The rate of Alzheimer's disease is predicted to triple by the year 2056. The question in personalised medicine is, can genetic screening and targeting modifiable risk factors downgrade the disease onset in identified at-risk individuals?
In this week’s episode, nutritional genomics consultant Dr Sasja Beetstra-Hill guides us through the emerging connection the ApoE4 gene is showing as a predictive screening option for Alzheimer's disease risk. Could this assessment lead to earlier intervention and help clinicians and patients get out in front of Alzheimer's disease before it's progressed beyond the reach of therapy? Covered in this episode
[00:38] Welcoming Dr Sasja Beetstra-Hill
[01:06] A quick look: Alzheimer’s & Dementia prevalence, treatments and reducing risk
[05:53] The benefits of testing for ApoE genes
[09:20] Current pharmacology for Alzheimers
[12:52] Risk profiles
[16:54] ApoE distribution across different populations
[20:25] The work of Dr Dale Bredesen in Alzheimer’s
[22:17] Lifestyle factors that reduce risk
[34:35] What is ApoE?
[39:04] CRISPR and drug technologies
[45:56] Should we test for ApoE4?
Mark: Hi, everyone, and welcome. My guest today is Dr Sasja Beetstra-Hill, Master of Science in Environmental Health, PhD in Nutritional Genomics, and holds a postgraduate degree in human nutrition from Deakin University. She's done research in the area of BRCA1 and BRCA2 with breast cancer risk, but today, we're talking about Alzheimer's disease and the genetics underpinning it.
Hi and welcome, Sasja. How are you going?
Sasja: I'm good, thanks. Thanks for having me.
Mark: Oh, it's my pleasure. We're going deeper into this area of Alzheimer's, a very, very, very big issue here. I'm going to get you to give our listeners and myself a bit of a perspective on just how big an issue this is, because we hear terrible stories about how it's the plague of the next, you know, 20 to 30 years. Can you put some figures on that for me?
Sasja: Well, in Australia it is...at the moment, there is about 1 in 10 people by the age of 65 to have dementia, which increases to about 3 in 10 in those over 85. Most of those are diagnosed with Alzheimer's disease and, at the moment, the predictions from Dementia Australia are that this number of people that have dementia is going to...about more than triple in 40 years' time, so by 2056.
Mark: Which is an increase just as the natural process of ageing in the population or is it increased incidents at given ages over that time?
Sasja: It's at given ages, indeed. Yes. Just the incidence is what they predict is going to increase if nothing gets done. So if no new treatments are being identified or new interventions are being found…
Sasja: …that’s what they're predicting because of...partially, because of the agent in our generation and indeed. But that's what they think.
Mark: It's a depressing scenario, isn't it? I mean, when you've run your best science and the drugs have failed one after another after another?
Sasja: Yes, it definitely is.
Mark: Where do we go next in this? I mean, do we look at it as an unsolvable problem? Is there known proven early life events, or diet, nutrition, things that we do early on in life that we know for sure are going to reduce the incidence and the prevalence of Alzheimer's?
Sasja: At the moment, there is no... As I said before, there's no proven interventions, but there is more and more research coming out that if you start looking at 20 to 25 years before Alzheimer's onset, so that's usually when you're your in midlife, that there are certain factors that you can change, like lifestyle factors, like being active, not smoking, sleeping well, having a healthy diet, indeed, and being aware that you don't get type II diabetes.
Sasja: And also looking at other risk factors like your cholesterol, mental health, depression, hypertension, cardiovascular disease…
Sasja: There is a lot of research coming out that if you look at those ones and you treat those, that might, in the long run, reduce your risk of getting Alzheimer's.
Mark: So some of those, I mean, the area we kind of roughly, as clinicians, break up vascular dementia versus Alzheimer's and tend to think of vascular dementia as the same as intervention in cardiovascular disease, stroke prevention.
Mark: We tend to think that we know a number of those risk factors and I think we tend to see Alzheimer's as that other mysterious one where amyloid plaques just appear and there's not much we can do about it. Do you have a thought about that? Would the management of one, say, the vascular side, which we feel more confident of, is that going to have an impact on amyloid plaque, Alzheimer's? Is there any research to suggest that that actually does work in Alzheimer's?
Sasja: From what I've read, yes, I believe it does. There is already… there’s been research shown that changes in amyloid and also the tau protein that is already changing indeed in your midlife…
Sasja: …before the clinical symptoms do appear of Alzheimer's and dementia. So they do believe that, indeed, looking at those things as well, and that's how you might also be able to identify people who might be at risk, and there you can say, "Well, if those levels start changing, then well, maybe you have to start looking closer at these, if you want to, of course, changing your modifiable risk factors, and make sure that your vascular health is up to scratch and everything yes."
Mark: How do you do that? Do you do MRIs on everybody to try and assist the very earlier stages of those changes? So can you see anything on the MRI, 25 years before?
Sasja: From the studies that I've read, they usually are all looking more and more about levels of tau and everything in the spinal fluid.
Mark: So you have to get pretty intervention? It has to be a very active surveillance.
Sasja: It's quite invasive. Yes.
Sasja: You’d be very keen on this, let's say, to have it all tested. Yes.
Mark: So I'm guessing that's exactly why we tend to move back to the ApoEs and grab blood from people to try and get a bit of a feel for the risk of dementia. Can you take us through that? Because the ApoE, the testing is controversial because one of the mindsets in the medical community is “why would you want to know when we don't know what to do?”
Mark: In other words, knowing your genetic expression or your phenotype and genotype is only a value if you can do something, and when there's nothing proven, what do you do about that?
Sasja: Yes, that's indeed at the moment the standpoint of most clinicians. But the value of knowing that you have ApoE4 and especially that you have both ApoE4 alleles is that, yes, it is a very high risk that you might get Alzheimer's down the line, but there is things that you might be able to do. You can look at lifestyle interventions, you can start living a healthier life, you can become more healthy, which newest research has been shown, might indeed delay the onset of Alzheimer’s…
Sasja: …for people with this allele. And it might also slow the progression. So if they would end up getting Alzheimer's in the end, anyway, it's not 100% cure, of course, if you start changing your modifiable risk factors, but it will also slow down the progressions in Alzheimer's. It won't go as fast as it would normally go in people with these alleles.
Mark: So slow down the phenotypic expression of what otherwise you would think of as probably inevitable if you live long enough? If you get the ApoE44, is it, you know, if you live to 90, you're pretty well doomed, or am I overstating that?
Sasja: At the moment, the risks that there have put to these alleles, so there's a lifetime risk if you have the homozygous version. So there's two ApoE4 alleles. They say that people, by the age of 85, about 70% of people that have two ApoE4 alleles will end up having Alzheimer’s.
Sasja: And the risk is lower for people who only have one allele. But yeah, there are plenty of people that have hit 90 years old who have the ApoE44, so two alleles and did not get Alzheimer's.
Mark: Did we study those people intensively to find out why they did well?
Sasja: The problem is, at the moment, because there's not much testing happening with the ApoE4 that, and the percentage of people that have these two alleles is only 1% to 2% of the population. So there's not many people that studies can use.
Sasja: And that's another positive behind getting more people tested or more people interested in testing for ApoE4 is that you will identify more people with the double...two alleles or just one allele, and they will be able to contribute to more research studies on what is exactly preventative and also for the pharmaceutical industry to be able to tailor better medication and maybe find better stuff that actually can treat Alzheimer's and those people that do get it in the end.
Mark: Do you think that we're moving forward in the area of pharmacology? It seems like there was high hopes, a lot of trials which showed either no benefit or even negative outcomes, and now a kind of pessimism that circulates around the pharmaceutical approach to Alzheimer's. Is that a fair reading of how things are going now?
Sasja: I think from what I've been reading in this, it seems to be a bit of a stagnant phase at the moment in finding new medications for Alzheimer's. They seem to struggle indeed with finding something that actually can cure it, or treat it, or reverse symptoms.
Sasja: So, at the moment, there's only a few that are approved medications for Alzheimer's. But the research at the moment is not looking very positive on finding any new medications for Alzheimer's. And that's why... And a lot of researchers have had suggested as well to look more at early life intervention and try to change something there.
Mark: Using the family history as a surrogate for the ApoE type testing, so if you've got a family history, the ApoE4, I would guess, would show up in the family line as Alzheimer's prevalence. Is that the simplest way of getting a surrogate marker for the alleles that we're worried about?
Sasja: It's not necessarily that yes, if you have ApoE4 in the family and you have ApoE4 then your risk is even higher. This is just purely because of the familial line.
Sasja: It’s like almost a lot of the diseases if you have, for example, type I diabetes in your family it's more likely that you can get it as well. And that's the one with Alzheimer's as well. If you have ApoE4 thrown in the mix, that chance, risk even gets greater indeed.
Sasja: And that's what some people want to know it as well. They know that their parents have had Alzheimer's, they've seen how devastating it is or they know other people in their family and that's why they want to get tested so they can prepare themselves for what is to come or to plan ahead for when they get older, what do they want to do? How do they want to approach if they do get Alzheimer's?
Mark: It's an important point because most people, I think, fear losing their minds more than almost any other type of disease. You know, the strokes that disable you neurologically and the loss of the ability to make that decisions…
Mark: …does mean that the living will, the concept of making the family informed is an important but very, very difficult conversation to have with a person 20 years ahead of whenever the expression of it may occur.
Sasja: Yes. And I think that's what the problem is. For a lot of people, it's a very, if you want to call it, a very scary disease, Alzheimer's, indeed. You're losing your mind and, yeah, and you might not notice it indeed, you might not notice it before, I don't know how long, before actually the clinical symptoms become really obvious to a lot of people, and that's one of the things that I think that maybe the current medication is not working. The pharmacological medication is not working because people get treated too late. They show signs, they can come that late to the doctors, maybe that's why it's not working anymore to stage. It's too late, too far progressed.
Sasja: So that's why it's also good to those people identify it earlier. So maybe it works better if you get early on in your progression.
Mark: This harks back to another area that I believe is your research, the BRCA1 and 2, that the idea, whatever you decide to do with that knowledge is that you intervene early rather than wait for cancer to occur and then try and use techniques that are harmful. So the prevention, the bilateral mastectomy…
Mark: …approach is a prevention that's not applicable to the brain. Obviously, you cannot chop out parts of the brain…
Mark: …but you can remove the breast. So are these numbers similar for BRCA1, BRCA2? Is this like in the order of 70% risk if you...lifelong risk of cancer or is it very different?
Sasja: It is, yeah. No, the risk profile is definitely very similar probably for the BRCA1 and 2 carriers. The onset is usually a bit earlier than, obviously, for the Alzheimer's disease, but the risk profile is very, very similar indeed.
Mark: Except that in that, you can make choices about whether to keep the breasts…
Mark: …or not to keep the breasts, whereas you have to keep your brain, you only get given one as far as we know.
Sasja: Yes. The options for the breast cancer is indeed much more at hand indeed. You can do more screening, you can do a testing of yourself and those type of things. And indeed some people can...they have the option, if they want to, indeed, to have a mastectomy, whereas certainly for the brain it's much more difficult. And yeah, the symptoms are also much more subtle, obviously, than breast cancer. They're not as easy to identify.
Mark: In the progression of Alzheimer's, is there any good evidence one way or another about use it or lose it, that if you are in active problem-solving, if your life is full of challenges and the like, does Alzheimer's speed up, slow down, or has it have no effect on Alzheimer's?
Sasja: There is evidence that indeed, that if you are in the early stages of Alzheimer's, so you've got mild cognitive impairment, as they call it, but if you are depressed and not feeling happy, and I can't recall exactly which the artifacts were, but yeah, that will speed up the progression of the disease. So that's definitely possible. Yes.
Mark: As it does many diseases. I mean, we found that all the time that depression and the neurological and mental associations seem to be a factor in cardiovascular disease, cancer risk, there seems to be a lot of areas where depression, and it's almost like the body's slowing down and giving up and...
Sasja: Yes. And there's also stress, obviously, is also a very big one that's associated with it.
Mark: Except that what I have noticed with the Alzheimer's patients that I have is often they're not stressed because of the lack of recognition of what is going on by that time, that the stress is largely of the family, the carers…
Mark: …and the distress about well, you know, what can we do to help? Whereas with cancer, you don't lose mental faculties, you don't lose the ability for self-reflection. And so, decision-making with breast cancer risk is a lot easier to give back to the person. Alzheimer's, the decision-making is largely lost by the time you see them to late…
Mark: ….and the ability to reflect and to make their own life decisions is part of the general stress but not the stress for the person, necessarily.
Sasja: Yes. No, I agree to that. And one of us mentioning this stress, indeed, is also mainly also, as I mentioned before in midlife, your work stress, what you're involved with and those type of factors, not just stress of actually having the disease or noticing that your mind is not there anymore the way it used to be.
Sasja: So it's more of the lifestyle stress indeed from working too much or worrying about things or, yeah. Those. Yep.
Mark: Does epidemiology help us out at all here? Are there populations where there is clearly reduced risk of Alzheimer's despite the genetics, or is it that, you know, genetics are only evenly distributed through different populations around the world? It seems far more common in, you know, first world countries where sugars, and maybe stresses, and other modifiable risk factors are high. But does that actually carry out in epidemiology? Do you know that?
Sasja: There's a few studies that has looked at, for example, diet and those type of things. And they're saying, for example, well, people who adhere very closely to a Mediterranean diet that's high in fish and those other things, omega-3s, that they seem to have a bit more less degree of Alzheimer's disease than the other people who live and do the Western lifestyle.
Sasja: Lots of fats, that's saturated fats and sugars and those type of things, which inevitably, usually leads to indeed obesity, type 2 diabetes, those are some things which are all risk factors.
Mark: I suppose that's what I'm asking, is the ApoE distributions are similar across those populations, but outcomes are changed by dietary lifestyle, exercise, and other interventions, or not interventions, but just those people who naturally fall into those categories, I would assume, have a lower incidence of Alzheimer's.
Sasja: There is a change in...what's it called? The allele, the ApoE4 allele. There is…it’s more prevalent in populations that stem from around the equator and near the poles…
Sasja: …and it's less indeed in the middle, like in between. And I think it has to do something with metabolic burden in olden ages and those type of things. They're suggestive, but that's what they think.
Mark: Okay. I had not heard of that. Equatorially, is Alzheimer's more common or...?
Sasja: I don't know exactly about that, but around the equator and poles, there's the highest levels, but it doesn’t mean, I think that is because the body copes for different ways with metabolic stress and food and the way the foods that they were eating at that stage…
Sasja: …all the time, hundreds and thousands of years ago. It's hard to explain indeed. So, yeah, so the body adapted to whatever foods they're eating and that's why they were more ApoE4 alleles in those people. And I think, I believe if people would probably adhere to the diets that the ancestors would be eating, have been eating, kind of thousand years ago, then it probably would be all right. But indeed, we are changing the way we eat. We are moving around the globe, and those type of things. So, yeah, they may be, indeed, increasing their Alzheimer's.
Mark: Well, the problem is, of course, evolutionary biology doesn't seem to really apply so much to this because, by the time ApoE4 Alzheimer's is expressed, breeding is already finished well and truly, whereas other areas such as breast cancer could decrease reproductive fitness. Whereas, it seems that Alzheimer's, you have to live long enough to be able to see it as a problem that emerges certainly in communities.
Sasja: Yes. Yes.
Sasja: Yes, I am.
Mark: ...and his kind of approaches. What's your thoughts on him? Dale's written a book, which I've read, I think it's called, "The End of Alzheimer's." I found it impressive, I found it that there is evidence that you may be able to reverse moderate Alzheimer's. But more impressively, if you can reverse moderate Alzheimer's, taking those ideas back 25 years, should have the capacity to be able to prevent as well. Do you have a bit of a take on Dale and his approach?
Sasja: I've read the research that Dale has done indeed, and I do believe, I absolutely do believe that what he's shown is absolutely correct, that it is possible in people who have already showing signs of Alzheimer's that you can reverse the signs of the... You can reverse the cognitive impairment that's being seen at that moment. And I do think it has a great application, that type of work that he does also in people indeed, not showing signs, the people are at midlife, and is actually currently, there is a lot of data coming out from research studies that have been set up in Europe, and Australia as well and the U.S., which looks at Alzheimer's prevention, and they're looking indeed at a much more personalised approach like Dale is doing and then people who haven't got Alzheimer's yet.
Sasja: And it's showing very promising signs indeed there as well, that people who do try to address the modifiable risk factors for Alzheimer's earlier on in midlife, that their cognitive mind and cognitive factors are much better than people who don't do that.
Mark: …that just because you may have Alzheimer's as different from vascular dementia, if you have vascular degeneration, it can only make it worse, right?
Mark: I’m guessing that the same things when you talk to the Mediterranean diet, what we know for cardiovascular risk reduction would apply in principle, irrespective of whether the amyloid plaques are, you know, vascular or not. You don't want additional problems. So is that fear from what we understand?
Sasja: Yes. Yes, I believe so, yes.
Mark: Okay. So that gives us concepts of diet. There is a question of your kind of social network, not on your iPhones or anything, but the number of other people you interact with. And I'll say this because one patient of mine was diagnosed as suffering Alzheimer's, got a carer in who was fascinating to her. They became friends, the carer spent time with them, they went travelling. She clearly improved dramatically over a period of a few years. And at the same time, this carer looked after her diet, looked after health, but engagement in conversation and the using of the brain in that complex social interaction made a massive difference to her. That carer disappeared after a couple of years and there was a clear deterioration, not with any other factors, but simply the ability to communicate with another human seems to have a protective factor there. Isolation seems to accelerate it. I don't know if there's any science to that, but it seems likely that that plays a big part as well in one's ability to function.
Sasja: Yes. Absolutely, the research shows that, indeed, social activity is very important and it keeps your brain engaged basically as... It was an interesting study, I believe it was earlier this year, it basically said, indeed, that, if I got it correctly, indeed, that people who are married have less Alzheimer's disease than people who are single. And that is exactly that reason. It's social activity, you've got someone to talk to, you're more interactive. Yeah, and there's way more studies than just that one, indeed…
Sasja: …that have shown that indeed, that being socially active, being amongst the people, it challenges your brain, indeed. And it makes you also feel happier…
Sasja: …most of the time, I would assume.
Mark: Oh, hang on. I think my understanding is marriage tends to benefit males and doesn't benefit females all that much. Marriage is a great idea if you're a man to live longer or maybe better, but I think that the tradition of the past has meant that that just ups the workload for the women.
Mark: So, social interaction, we can put on the list of things that are probably highly valuable.
Mark: Cardiovascular risk management. There's this idea of, you know, if you do Sudoku or Sudoku, I forget how to pronounce it, it's become so common. But if you do simple little puzzles that that somehow exercises the brain like we exercise muscles. Is that true or is that just mythology?
Sasja: There is also indeed a lot of research on that indeed. I think they call it cognitive reserve, basically, indeed.
Sasja: And yeah, there is a tendency, I believe, to decline as well over age, but if you keep your brain active and you keep on doing those, you challenge your brain, that's apparently very beneficial forward. And most of the cognitive stuff also focuses on way more early in life, like completing your schooling and those type of things.
Sasja: That’s the basis of your cognitive reserve. And then later in life, indeed, when it declines, they say, yeah, keep your brain active. Try to challenge your brain, try to do puzzles or something like that. It definitely helps.
Mark: Okay. So you're educational...your kind of level of education is a predictive factor, is that what you're saying? Or is it cause or effect? Is it that people...?
Sasja: Not the level of education, but keeping yourself educated. So, yeah, don't... You can, that's on the line, but yeah, complete your education.
Sasja: And whether you're going to be a brain surgeon or a mechanic, yeah, keep on challenging yourself, keep on updating things. Go and do courses while you're working and things that keep your brain active, and that definitely has a big benefit…
Sasja: …for your cognitive reserve, which may benefit in the end towards reducing your risk indeed for getting cognitive decline as you get older.
Mark: That is a separate issue there of what vaguely is called socioeconomic class, that if you are a wealthier and higher access to medical care, a lot of things go away, not necessarily, maybe obesity, but there are a lot of things that go away. So is wealth or something as simple as access to medical services, is that at all predictive of onset of Alzheimer's or delay of onset of Alzheimer's?
Sasja: To a certain degree, I would believe that maybe, indeed, yeah, because you have more access to stuff and you can fork out more money for maybe, indeed, a diet.
Mark: Survival of the richest.
Sasja: Yes. It sounds horrible, but yes. But, yeah, there is also the problem usually with lower socioeconomic class, that they indeed have lower education.
Sasja: They haven't gone to school for as long and, yeah, they may also not have the interest in it. They may not care about it, whereas people usually who have a better education and hence more likely earn more money, they're more interested in it today. Yeah, they're more willing to spend money on things like that.
Mark: The big one that comes up in lifestyle medicine, cancer risk, cardiovascular risk now, is the part of moving the body, exercise, just getting around, getting sunlight exposure, but is exercise positively, negatively, or not at all correlated with Alzheimer's or progression of Alzheimer's? If we get people exercising, move them around, does it have a positive impact or not much?
Sasja: Again, yes, there's definitely a research showing that if you are moving around well, and doesn't mean that you have to be top athlete, but if you do regularly exercise, and especially already starting in your midlife, again, exercise regularly, yeah, it keeps your brain working and it does indeed benefit. It may benefit towards reducing your Alzheimer's risk.
Mark: Does sleep play a part at all?
Mark: There are chronically poor sleepers that are always tired, that have, you know, decreased mental capacity, partly just simply because they can't sleep enough. Should we focus on sleep or is sleep again, no evidence one way or the other?
Sasja: No. Sleep is not a very important one. That's true. And there's more important, and they'd say at the moment from the research I was reading, as more when you get a bit older that you definitely should start, make sure you get enough sleep and those type of things. But sleep is definitely another one.
Sasja: Well, yeah, people should look at and I believe that in some of the personalised approach that people have been looking at indeed for treating Alzheimer's is indeed that they're definitely focused also on making sure that everybody gets enough sleep. Definitely also part of it. Yes.
Mark: So you mean once the person does suffer Alzheimer's sleep, what happens with sleep? I had assumed that with Alzheimer's, sleep would be longer hours simply because there was less activity, but that's a misinterpretation, I think. I'm guessing sleep impairment can be just as common, if not more common in Alzheimer's than it is in the general population.
Sasja: I don't know the exact data on it. I just know indeed that, indeed having a good sleep for people who have early Alzheimer's and everything like that, definitely, can be beneficial for them.
Mark: Reduces the expression of it, or reduces the symptoms. All right. Is there anything else I've left out there as what we regard as modifiable risk factors that we should start 25 years before in the susceptible...oh, probably in everybody for...I'm trying to be truthful, but in those with the highest susceptibility or the highest likelihood of Alzheimer's, is there anything else that we can do 25 years ago that we know makes a positive impact?
Sasja: I think we've covered most of them. There is the general ones, which is basically more attributed to heaps of other diseases as well, just basically watch smoking…
Sasja: …don’t drink too much, those type of things, yeah, and try to eat a healthy diet. But I think we covered that already.
Mark: Yes. I think that good quality nutrition, nutrition does tend to go down. Once people develop Alzheimer's, their ability to care for their own diet certainly goes down, and carers have to be quite committed. And often, you know, this comes back to what are we going to talk about now, the ApoE-type problems. Often, when people around a person suffering early Alzheimer's realise it's Alzheimer's, they internally give up on that person and that accelerates things. I'm convinced now having seen that in my practice many times that that negative expectation says, "Well, what can you do about it? Why would I want to do anything? Why would I look after diet? Why exercise?"
Mark: This is just running downhill in a bad way. And it's important that we break that, I think.
Sasja: Yes, absolutely. I think the general mindset of the majority of the population is, indeed, there's nothing you can do about it. But the research is showing that and, for example, like Dale's work is that, yes, there is something you can do about it. If you make sure they eat well, make sure they sleep well, maybe take them for walks every day or something that they can go and engage, take them to places where they can interact with other people…
Sasja: …play games with them. Yes. So there is a lot more things that definitely can benefit those people, but it's just not known yet, I believe, to the wider population.
Mark: There is one thing that I think is universally pretty good, and that's grandchildren or great-grandchildren, youngsters…
Mark: …who don't have prior expectations tend to challenge adults, whatever their cognitive capacity. And there's delightful interactions that I watch all the time between kids that don't know anything about Alzheimer's, have no negative expectations in grandma or grandpa, or it's just grandma and grandpa…
Mark: …they tend to bring them back to life. And so, I'm not sure that you can therapeutically prescribe grandchildren. It'd be an interesting script.
Sasja: It's interesting that you mention it, but there is places in Europe and I believe...I think there's someone in Holland, indeed, where they have integrated nursing homes or care homes with either student accommodation or with childcare places.
Sasja: So a kindergarten. So indeed, there's much more interaction between the elder people who are at risk of cognitive decline or already have cognitive decline, and they get much more interaction with younger people and, yeah, and it stimulates them, indeed. It has a positive effect on the elderly.
Mark: It certainly does. When grandchildren are born to a person with cognitive decline, it is remarkable in my clinical practice to see them come back to life, that there's almost like “my job here is finished. Oh, no, it isn’t."
Mark: There is a next generation that we're taking on from here and they find a reason to live again. And whether it is temporary or permanent, I have no real take on, but there certainly is an improvement in function and that interaction without the expectations and the negativity surrounding their previous decline, just does wonders for them.
Sasja: Yes. Definitely, I absolutely agree with that. Yes.
Mark: Yes. So what I'd like to do is just take a little bit of a dive. I wish to understand this ApoE, and the different alleles, and what we should be doing as clinicians, while listeners are, you know, primarily practitioners. And so, I want to try to kind of work through this of, do we test, don't we test? What is Apolipoprotein E and why is it important? Why do we think it's important in Alzheimer's, and like BRCA1 and 2, is it only Alzheimer’s, or is it a more generalized metabolic issue that we're dealing with with ApoE? So could you just give me a bit of an overview? What is ApoE?
Sasja: So ApoE, the protein that it encodes, it's involved in the transport of cholesterol and other lipids in the body. And it also helps in the clearance of the amyloid in the brain…
Sasja: …and neuro cyclin in the brain as well.
Mark: So amyloid accumulates in the brain in a normal person all the time and the ApoE is a remover of that amyloid?
Sasja: Yes. Yes. That's how I understand it, yes.
Sasja: At the moment, there is three different variations of the ApoE gene, if you can call that. There's three different alleles.
Sasja: They’re called E2, E3, and E4. E3 is the most common one. That's like in about three-quarters of the population will have two copies of the E3 allele…
Sasja: …that’s usually what everything is measured against. You've got the E2 and E4, and E4 they'll compare to the E3 for risk, and E2 to compare to E3 for risk factors, basically, for calculating risk.
Mark: Are these SNPs? Are these just a single nucleotide replacements?
Mark: So they have three snips, three variants of exactly the same gene.
Sasja: Although they're actually two SNPs. If you don't have either one of the SNPs, you are the E3 type, yes.
Sasja: So they have associated, the E4, obviously, with Alzheimer's disease, but it's also related to cardiovascular disease, indeed. People who have that, E4, they seem to have a higher risk of cardiovascular disease. They seem to have, in general, higher levels of LDL cholesterol and total cholesterol. Whereas the people with the E2 allele, which is not as common, they usually have a reduced risk. So the risk of cardiovascular disease is less…
Sasja: …and they usually have lower levels of LDL cholesterol and total cholesterol.
Sasja: So that's basically how it is. And E3, basically, it's in the middle.
Mark: Okay, so…
Sasja: And the risk of Alzheimer's, and people have two, three alleles is basically the same as what you expect in the general population.
Mark: So the E33 is about 75%.
Mark: So the other ones are the heterozygous, the E34, or E32, or E23, and then homozygous ApoE2 and homozygous ApoE4 are the rare variants, aren't they?
Sasja: Yes. Yes.
Mark: Approximately what percentage are we talking about? Two, three, 4%? Is it around that range for the homo?
Sasja: The E44 is about 1% to 2% of the population. Yes.
Sasja: So it's very small, and the E22 is even less than that.
Mark: Okay. So the common variants, the ones that we think of as the tsunami are really the E34, primarily, so that they're heterozygous and there is a bit of a mopping up. So I'm guessing, in the genetic sense, this is kind of partial penetrance, that as you have two copies of the gene, where do you fall? With an E34, is it halfway between the E3 risk and the E4 risk? Is that approximately right?
Sasja: It's not exactly halfway. I would say it's a bit below halfway…
Sasja: …from all the data that I've read. But you definitely have a higher risk than just E33. That definitely is that, but it's not... Yes, I think it's closer to the E33 when you have 34 than the 44.
Mark: Okay. So if you're a Buddhist and you're coming back to choose parents carefully, get the E2 variants of your parents, is that what we're saying?
Sasja: Yes. If you can find someone.
Mark: So I'm guessing it's not beyond the pale to think that people may start actually, you know, manipulating for the ApoE2.
Mark: I don't want to go down that pathway, but that gives me a bit of a perspective. So about 1% homozygous allele or a bit lower than 1% homozygos allele lower risk, 1 to 2% at clearly higher risk, which is the ApoE44, and then most of us in that middle range where we have average risk, were slightly moving up towards the 4 risk end of the spectrum.
Mark: Okay. Do you know what they do? Like they shunt out the amyloid? Is there a binding method or is the process known? Because, usually, if the process is known, a drug is developed to fiddle with that process and the drug should have been successful, and they're not.
Mark: So what I wonder is, do we really understand that process? I know Dale Bredesen's got the view that the amyloid is a protective response, not a pathological response. But if the ApoE, its job is to keep on removing the amyloid, I don't know that you can sustain that view, can you?
Sasja: Well, the pharmaceutical approach has been, as far as I'm aware, usually indeed to target the amyloid build up in the brain…
Sasja: …and that hasn't been working. So the medication that had developed that it's not working forward, it's not doing as well as they were hoping it would.
Mark: My understanding is, though, that it did the job, right? It actually did reduce the amyloid, it just didn't change the progression of the disease or...?
Mark: So if it does the job as Dale Bredesen kind of points out, if the drug you give does the job that you wanted it to do and it still doesn't work, then you need to go back to first principles about exactly, what were you doing? The surrogate of the amyloid may not be the disease itself, it may just be a marker of a protective process…
Mark: …and that could be why the trials go the wrong direction.
Sasja: Yes. Yes. There is a lot of, indeed, talk about why the medication is not working, indeed. And I think partially, it is indeed from what I've been reading about ApoE4. And yeah, there is still uncertainty indeed about exactly what it's doing in the brain, or whether it's good or bad.
Mark: So there, I think, is only one or two medications left out of the many that were tried. And even those, I mean, at their best, they work poorly.
Mark: And so, we're left in medicine with a problem that if what you're using doesn't work, and it doesn't work, and it doesn't work, just doing it again, and again, is just mad. And so, a new approach is needed.
Sasja: Yes. I think U.S. has, indeed, two approved medications, drugs for Alzheimer's at the moment. Yes.
Sasja: I don’t know exactly how it is here in Australia.
Mark: So where do you see this going next? So we have Alzheimer's as a building tsunami. We've got poor evidence so far for the lifestyle factors. Is that simply because we haven't looked hard enough and we were putting too much onto the pharmacological treatment, or is it because, you know, at best, lifestyle intervention is only a minor factor in whether you develop Alzheimer's or not?
Sasja: I think we just haven't looked at enough on the lifestyle factors, indeed. There has been research coming out that basically says, "Well, if we start looking at the modifiable risk factors or lifestyle factors, they think that about one-third of the cases of Alzheimer's disease can be attributed to those factors. So that's quite a lot if you think about the incidence of Alzheimer's and the way it's going. It's sort a third of the cases might be prevented or delayed with onset. That's quite a lot.
Sasja: That would have to have a big social impact, but also economic impact, indeed, economic burden, would be a massive reduction in that.
Mark: Yes. And if any drug were to achieve that, it would be called a breakthrough drug and it would be all over the front page of newspapers.
Sasja: Yes, yes.
Mark: In typical terms, lifestyle intervention works, but it works in a slow and non-dramatic way and no one's getting any money from putting people in into a good lifestyle.
Sasja: Yes. Yeah. But there is more... And as you mentioned before, yeah, I think that the research has mainly focused in the past on pharmacological approaches. But it has been in the last, probably, five, 10 years that they have actually decided, "Well, it's not working. Maybe we should look at preventing it. Maybe we should look at other things." And it is now definitely money being put into a lot more preventative research. The problem is, of course, that those studies run for a very long time to be able to get all the data because you have to start when people are not showing symptoms yet.
Sasja: But the first data that is coming out is looking very promising, that is in the U.S. at the moment, is about three or four, I believe, Alzheimer's prevention clinics. So if people who are at high risk can go and say, "Hey, I'm interested in reducing my risk and I've had Alzheimer's in the family," whether they noted ApoE4 for or not…
Sasja: …they will get tested for it there usually then. But yeah, they can go and say, "Look, I'm interested in reducing my Alzheimer's risk." And they look at the people and all the factors, their blood works, the genetics, whether they do sports, etc. etc.
Sasja: A lot of factors. And they tailor our approach for them, for those individual level, they get basically told, "Well, this is your plan. And if you stick to this, that might reduce your risk of getting Alzheimer's and living to old life."
Mark: But it sounds to me like though they're doing these studies then mainly on the ApoE44 in order to have a high-risk population. And so, we do this in medicine a lot, we choose the highest risk population and then extrapolate backwards about what's good for the rest. And, you know, in, say, cardiovascular disease, we like people who have already had a heart attack before we try and intervene and we like to have people that have got clear Alzheimer's symptoms before we go and say, "You could develop Alzheimer's." It's an economic issue often in the studies. You want the worst to find out what you can do with them. Do you think that what applies to the worst is likely to also apply to, say, the ApoE34 group or even just the, you know, the normal risk of Alzheimer's for the ApoE33?
Sasja: I would say yes in this case…
Sasja: …and the ApoE44, they have just been shown that they progress quicker than normal..
Sasja: …and those sorts of things. So I think if it is working for them in theory, it should also work for the other people. Yes.
Mark: So I'm going to put the question to you. Should we be testing for the ApoE4 for people where there is any suggestion, any, say, family history? Is it a worthwhile thing to do to go out and test the ApoE4 or should we leave it alone? What's your approach there?
Sasja: I think it's definitely worthwhile risking...not risking, testing for.
Mark: The risk is that someone finds out about it and won't insure you, I suppose.
Sasja: Yes, but, indeed, there is a big but, and indeed, the person has to be wanted to be tested, obviously.
Sasja: The person who comes into the practitioner, he wants to know the result. He has to understand what the implications are if he finds out the result and they're not...they are, for example, 44.
Sasja: So they, yes, there's a lot of psychological things involved. And it's not just for the person itself, it's maybe also for the kids that they may have. So if you know that you carry an ApoeE4 allele, well, that might mean that maybe you pass it on…
Sasja: …especially if you're, of course, the homozygous, the 44, you will pass it onto one of your kids, one of the alleles.
Mark: And then everything depends on the spouse.
Sasja: Yes. And so, so it's really... Yes, it's really what do you want to do with the results? So I think it's definitely worthwhile, and especially in cases where there is a lot of Alzheimer's in a family and those other things. If people are interested in it, I think they should definitely have the option to test it, but they have to understand what it means.
Mark: This is one definitely that you need the counselling to go along with the testing.
Mark: You cannot just dump a test result and allow the person to walk off with them.
Sasja: Yes, they definitely need to receive genetic counselling. And if it comes back that they are carrier of one or two ApoE4 alleles, they should also be provided with options, what can you do about it?
Sasja: There’s some information, because a lot of people struggle from the research that I've read that they don't know what to do with it. They go, for example, to 23andMe, they get their data, they put it in a different website, and it tells them the ApoE44 a high risk of Alzheimer's and then they don't know what to do.
Sasja: So what does this mean? What am going to do? Am I going to get Alzheimer's or not? Yes. And a lot of people who find out that they have one or two of these alleles, they want to get information.
Sasja: So what can I do then now? Okay. I know I've wanted to know this information. Unfortunately, I have it. What can I do?
Mark: Yeah. Well, it's all right. I'm really looking forward. Dale Bredesen is coming over for the 2019 BioCeuticals Symposium.
Mark: I think that we're going to have a lot of questions to ask of him while he's over here, but I'm really looking forward to that because, for the first time, there does appear to be evidence building
Mark: But what we do as an advising...as a clinician, maybe I want to make a difference both in prevention and maybe in the management of early Alzheimer's.
Mark: So it will be eye-opening to me after years of depression about do I test or not? It may make the test really worthwhile to know where to target one treatment.
Sasja: Yes. And there is indeed also evidence indeed for people who do have the ApoE4 or both alleles, one or two alleles, that certain dietary changes might actually be more beneficial. They might respond even better to it than normal people who just...they're just ApoE33. So, yeah.
Mark: Dr. Sasja Beetstra-Hill, it has been delightful to talk with you. You've eased my mind on a few subjects to do with the Alzheimer's. When you reach my tender age, in my mid-60s, we always want a bit of confirmation that the future is bright, and I haven't done any gene testing yet, but thank you so much for your input and for the information that we've got for our listeners today.
Sasja: Thank you. Thank you for having me. I'm glad I could be of help.
Mark: I'm Dr. Mark Donohoe, and thank you for joining us today on FX Omics.