying to untangle the genetic factors involved in Alzheimer's disease.

“Although the exact mechanism of the illness is still a mystery, researchers hope work like”

this could point to new areas to study and maybe potential treatments. Joining me now is Dr. Dylan Williams, his principal research fellow in molecular and genetic epidemiology at University College London in the UK. Welcome to Science Friday. Thank you very much, it's a pleasure to be speaking to you.

Thank you. You're looking at variations if I understand it in one specific gene called APOE. What does that gene do normally? Why are you looking at that?

So it's background disproting upper lipoprotein A or upper E for shorts.

It's a small protein which is a well-established role in shutting fat around the body. We also know it has diverse roles in the brain. People can inherit one of three types of the gene, which we refer to as E2E3 and E4. So we've known for about 30 years that the risk of Alzheimer's disease differs between people depending on which type of APOE gene they inherit.

E2E is low risk, E3 is medium risk, and E4 is high risk. And this gradient of risk is common knowledge amongst Alzheimer's disease researchers. However, knowledge of this gradient alone doesn't tell us that there is full importance.

“And to grasp that, I think we need to answer what is a face value of fairly simple question.”

So what proportion of Alzheimer's disease cases would not occur without the impact of the medium and the high risk forms of the gene? In other words, if you were to take away effects of E3 and E4, the medium and the high risk versions of the gene from people, with approaches such as gene therapy or other drugs, how much Alzheimer's disease do we think we would prevent?

So you would leave the other population people with that other gene alone and just tack off the medium or high risk factor. That's right. The interesting in knowing what this one gene's contribution is and this is really important because we've got potentially a single target for people to be thinking about in terms

of therapeutic development and other strategies. And APOE is a little bit odd in the sense that despite this historical link and these really strong effects, it's rolling outside of the disease has been overshadowed and certainly I don't think proportionate to it's importance. Well, then put this in perspective for as how big a role does this gene seem to play compared

to other risk factors? So we estimated this proportion as it were in four different settings and we found that around 70 to potentially more than 90% of Alzheimer's disease cases would not have occurred without a contributing role of E3 and E4. Wow, that's a high number already.

Exactly. And just to stress, this is not the usual case for any particular gene. We couldn't pick one of the many other dozen genes that we know affects a susceptibility of Alzheimer's disease and get anywhere near that type of proportion individually. So if you're able to find medications or some sort of a way to attack these two versions

of the gene, that would be really a large contribution to fighting Alzheimer's. I think there's a strong case here for more research activity in funding towards our objective, yes. So where do you go from here?

“Well, in the case of our own research, I think there are a few key questions to answer.”

So, this research was conducted using samples of individuals who were European ancestry. We know families rolling outside the disease, my death or other ethnic groups, and that's

quite critical to understand.

It might tell us what other characteristics that are present in different ethnic groups could be either amplifying or buffering the effects of apole on Alzheimer's. So that's one important thing to investigate. The second would be other genetic and environmental factors, which could also be modifying this risk.

And I think, for example, it's worth considering that even the people in the highest risk variation of apole, so if they inherit two copies of E4, they might have a lifetime risk. So the risk of developing Alzheimer's in the typical lifetime of perhaps 60%. And that's reassurance in the sense that many of these individuals, perhaps 40%, will live

a full lifetime without developing dementia due to Alzheimer's disease. So there's clearly other factors that play that are of importance too. So finding those factors will also give us other ideas for interventions that might help

And the third thing that I think, again, has been overshadowed in Alzheimer's disease research

“for a long time is what is special about this low risk form of the gene E2?”

What properties does it have that mean these people have a very low susceptibility of Alzheimer's disease. And the flip side of that is what other health consequences might there be to having E2 relative to having the much more common E3 and E4 versions of the gene? And that can tell us both about the prospects for being able to prevent Alzheimer's disease but also about the safety of related therapeutics if you were to try and modify apole-related

risk for individuals. Well, do most people have, as you say, from what I hearing you correctly, most people don't have the lower risk, very, too, they have either the three or the four? Well, that's right, about 15% of the population will, will have inherited one copy of E2. It's uncommon.

It's not exceedingly rare, but uncommon to have inherited two copies of E2.

So it's somewhere between about half a percent and one percent of people. So maybe one in 200 to one in every hundred people will have two copies of E2. This is one of the reasons why studies like I was at the awful in the sense that you need very big resources to find a large number of this group to be able to compare the risk with everyone else.

I see. When we say this gene has a role in Alzheimer's, are we talking about the memory symptoms and dementia, or are you talking about the physical presence of the plaques and the tangles

“and the brain that have been associated with Alzheimer's?”

Well, we would probably think of it in terms of both. So we know that the actually build up of the hallmark characteristics of Alzheimer's in the brain varies by these forms of apoi and similarly, we know that apoi will relate to the clinical symptoms in terms of the problems that we see in dementia, the problems with memory and thinking and so on, and obviously these things are very closely interrelated.

It isn't really to sideline. You know, our study doesn't really suggest that we should be sideline in investigations into the more classic we're thinking about how we could prevent Alzheimer's disease, which is to try and remove these characteristic proteins, other proteins that we see build up in people's brains.

It's more that progress towards doing that, removal of these proteins that build up has been very slow. We don't have that much to show for 30 years of progress and things are looking more optimistic now, but I still think there's a case for diversifying how we try and tackle this disease and, as I say, interested in apoi is probably not been proportionate to any extent to its importance.

Yeah. That's what I hear you saying. Let's talk about using this research for possibly treating or preventing Alzheimer's. Would this show you where to target or drug, for example, or would you potentially be looking

“to gene edit that bad variant of the gene or would that be the drug itself?”

Well, I think those are both viable routes to be considering. So obviously with the maturing technologies in gene therapy, being able to switch genes on and off or being able to transfer in genes and individual might not have inherited themselves, these are all emerging technologies and they're being used in the clinic now for certain diseases, including some examples in the of diseases of the central nervous system.

So what's nice about these potential, and as I speak about this hypothetically, but what's nice about the potential of these therapies is to some extent, we can circumvent some of the uncertainty about what it is that apoi is doing to increase people's risk by say much, you can kind of tackle the problem at its root, so to speak.

And then obviously the second approach will be more in terms of more conventional pharmacology.

So genetic risk, really points is to potentially pathways by which a gene leads to a disease so we can think about trying to modify certain aspects of the pathway with more usual therapeutic approaches. At what point does it become, I guess, a good thing to start screening people for this gene earlier in life, would that be useful or would it just be scaring people too much?

I think the latter at this point, I mean, there's certainly wouldn't be recommended in the UK for people to seek it out other than fire direct to consumer testing, because these genes are not going to be destiny, as it were, not determined in risk to the point where you're guaranteed to be getting Alzheimer's or not. They don't really help us predict very well who's going to get the disease, but we know

that they have some fundamental role in most people who do go and to get it. So, yeah, we wouldn't really recommend people seek their appoeery genes because at the moment that it wouldn't really give anyone much as actionable information. You don't want the gene to get a reputation as, oh, this is what causes Alzheimer's.

I mean, one analogy I use is smoking at lung cancer, where a life-long heavy smoke, for

example, might have a lifetime risk of lung cancer in the region of about 15%, so again, maybe 85% of long-term smokers could go a full lifetime without getting lung cancer. This is clearly a strong predominant cause of lung cancer, and yet that on its own is not sufficient to produce a disease.

“Other causes are sort of needed in concert, and I think that's true also of the role”

of apoeery and Alzheimer's disease.

So other factors will be needed to kind of amplify or buffer apoeery's contribution ultimately

the disease would not occur for most people without its effect, and equivalently, if we remove that effect, most of these could be preventable. That's a very good analogy. You said this has really been under-investigated over the years, is it being fully investigated

now by you and other people?

I think there's more attention for it.

“One fact that I think is quite telling is that amongst about 140 or so different types”

of drugs that are in clinical trials, for Alzheimer's disease now, only one directly relates to apoeery as a form of gene therapy, actually. And so I think it's quite telling after 30 years of knownness link. This is the only form of therapeutic we have amongst a repertoire of a hundred others. Very interesting, and thank you for taking time to tell us about it.

Are you very welcome?

“It's good to step out the ivory tower every now and again.”

Or in 1960's town block in the case of University College, and I'm dead. Yeah, I get it. Back to Dylan Williams. He's a principal research fellow in molecular and genetic epidemiology at the University College of London in the UK.

This episode was produced by Charles Berquist. Thanks for listening, and please rate and review us on your favorite podcast platform if you like to show it, of course. We'll see you soon.