Can Alzheimer’s Be Prevented by Targeting a Single Gene?

A recent headline claimed that most Alzheimer’s cases could be prevented by targeting a single gene. But what does the research behind this bold statement really show? In this episode, we unpack a large genetic study examining the role of the APOE gene in Alzheimer’s disease. With help from Emeritus Professor James Vickers, we explore genetic risk versus genetic destiny, what population‑level findings mean for individuals, and how close — or far — this research is from real‑world treatments. The focus is on understanding the evidence without overstating hope or ignoring uncertainty. 

Based on:
 The Guardian (Jan 2026) – “Alzheimer’s therapies should target a particular gene, researchers say” 

Listener Reflection Questions

1. How did hearing more about how genetic risk is calculated change the way you interpreted the headline about APOE and Alzheimer’s?
2. What’s the difference between research that identifies risk and research that leads to treatment — and why does that distinction matter here?
3. When you see strong claims about genes and disease, what questions could you now ask to better judge what the research is really saying?

Brought to you by the ISLAND Project and Wicking Dementia Research and Education Centre at the University of Tasmania. To continue the discussion and for more information visit https://island.mooc.utas.edu.au or email island@dementia.uas.edu.au

Transcript

Neil Broomfield 0:01

Welcome to Brain Matters, the podcast where we slow down health headlines and look at what the evidence really tells us. And just as importantly, what it doesn't. I'm Neil Brunfield, and we're recording on Paloa Pacana Land. Today's episode tackles a headline that's big, bold, and gained a lot of attention. It comes from The Guardian, and it says, Alzheimer's therapists should target a particular gene, researchers say. Well, that's a powerful claim, and one that raises hope, questions, and a fair bit of uncertainty. To help explain this, I'm joined by neuroscientist and emeritus professor James Vickers. James, thank you so much for joining us.

James Vickers 0:44

Thanks, Neil.

Neil Broomfield 0:44

It's great to be here. Now, this podcast isn't about hyping breakthroughs or dismissing promising research. It's about understanding what the study actually shows, how strong the evidence is, and what it means, or doesn't yet mean, for people interested in brain health. What prompted this headline? Well, this headline is based on a paper published in analyzing how much Alzheimer's disease risk at population levels can be attributed to variants of the APOE gene. This topic is particularly relevant to Island Project members, as some of them have opted in to be given their personal results for the APOE gene. For listeners who haven't read the article or the paper, uh James, can you stop by explaining what question the researchers were really trying to answer?

James Vickers 1:37

Yes, this is a really interesting paper that um did did garner a lot of interest um in the in the media across the world as well. It relates to a gene called the Apollipoprotein E gene, and we shortened that to the ApoE gene. This builds on research and an understanding of the role of this gene that we've actually known for some decades. So it was back in the 90s where scientists first demonstrated that this gene was probably important for your risk of Alzheimer's disease. And it comes in three forms. There's an epsilon-2, epsilon-3, and epsilon-4 uh versions of this gene. So these aren't abnormal versions of the gene, they're just normal variations in the human population. And then the most common one that we find in most communities is the apoloproprotein E3 gene. So the ApoE3 gene. And this is probably 60 to 70 percent of people in a given community probably have that gene. There's there's infrequent variations, that's the apoloprotein E2 gene or epsilon-2 gene, and then there's the epsilon-4 or E4 version of the gene as well, too. So they're not as common. A small percentage of people have the E2 version, and about 20 to 25% of the population will have the E4 version. And not to go into too much detail, but basically you inherit one version of this gene from your from each of your parents. So in fact, you have two copies of this gene normally in your chromosomes, and so you might be a combination of two E3s, or or you could be an E2, E3, or an E3, E4. And what was determined again all those decades ago was that the more of the E4 version of this gene that you had, then the higher risk you have of developing kind of a standard version of Alzheimer's disease. And practically what that meant is that you were probably at a much higher risk of developing Alzheimer's disease in your late 70s through to your early 80s than the rest of the population.

Neil Broomfield 3:45

Now, just as a point of clarity, and I guess most of our listeners know, but you've referred this to uh to these genes as epsilon and e. Should I just explain that epsilon is the Greek alphabet letter for E?

James Vickers 3:57

I think that you've just done that, Neil. So that's that's really good. Yes. So that's right. So we we sort of interchange those a little bit in in the scientific literature as well, too. So epsilon refers to the actual uh gene variation, so epsilon 2, epsilon 3, epsilon 4. And then sometimes we reserve the E2, E3, E4 for the product of those genes, so the protein that they make. But in practice we tend to use them interchangeably.

Neil Broomfield 4:25

subtle difference, so effectively the same. And could you explain in simple terms how these variants differ, there being four of them, and why ApoE4 has been such a focus in Alzheimer's research?

James Vickers 4:38

Yeah. So there's there's only really very small differences between these three versions of of the gene, and they all give rise to functional versions of that gene in terms of protein production, but they are subtly different. Now, despite there being decades of of interest from the research community in these genes, we don't really understand what ApoE does normally, particularly in terms of the brain, perhaps what happens with aging and then with neurodegenerative conditions such as Alzheimer's disease. What we do and know a bit about its function is that it its job is to bind to lipids, in particular cholesterol and then other lipids as well, too. And maybe as part of this function, this job is to move those those lipids around. And if you look at the brain, um an uncomfortable fact maybe for many people, but about 60% of your brain is actually fat, so made up of lipids. And they're very that's very important for the membranes of all of the um of the cells that you see in um in a normal brain. And then the various coverings that we might see around processes of cells, um a process we refer to as myelination. So it may well be that ApoE has a role in shuttling cholesterol and other lipids uh into and around neurons so they can have a normal function. But it would seem then with aging, though, there is something that goes awry, particularly with ApoE4 compared to other versions of the gene. Aaron Ross Powell Right.

Neil Broomfield 6:12

And just for clarity, again, lipid equals fats. Aaron Ross Powell That's right. Exactly. Okay. Thank you for that. And I guess it might be worth emphasizing here that having a higher genetic risk does not is not the same thing as certainty.

James Vickers 6:26

Exactly. So when we when we talk about uh genes that provide risk, that really just means shifting the dial so you have a higher or a lower susceptibility, say, to developing any particular condition. They're not causative. If in in in other examples, in in a condition we call familial Alzheimer's disease, there are specific genes, different genes, where there would be a mutation. And we know that that mutation then is linked to that person developing dementia, Alzheimer's disease, usually at a r at a fairly early age into your 50s and 60s. So it's not we're not talking about a mutation here. We're talking about a gene that through evolution decided that we were going to have three variations on this gene. And it turns out then that particular variations are not helpful as you get older. And we and we also, putting that in evolutionary context, you know, most animals with all your genetics and the things that you inherit from your your parents, etc., we we weren't necessarily designed for living a long period of time. So normally it was that you would have your children see that they were doing okay, and then you would sort of shuffle off. So humans are really quite remarkable in that we can um expect to have many decades of life after we've performed our reproductive duties, if you like, if we're talking purely in evolutionary terms, passing on our genes. Uh so it may well be uh in a s in an unplanned for and unexpected um outcome, not driven by evolution, just by circumstance that we we've got these genes that were probably really useful when we're younger or into middle life. But as it turns out, if you get older, they seem to have uh an unfortunate um role in driving helping to drive neurodegeneration.

Neil Broomfield 8:16

Excellent. So this is where the headline gets dramatic. Researchers estimate that 72 to 93 percent of Alzheimer's cases, and around 45% of all dementia cases, would not have occurred without the contribution of the common Apo variants. When you first read those figures, what was your reaction?

James Vickers 8:38

Well, I I was a a little stunned to be to be honest, because we normally focus on ApoE4 as the risky gene. And again, that's only in 25% of the population at best. So where where does all this other large number come from? And what what is what this study has done, and it's really more of a technical study than than actually developing new information or knowledge. What they've done in the study is they decided, well, we've always assumed that the ApoE3 gene was neutral in terms of risk. So go back to the 90s when the initial discoveries were made, and that most people had ApoE3. So that everyone decided that, well, that was just the standard um gene that we've all got, and then we need to compare ApoE2 and ApoE4 against that standard um presentation. And it well, I think most people didn't give that probably a lot of thought, strangely enough. So what they've decided to do is say, well, actually, what we only really know is that the E2 version is protective. So maybe we should be looking that at all the other genes relative to the E2 gene. Now keep in mind that hardly anybody has the E2 gene. And to have two E2 genes is even less common. But we've we've known again for decades that having, say, one or two versions of this gene, can you inherit from your parents, what seemed to be protective. So it was the opposite of E4. So what they've done in this study is said, well, let's use that as the base, not not the common E3 version, which which people have been using as the base for decades. Let's look at everything relative to E2. And what comes out of their studies is an idea that, in fact, E3 might also be contributing towards your risk, and then E4 even more. So again, keeping in mind you can have one version of this gene from one parent and another version of the gene from another parent. So the more E4s that you've got, it could be E4, E3, for example, that that provides extra risk. And then if you're E4, E4, that's a very high risk. But even having the E3 gene in any of those combinations might be um might be attributed towards risk. And so if you add up everybody who's got the E3 and the E4 gene, which is most of the population, um, then that puts most of the population at risk of um Alzheimer's disease.

Neil Broomfield 11:14

I'm intrigued by this uh use of the word study, because I suppose you can't arrange for people to have variations and then look at them. This is presumably a statistical study, is it? Trevor Burrus, Jr. Exactly. That's right. It's a statistical study really um focused around epidemiological method. That said, it makes use of a number of very large cohorts that involve hundreds of thousands of people in different studies. And so what what it was doing was using these large studies and the available data that's been generated through those studies to test test this idea. And um accordingly, through their paper, it does show that if you take, again, if you take E2 as the um the most unrisky gene, if you like, um, it's not probably then it's protective, it's probably just the the neutral gene in terms of adding to risk, that any more E3s that you have or E4s that you have, then you're going to be at at higher risk. Trevor Burrus, Jr. So again, when the paper came out, it was really a a a stunning um result or set of observations that's um that has been quite controversial in in the field. And then that's really for a couple of reasons. That there would be people who are involved in studies of populations, um, which would say that you don't take what we think is a protective gene as your baseline. You've got to look at at what what is the most common gene and and what is might we might refer to as common risk. Um the other thing that the study clearly does show, it does support this idea that the more of the E4s that you have, then the higher risk you're going to have of developing Alzheimer's disease. And so that's really quite important because that means if your E3s, if you've got one or two E3s, yes, you might be at high risk relative to the E2s, but it also certainly doesn't mean that you're going to get Alzheimer's disease in your lifetime. And that's probably where other potentially modifiable risk factors might have a role. But one of the things that was good about the study, I think, though, and again, it's created controversy. I think the authors were really trying to reinforce that that research in Alzheimer's disease has followed along particular lines for for a long time and not necessarily borne fruit in terms of new treatments. So there's been a lot of research into a protein called beta amyloid, um, and important work, uh that it has been as well, too. But there's been a focus that this is probably the most important protein, and abnormalities in that protein are really important for Alzheimer's disease. Is beta amyloid a protein as well? It is another naturally produced protein that we're all producing all the time, but somehow with aging and then into neurodegeneration becomes misconfigured, if you like, an abnormal, and then clumps together to form what we call plaques inside the brain. And so this people used to think that this was um the most important pathway leading to Alzheimer's disease. And another protein people have been interested in is one that occurs inside nerve cells called the tau protein. And so there's another camp, if you like, that are interested in how tau becomes abnormal and that leads to nerve cells um dying. But what this paper is saying was that if we kind of stand back and we think about ApoE, it's also got maybe got a tremendous role in adding to our risk, because they make the really good point that if everybody was Apo E2E2, which is again the most infrequent combination you could think of, but if we could make everybody E2, E2, then there probably wouldn't be any Alzheimer's disease in the human population. So maybe we need to think about what we can do therapeutically to focus more on Apolloproprotein E rather than this substantial effort that's gone on in terms of looking at beta amyloid, plaques, and tau inside the nerve cell. So it could open up new vistas for interventions. Trevor Burrus, Jr. Right. And it may be important to say here, uh just for the sake of clarity, that if you don't have E2, E2, it doesn't mean that you will get Alzheimer's.

James Vickers 15:39

It's just that there's a risk. Trevor Burrus, Jr. That's right, yeah. Because still underlying everything is probably the major risk factor is aging. So really the older you are, um, then your risk will go up substantially. What can we do about that? Well, I think I think that there should be more research on on aging, per se, less maybe um rather than just on the disease, because there is something about the aging brain and how that changes to then put you at at higher risk of developing these conditions. Because conditions such as Alzheimer's disease, unless you've got one of these genetic mutations um mentioned before, is really rare, you know, into your 50s and 60s. But as you get into your late 70s and 80s, then your risk will go up um quite quite substantially.

Neil Broomfield 16:28

So having thought about that a little, James, um you're speaking about lifestyle. Um is there anything you could particularly point out uh that would be helpful for our listeners to know about this?

James Vickers 16:40

Yes. This is again another vi vibrant area of research and it's evolving all the time. And we do have a pretty good understanding now that there are um environmental and and lifestyle factors that will influence your risk of developing dementia. And we're up to 14 or so factors that each play individually a small role in perhaps in um in manipulating your risk, um, but most of which then could be um theoretically modified. Now, um so even if you have got some of those high-risk genes, the ApoE4 version as well, too, these may be things that you could look at at undertaking to try and balance out your risk. So again, risk is all about this dial, you know, you've got low amount of risk or a high amount of risk, and that just pushes your susceptibility in different directions. So yes, you might have a a riskier genetic um background at at one level, but then perhaps we can do something about that by attending to to some of those lifestyle factors.

Neil Broomfield 17:41

Uh and could we inter interfere with this by, for example, drugs?

James Vickers 17:47

Yeah, so drugs is uh clearly another um uh avenue. And this paper is really advocating for a a greater uh degree of focus around developing new drugs that might manipulate apoloproprotein E. Now, but we always have to keep in mind when we're looking at drugs that that infec that might have a um a role in um some of these some of these proteins, because clearly these proteins have a normal function, for example, in our brain. And we really want to be careful about manipulating those in case we we might have some really um unpleasant side effects as a consequence. But the um the other interesting, I guess, development around um uh human research more generally is that now our ability to manipulate your genes. So we can we can um pre potentially introduce, for example, more more copies of the the good versions of these genes to our brain, and that might then correct for having the the less um uh you know the less useful versions of those genes. And how how how would you introduce them to your brain? Aaron Powell Yeah, there's lots of different ways of of doing it. Um there's some ideas around uh what they call mRNA vaccines. So this is where you might introduce directly uh the necessary machinery to make ApoE2. mRNA? Yeah, so mRNA is part of this genetic architecture, if you like, that that encodes for the production of um of those genes to become proteins. So it goes from DNA to mRNA to protein production. And this is now the basis for new vaccines, for example, for for COVID, et cetera, as well. So maybe we could top ourselves up with mRNA for the good versions or the better versions of this gene. There's also a view that we might be able to come in and directly manipulate our DNA. And there are new techniques to do this, where you can basically edit out parts of the code or introduce bits of the code. So you might be able to turn your ApoE4 gene into an ApoE2 gene. Again, technically quite difficult to do, but it's a field that's advancing uh quite rapidly.

Neil Broomfield 20:07

It sounds very promising, James, this, but it's also a long way from being something that people can access through routine care by the sound of it.

James Vickers 20:15

Well, there there is a growing feeling that people should be able to get access to their, for example, to their genetic risk profile. And this includes ApoE, but there are a number of other genes that provide a small degree of risk as well, too. So these are things, again, in certain countries you can send a biological sample in and they'll they'll give you the um give you that um outcome. Um and we're at a point too with some of our research where we routinely look for variations of the Apolloprotein E gene to see what influence it might have on our and our results from our studies. And now we've got some projects looking at um providing that information back to uh the people who are in that study. And this may be a bit challenging for the individual. They'll need to learn about that gene and what it what its role is and and isn't as well. But it also could be a real motivator. So that, for example, if you know that you've got the very high risk versions of these genes, then that might that might um push you to looking at those things that you can do in your lifestyle to then counter um that potential risk. And there was a famous example of that quite recently with the Australian actor Chris Hemsworth, who is part of a documentary series that he was involved with. Um they were looking at his health across a number of dimensions, and this included looking at the ApoE gene, and he discovered that he had um two versions of the ApoE4 gene. Now, of course, that might is potentially quite confronting, um, but he was a fellow obviously was interested in health and and wellness, and then now equipped with information about some of those things he might do too on the Lifestyle side that he might do to reduce that risk, you can perhaps look at where you might try to balance these things out over your lifetime.

Neil Broomfield 22:09

Thank you for clarifying a lot of that. James, so if we get back to the original question that led to this chat of ours, every study has its limitations. Now, if you were reading this paper critically, what gaps or unanswered questions would stand out for you?

James Vickers 22:28

I think the major issue really is whether E2 is the baseline in terms of risk or whether it's particularly protective. If it's particularly protective, I think we need to rethink our interpretation of this paper. If E2 turns out to be the neutral or baseline version of this gene, then it becomes a really important contribution, which says really there is something about aging and apoloproprotein E that for somewhere around 90-something percent of the population, it's going to be important in terms of your risk of developing Alzheimer's disease. So I think this is the probably the first paper in what's likely to be a series of papers and research that's undertaken to try and understand the ramifications of this, I guess, potentially new understanding. We might find that it could evaporate over time and that the E4 gene is the one that we need to focus on. Or we could find that it's super important, and then we really need to know more about abilopropine and the brain and aging and then risk of Alzheimer's disease.

Neil Broomfield 23:40

T And we could probably anticipate there being papers about other things like tau, for example, that's right, yeah.

James Vickers 23:48

So uh the the most common areas of research, and we're talking thousands upon thousands of papers, tend to focus around B-ramyloid, and then also now um the tau protein. And I think again, these these authors make the point that, well, they're probably going to be important, those things are going to be important, but here's apolipropriateine E, which we really need to rethink and refocus and fund and contribute towards more research into understanding what it does.

Neil Broomfield 24:16

Great. Well, what is super clarification so far? Now, for people worried about dementia, either for themselves or somebody they care for, what would you say is the most important takeaway from the research as it stands today?

James Vickers 24:30

l It's it's more of a watch and see because it's it's not a genetic test that's done routinely in in Australia. Again, you could could get the results if you wanted to pursue them by sending samples overseas. Um but I suspect it'll be will become more um routine or more achievable in Australia because it's not a particularly tricky test to do from a um uh a technique point of view. Aaron Ross Powell And not massively expensive. No, no, that's right, yeah. So I think that you'll probably and there'll be private providers who will come into the marketplace if you like and and provide these kinds of um tests. So you could probably get access to it, but then then it's to make sure that you understand the context a little more. And while the there's a big claim in here about apoloproprotein E becoming the most important thing in terms of your risk of of Alzheimer's disease, we're also pretty certain that that the things that you're exposed to through your lifetime, um, you know, various other health and lifestyle factors are going to be important as well, too. So while you may have a unhelpful genetic profile, there will be lots of other areas that you can um uh focus on. And um, of course, in the Wiking Center we have some a number of educational programs and research programs that that speak to that and people can become involved with.

Neil Broomfield 25:53

Indeed so. So this study then doesn't change clinical advice today, but it does change how researchers are thinking about prevention and treatment priorities.

James Vickers 26:03

Yes, uh yes, absolutely. Yeah. So I think um because there's not the thing about providing somebody with a I guess a genetic test or genetic outcome, if you don't have a um a drug immediately available to to do anything about that risk, then clinicians may well be reluctant to to get involved in in finding out and then disclosing that information. But I think again, as research moves on and the ethical framework around your your genetics also moves on as well, too. People should have the right to know if this is something they want to to know about.

Neil Broomfield 26:39

Right. So uh time's moving on, James, so we must get towards the end. But before we do that, if listeners come across a headline making a bold claim about genes and disease, what question should they pause and ask?

James Vickers 26:55

I think it's really, really important to to to look at the research, in a sense taking it at face value, but often it's it's often the first research report in an area. It's the one that grabs all the headlines, and then to look over time whether other researchers um support the view, whether some of these national dementia organizations also get on board and and say, for example, would be suggesting from a policy point of view that more people need to be tested for their ApoE genes. So it takes time for for us to settle on the best interpretation of these kinds of results. And and unfortunately, too, it's almost daily that we get bombarded with with news about breakthroughs and and big advances and and um treatments only being a you know three or four or five years away. And I would certainly take a lot of that with a grain of of salt because it takes takes a while for the for the you know the science around these issues to become settled. But it's also to maintain a degree of uh hope and optimism as well, too, because these are conditions that have been studied by thousands of people um across the globe and um who are all contributing to to our understanding, in this case of Alzheimer's disease. And then it is the hope is that something will bubble out of that that will be meaningful, become a meaningful treatment.

Neil Broomfield 28:23

Well, James, thank you so much for helping us break the story down and bring some nuance into a very complex topic. For you listeners, uh, genetics can inform research priorities without defining personal futures, but as always, a single headline rarely tells the whole story. How did hearing more about genetic risk is calculated change the way you interpreted the headline about AIPO and Alzheimer's? We'd love to hear your answer to this question and what you thought about this episode. You can continue the discussion within the Island Portal or find the link in the show notes. In future episodes, we hope to have a listener question at the end, so please do send us in your burning questions and we'll try our very best to answer them. This has been Brain Matters, brought to you from the Wicking Dementia Research and Education Center at the University of Tasmania. Thanks so much for listening. Do tune in to the next episode to keep slowing down health headlines together. Goodbye for now.