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 Broomfield, and we're recording on Palawa Kani 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. It’s great to be here. 

Neil Broomfield 0:44 

 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, James, can you start by explaining what question the researchers were really trying to answer? 

James Vickers 1:37 

Yes, this is a really interesting paper that did garner a lot of interest in the media across the world as well. It relates to a gene called the Apolipoprotein 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. 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 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 apolipoprotein E3 gene. The ApoE3 gene. And this is probably 60 to 70 percent of people in a given community probably have that gene. There’s infrequent variations, there's the apolipoprotein E2 gene or epsilon-2 gene, and then there's the epsilon-4 or E4 version of the gene as well, too. 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 each of your parents. 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 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 really good. Yes. So that's right. So we interchange those a little bit in the scientific literature as well. Epsilon refers to the actual 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 

A 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. There's only really very small differences between these three versions 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 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. We do know a bit about its function, that it’s job is to bind to lipids, in particular cholesterol and then other lipids as well. And maybe as part of this function, this job is to move those lipids around. And if you look at the brain, an uncomfortable fact maybe for many people, but about 60% of your brain is actually fat, so made up of lipids. And that's very important for the membranes of all of the cells that you see in a normal brain. And then the various coverings that we might see around processes of cells, a process we refer to as myelination. It may well be that ApoE has a role in shuttling cholesterol and other lipids 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.  

Neil Broomfield 6:12 

Right, and just for clarity again, lipid equals fats.  

James Vickers 

That's right. Exactly.  

Neil Broomfield 

Okay. Thank you for that. And I guess it might be worth emphasizing here that having a higher genetic risk is not the same thing as certainty. 

James Vickers 6:26 

Exactly. When we talk about 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 other examples, 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 fairly early age into your 50s and 60s. 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 also, putting that in evolutionary context, most animals with all your genetics and the things that you inherit from your parents etc, 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. Humans are really quite remarkable in that we can 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. So it may well be an unplanned for and unexpected outcome, not driven by evolution, just by circumstance that 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 an unfortunate role i helping to drive neurodegeneration. 

Neil Broomfield 8:16 

Excellent. 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 was a little stunned to 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 does all this other large number come from? What this study has done, and it's really more of a technical study than actually developing new information or knowledge. What they’ve done is decided, 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 was just the standard gene that we've all got, and then we need to compare ApoE2 and ApoE4 against that standard presentation.  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 at all the other gene 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 known again for decades that having one or two versions of this gene, that you can inherit from your parents, what seemed to be protective. It was the opposite of E4. What they've done in this study is said, well, let's use that as the base, not the common E3 version 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. The more E4s that you've got, it could be E4, E3, for example, 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 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, then that puts most of the population at risk of Alzheimer’s disease. 

Neil Broomfield 11:14 

I'm intrigued by this 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?  

James Vickers 

Exactly. That's right. It's a statistical study really 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 it was doing was using these large studies and the available data, that's been generated through those studies, to test this idea. And accordingly, through their paper, it does show that if you take E2 as the most “unrisky” gene, if you like, it’s not probably then as protective. It's probably just 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 higher risk.  So again, when the paper came out, it was really a stunning result or set of observations that has been quite controversial in the field. And that's really for a couple of reasons. There would be people who are involved in studies of populations, who would say that you don't take what we think is a protective gene as your baseline. You've got to look at what is the most common gene and what we might refer to as common risk. 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. That's really quite important because that means if you've got one or two E3s, 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. One of the things that was good about the study, I think,  and again, it's created controversy, is  I think, the authors were really trying to reinforce that research in Alzheimer's disease has followed along particular lines for a long time and not necessarily borne fruit, in terms of new treatments. There's been a lot of research into a protein called beta amyloid, and important work, that it has been as well, too, but there has been a focus that this is probably the most important protein, and abnormalities in that protein are really important for Alzheimer's disease.  

Neil Broomfield 

Is beta amyloid a protein as well?  

James Vickers 

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 these people used to think that this was 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 dying. But what this paper is saying, was that if we, kind of stand back, and think about ApoE, it's also maybe got a tremendous role in adding to our risk. They make the really good point, that if everybody was Apo E2E2, which is the most infrequent combination you could think of, but if we could make everybody E2E2, 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 Apolipoprotein 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.  

Neil Broomfield 

Right. And it may be important to say here, just for the sake of clarity, that if you don't have E2E2, it doesn't mean that you will get Alzheimer's. It's just that there's a risk. 

James Vickers 15:39 

That's right, yeah. Because still underlying everything is that probably the major risk factor is aging. So really the older you are then your risk will go up substantially.  

Neil Broomfield 

What can we do about that?  

James Vickers 

Well, I think that there should be more research on aging, per se, rather than just on the disease. There is something about the aging brain, and how that changes, to then put you at higher risk of developing these conditions. Conditions such as Alzheimer's disease, unless you've got one of these genetic mutations mentioned before, is really rare, in your 50s and 60s, but as you get into your late 70s and 80s, then your risk will go quite substantially. 

Neil Broomfield 16:28 

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

James Vickers 16:40 

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

Neil Broomfield 17:41 

Could we interfere with this by, for example, drugs? 

James Vickers 17:47 

Yeah, so drugs is clearly another avenue. This paper is really advocating for a greater degree of focus around developing new drugs that might manipulate apolipoprotein E. We always have to keep in mind, when we're looking at drugs that might have  a role in some of these proteins, because clearly these proteins have a normal function, for example, in our brain,  we really want to be careful about manipulating those in case we might have some really unpleasant side effects as a consequence. The other interesting development around human research, more generally, is now our ability to manipulate your genes. We can potentially introduce, for example, more copies of the good versions of these genes to our brain and that might then correct for having less useful versions of those genes.  

Neil Broomfield 

How would you introduce them to your brain?  

James Vickers 

There's lots of different ways of doing it. There's some ideas around what they call mRNA vaccines. This is where you might introduce directly the necessary machinery to make ApoE2.  

Neil Broomfield 

mRNA?  

James Vickers 

MRNA is part of this genetic architecture, if you like, that encodes for the production of those genes to become proteins. It goes from DNA to mRNA to protein production. This is now the basis for new vaccines, for example, for COVID, etc, as well.  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. 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, technically quite difficult to do, but it's a field that's advancing 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 is a growing feeling that people should be able to get access to their, for example, genetic risk profile. This includes ApoE, but there are a number of other genes that provide a small degree of risk as well. These are things, again, in certain countries you can send a biological sample in and they'll give you that outcome. We're at a point, too, with some of our research, where we routinely look for variations of the Apolipoprotein E gene, to see what influence it might have on our results from our studies. Now we've got some projects looking at providing that information back to the people who are in that study. This may be a bit challenging for the individual. They'll need to learn about that gene and what its role is and isn't, as well. But, also, it could be a real motivator. For example, if you know that you've got the very high-risk versions of these genes, then that might push you to looking at those things which you can do in your lifestyle to then counter that potential risk. There was a famous example of that, quite recently, with the Australian actor Chris Hemsworth, part of a documentary series that he was involved with. They were looking at his health across a number of dimensions and this included looking at the ApoE gene. He discovered that he had two versions of the ApoE4 gene. Now, of course, that is potentially quite confronting, but he was a fellow obviously was interested in health and wellness. Now, equipped with information about some of the things he might do on the lifestyle side, that he might do to reduce that risk, he can, perhaps, look at where he might try to balance these things out over his 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 apolipoprotein 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. I think this is 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 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 apoliprotein E, the brain and aging and then risk of Alzheimer's disease. 

Neil Broomfield 23:40 

And we could probably anticipate there being papers about other things, like tau, for example. 

James Vickers 23:4 

That’s right. The most common areas of research, and we're talking thousands upon thousands of papers, tend to focus around Beta amyloid, and then also now, the tau protein. And I think again, these authors make the point that, those things are going to be important, but here's apolipoprotein E, which we really need to rethink, refocus, 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 

It's more of a watch and see, because it's not a genetic test that's done routinely in Australia. Again, you could get the results, if you wanted to pursue them, by sending samples overseas. I suspect it will become more routine, or more achievable in Australia, because it's not a particularly tricky test to do from a technique point of view.  

Neil Broomfield 

And not massively expensive.  

James Vickers 

No, no, that's right. I think that there'll be private providers who will come into the marketplace, if you like, and provide these kinds of tests. You could probably get access to it, but then it's to make sure that you understand the context a little more. While there's a big claim in here about apolipoprotein E becoming the most important thing in terms of your risk of Alzheimer's disease, we're also pretty certain that the things that you're exposed to through your lifetime, various other health and lifestyle factors, are going to be important as well. So, while you may have an unhelpful genetic profile, there will be lots of other areas that you can focus on. In the Wicking Centre we have some a number of educational programs and research programs 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, absolutely. The thing about providing somebody with a genetic test or genetic outcome, if you don't have a drug immediately available to do anything about that risk, then clinicians may well be reluctant to get involved in finding out and then disclosing that information. But I think, again, as research moves on, then the ethical framework around your genetics, also moves on, as well. People should have the right to know, if this is something they want to know about. 

Neil Broomfield 26:39 

Right. So 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 important to look at the research, in a sense taking it at face value, but often it's 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 support the view, whether some of these national dementia organizations also get on board,  and, 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 us to settle on the best interpretation of these kinds of results. And unfortunately, too, it's almost daily that we get bombarded with news about breakthroughs and big advances and treatments only being three, four or five years away. I would certainly take a lot of that with a grain of salt, because it takes a while for the science around these issues to become settled. But it's also to maintain a degree of  hope and optimism, as well. These are conditions that are being studied by thousands of people across the globe, who are all contributing to our understanding, in this case, of Alzheimer's disease. It is the hope 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, 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 how 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 Centre 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.