In this episode I chat once more with our resident genetics expert Helen Gauche. This episode is dedicated to a discussion of the APOE gene. In particular we will discussing the APOE4 variant of this gene - this variant is most highly associated with increased Alzheimer's and Cardiovascular risk. It has a powerful effect over many processes within the body. This episode is a must for people who want more understanding of genetic predisposition to Alzheimer's and cardiovascular disease but importantly what lifestyle changes you would want to make if you discover that you have an E4 variation of the APOE gene.
Thanks for listening to our podcast and please feel free to get in touch:
We would love to hear from you!
In this episode I chat once more with our resident genetics expert Helen Gauche. This episode is dedicated to a discussion of the APOE gene. In particular we will discussing the APOE4 variant of this gene - this variant is most highly associated with increased Alzheimer's and Cardiovascular risk. It has a powerful effect over many processes within the body. This episode is a must for people who want more understanding of genetic predisposition to Alzheimer's and cardiovascular disease but importantly what lifestyle changes you would want to make if you discover that you have an E4 variation of the APOE gene.
Thanks for listening to our podcast and please feel free to get in touch:
We would love to hear from you!
Welcome to functional medicine bite sized the podcast where Pete chats to experts in the field of functional medicine and health, giving you the listener pearls of wisdom to apply on a daily basis.
Peter Williams:So, welcome to this episode of functional medicine bite sized. As you know, we travel around the world. So we're going to speak again to our resident nutritional genomics expert, Helen. Helen, good morning, how are you doing?
Helen Gauche:Good. Hi, good morning, Pete. I'm well, how are you?
Peter Williams:I'm not too bad. What time is it for you? Is it an hour later?
Helen Gauche:Same time 10 o'clock.
Peter Williams:Okay, so you're an hour ahead. Of course if you don't know and if you haven't listened to Helen yet, she's based in South Africa. But she really is this incredible expert in in the field, well she's a dietitian but in the field of nutritional genomics. And basically, me and Helen have worked together for quite a few years now. And what Helens absolutely incredible at is taking my ideas and my assumptions, and then actually nailing the science and the science that is applicable. And the science that when we're looking at gene SNPs, we can actually have something that is actionable through lifestyle, which is that which is the crucial thing about it. So we're gonna talk this morning about what I think probably my favourite gene and gene SNP, which is the APOE gene, which can be bit problematic can't it from a point of view of its association. Again, and the reason why I'm so into it is because it's it's definitely one that is the one I've got to think about because the it has a very strong association with cardiovascular disease, but also with Alzheimer's. So Helen, as you say, I want to pick your brains on this because I think it's an important gene, it's probably the most important gene that, that DNA life put on all of their panels because simply because of its influence, so can we can we but start with the absolute basics? What is it? What does it do? And maybe with some particular references to cardiovascular disease and Alzheimer's, I suppose to sort of give us an overview first, and then we can jump in, I suppose later on into the different alleles and the risk factors with that, that'd be cool.
Helen Gauche:Okay, so APOE is a gene encoding an Apoe lipoprotein. And in simple terms, it's it's really important in cholesterol transport and metabolism. So that's where it plays a really important role. And what it's responsible for doing is shuttling different types of cholesterol around our bodies and delivering it this cholesterol to where it needs to go. As we know, cholesterol is really important for making our hormones for looking at neurotransmitter synthesis. So we really need our cholesterol in amounts.
Peter Williams:And this is the point isn't it, just to be clear, is that every single cell needs cholesterol. Yes, okay, because I think some people sort of maybe don't realise that carry on.
Helen Gauche:Yes that's right, cholesterol is really important, really, really important in relation to APOE. So we want this transporter to be working as well as possible. The thing is, though, that how it's related to cardiovascular disease and then also Alzheimer's disease is because there's a genetic variant that can be found on this gene. So now when we are talking genetic variants, where obviously we're looking at the DNA and and we are identifying specific changes in our genes or our DNA, that may then lead to a change in how
Peter Williams:They would be the E3/E3 would be the normal a protein might express, how a gene might express, how a protein might function. So what we see in the APOE gene is that there are in fact two changes that occur. And because of those two changes, it leads to what we call different isoforms. So that's just all the genetic jargon, that if we're thinking of this change, we can end up receiving or having in our genotype having an E2, an E3 or an E4 genotype and with this change in the protein what happens is the complete structure of the protein changes so if we're thinking of, I like to think of it as you can do horse and cart or taxi or an Uber kind of service and depending on the change that you have, you're going to choose different customers to be transporting. So if we're thinking of I go with Uber so if we go with an Uber service, you get your you know you get to different tiers of Uber how luxurious you want to go and sometimes you might have you, the kind of the taxi service if you doesn't, you're really desperate for business you will pick up anything. And that's what your E4's do they kind of they're a little bit rundown, they're not working as well as they should and and they pick up any customer and all customers and often if we're thinking about now that in terms of cholesterol, we think of LDL and VLDL, which is your cholesterol that that can be more easily oxidised. It's not so friendly to our, to our vascular system. And so because of that, it can increase your risk for heart disease. And so that's where, you know, if we're thinking of this transporter, this E4 allele, this E4 genotype, it just doesn't work as well as we would like. Whereas with an E3/E3, they kind of run of the mill, they are a little bit more picky, they look after their a bit more maintenanced in terms of their services, and and they get the job done. at a good level, variant that we'd expect to see in the majority of the population that sort of middle of the road, I think your analogy is absolutely fantastic, by the way. So go on because you're going to maybe say the super luxury is coming up with the E3 or E2 or something like that.
Helen Gauche:Luxury, exactly. That's where you pay a little bit more. And then you choose a really nice luxury car, that's really clean, the service is great. And the customers are really fussy as well. So those luxury taxis that choose more of your HDL cholesterol, they not so crazy about picking up just any old person on the side of the road. So your your LDL and VLDL is not so high in your E2 carriers. And so they seem to have protection, when we thinking of what types of cholesterol are kind of moving around our body, the E2 carriers, it tends to be that they get better protection, that's more HDL and not so much LDL and VLDL, which is not the great cholesterol that we want in high mass. And E3/E3 as you as you mentioned, it's sort of the the majority of the population, and then the E4s, that's where it's literally this protein or this car that is not the shuttle service that is run down, it's not working as well and just doesn't do its job as well as it's supposed to do.
Peter Williams:Yeah, this is really funny, isn't it, because years ago, I used to always think about cholesterol floats around the body, no problem. But actually, it doesn't float around the body at all because it's highly hydrophilic or lipophilic is a bit like when you drop oil in water, they don't mix, the cholesterol doesn't mix. And so it has to be coated doesn't it it has to be contained in a in these lipoproteins, and they have these a lipoproteins on the outside. So it's almost like as you say, it's the taxi picking the cholesterol up and maybe some triglycerides as well and floating off around the body to deliver it.It's an absolutely brilliant analogy you are doing at the moment, keep it going. It's great.
Helen Gauche:So now, I mean the analogy kind of stops now, but what happens is with this kind of this taxi or this, this protein that isn't working as well, isn't maintenanced as well, we often think of you know, APOE, if someone mentions APOE we always think, oh bad, but actually, the protein itself performs really important jobs. And so we need to ensure that this protein is working as well as possible. And that's where the E4 genotype that E4 Taxi is just it's not been maintenanced, it's not working as well. It's just not doing its job as well. And because of that, it increases risk around it. So I think you know, if we think of the taxi, if you if you think of something, a car that's not maintenanced, it's a higher risk on the road, there's higher risk of of accidents and damage to everything around it. And thats the same that happens with E4 genotype carriers with this APOE protein is that it doesn't do its job as well. It tends to carry more of this LDL and VLDL cholesterol. And because of that there's a higher risk of these specific lipoproteins being oxidised, LDL and VLDL are very prone to oxidation. And then the other thing that APOE4 carriers have which is not so great as they're not such good communicators either. So if we're thinking about this Apo Lipoprotein it performs and actually has sort of a lot of downstream effects in our system as well where it sends messages to our antioxidant enzymes. When we have a lot of oxidative stress exposure, and we're exposed to toxins from our environment, we drink alcohol, or if you're a smoker, all of these things are free radicals that our body needs to deal with. And APOE is really good at saying listen, I'm under a lot of attack or I've got a lot of oxidative stress that I need to deal with. I want my intrinsic antioxidants, the antioxidants that we make in our body ourselves, I want these to work as well as possible. So it sends the message to do that
Peter Williams:Can I throw a question into you there so if you have, actually, I won't throw a question in, I'll come back to that one, because I think it's probably important that we distinguish between the APOE results that you might get. And obviously, if you can sort of determine risk, but also, if you could give us a bit more of an overview of just why we're so keen on this gene, because it does seem to have a very big influence and maybe not influence because cholesterol is needed in every single cell in the body. So I don't know whether that is its influence, but it is influencing 1000s of genes, as far as I remember, with regards to its influence. So as you're saying is that if there is so many genes it's influencing, and it's not working so well then that might that might lead into some problems. Could, can you just expand on that a little bit more?
Helen Gauche:Exactly. It's almost like if you think about, you know, a communicator in a company, or if you wanted to send a message, and you need this message to get to someone, and it's a bit like a broken telephone with the E4 carriers is that the message doesn't get to the antioxidants and enzymes as as quickly as efficiently as it should do. And if you're thinking of it as sort of a corporate and the communication doesn't work, well, well, then the company is not going to function well. So our body doesn't function well. So so it's the same thing with these e4 carriers as the communication to these genes is not as good as it should be. And so the the eventual expression of these other genes the antioxidant genes encoding these these antioxidant enzymes. It doesn't work as well. And so because of that, what we see with E4 carriers is they have a tendency, when we look at the research, they'd have a tendency to have lower levels of our antioxidant enzymes, our GTX and our catalase. These are really really important enzymes within ourselves to neutralise a lot of free radicals, our radical oxygen species, they really good at doing that, and GTX is involved in in also neutralising our oxidised fatty acids. So really, we want GTX around in high amounts, but E4 is just not doing its job to say, come, I need you to come and help me. So because of that E4 carriers, we now have this kind of pot of issues that occurs with E4 carriers it's where we've got a tendency towards higher LDL and VLDL cholesterol, that then is a risk factor for cardiovascular disease. On top of that, we have lower antioxidant status. So we have a higher risk for oxidative stress, especially if we're in an environment where there is a lot of oxidative stress. And then what it also seems to do is because of the transport properties of APOE and the E4 carriers, it seems not to really do such a good job in transporting our omega three fatty acids, especially our DHA to our cells. So if we're thinking of the fatty acids that sit on our cells, depending on what they are, they can make the cells be able to communicate with other cells, we need these cells to be almost elastic and fluid in nature. And when we are not delivering the right fats to the cells, they're not going to be able to work as well as they should. And that's another issue with your APOE, your E4 genotype carriers is that they don't deliver the DHA as nicely to the cells. And so there's there's this kind of this melting pot of issues. It's not just cholesterol, it's not just oxidative stress. It's not just the Omega threes, it's a mix of all of that. And because of that, it increases risk on a number of levels. If we think of you know, cardiovascular disease, I haven't, we haven't even got to Alzheimer's. But if we think of chronic diseases of lifestyle, it's not just one biological process, or one risk factor that is going to lead to the disease. It's a number of biological processes together not working as well as we would like them to. And that's why APOE is so important, so powerful as a gene variant there, it exerts functions on so many biological processes in our body.
Peter Williams:So on that again, that I suppose that runs into the value or not of knowing your gene result. So I wouldn't mind talking about that. Because there is I think we briefed on this last time when we're talking about genomics in practice, and certainly direct to customer genomics companies. And I'm sure you're worried to literature with regards to is this a good idea? Can you explain where that is at? Because, again, telling some because it is the gene that they say is the Alzheimer's gene, isn't it? And I know there are many genes involved in Alzheimer's but it is a very dominant gene with regards to Alzheimer's risk gene as in gene result, I suppose the way we've got to look at this isn't as you say, is that If you want the taxi that is at top of its game, you're gonna have a really nice journey, you're going to be always on time, it's always going to run smoothly. And hopefully you might have any E2/E3 variant. But once you start getting, and most of the general population, they're going to be E3/E3, I can't remember the numbers, but 50% Is it for E3/E3?
Helen Gauche:Ah it's more, it's around 60%,
Peter Williams:I think we've got about 25% of the population that will have an E4 allele in there. When we mean, alleles we get, we get one result from Mum one result from Dad don't we, so we might get E3 from Mum and an E3 from dad, or an E3 from Mum, and an the E4 from dad, or unfortunately, we might get an E4/E4. So can we just talk about that with regards to Alzheimer's risk and sort of lifetime risk? And before we and then we can get into well should you test and what are you're going to do if you do test? What's the moral implications of that, you know, are there risk factors with regards to direct to consumer sort of stuff? So can we just talk about fundamental lifetime risks of the different variants?
Helen Gauche:Okay, so when we're thinking your APOE e3/E3 genotype, that's because it's the most prevalent in the population, you know, it's the normal functioning gene as well. If we're thinking of lifetime risk for cardiovascular disease, and Alzheimer's disease risk, all other things being equal, you know, if everything else is equal, that is your general population risk. When we talk E2 carriers, that is where you have a slightly decreased risk. So it's protective. And it depends on from population to population, how protective, but if you thinking sort of your risk ratios, and we're looking at around point eight, and so it's below the one so so you're getting protection from an E2 carrier, and what
Peter Williams:population because I mean, I've done hundreds of APOE gene testing, and it's rare that I see an E2, but I did see one couple of weeks for E2/E3, I have to say he was pretty chuffed about it. But that's not that common is
Helen Gauche:No, no, the E2 carriers, it's around it depends it? whether you are heterozygous, so if you carry only one copy of the E2, or if you're homozygous E2 carrying both copies of the E2 allel. No it's rare, We in South Africa, this, there was a nice study done. And that was around 3% of the population that was E2/E2. Not a lot. And you also get an E2/E4 genotype, which is 2% or less of the population.
Peter Williams:I'm assuming an E2/E4 probably is pretty much equivalent to an E3/E3, as far as risk,
Helen Gauche:We think so we think so because it's such a rare genotype, it's difficult in the studies to actually get really solid outcomes when we thinking about you know, because there are just so few individuals with the genotype. And we are wanting you know, if you want really good statistical power, you sometimes need larger groups of these of these individuals. So we think it's around an E3/E3, but in terms of Alzheimer's disease, it may be that the E4 still trumps.
Peter Williams:Okay, here's a question for you. Because I can remember we had a conversation about my absolutely crappy vitamin D genes. With regards to no wonder I'm probably deficient most of the year round. And whilst we don't know, we feel as though there's probably there was probably some degree of protective mechanism hundreds of 1000s of years ago, or I basically lived on in sub Sahara, which probably fits, can we talk about why we have these different gene variations? Because they started with just the APOE4, didn't they? And sort of why did we need the APOE4? Why do we get these genes that we could look at and go Well, these are pretty rubbish ones I have potentially.
Helen Gauche:So so it's yeah, if you're looking kind of population genetics, and also just anthropology around genes, it becomes really interesting to find out, you know, certain individuals, or certain population groups have higher frequencies of certain genotypes versus other population groups. And the reason for that is you have to think about the environment in which these populations are living. And I mean, they really, they're great ones to look at from the Europeans, more northern Europeans who are more lactose tolerant compared to when you go south and they didn't have dairy cows. I mean, it was just simple as that. So you get used to the dairy over 1000s of years. With another one. If we look at your when you're looking at E4 is a good example is, if you thinking of, say Central African, there are a lot of nasty bugs that can get you, there a lot of pathogens that can get you. So you want to be on high alert all the time. And so that is where you may find high frequencies of E4 genotypes in these populations. Because your, your body needs to be on high alert to pathogens, so you want kind of a strong oxidative stress response to actually fight off the infections from your environment. And then at the same time, you're not eating a modern Western diet, so you're active. And when we talk about interventions, it actually comes down to this you're being active, you're eating greens, very plant based, so it kind of balances out. And so and then if you are not exposed to a lot of pathogens, and you have more more fat in the diet, then that's where the E3/E3 genotype comes about, as well. So it depends on you know, what your environment is over those 1000s of years as to what you actually develop.
Peter Williams:So this is the thing, isn't it? It's just a bit of certainly the APOE4 is a bit of a mismatch in I'd say, modern Western society, because the gene that was designed for pretty much getting you through the the early stages of your life where it was expecting it to be pretty traumatic, always, always battling against infection. So you need this sort of inflammatory sort of cascade, this immune this sort of hyper responsive immune system, because most people didn't survive that long
Helen Gauche:Exactly, that's the other thing if we're thinking Alzheimer's disease, you know, our population is ageing now. We weren't ageing 100s of years ago to where we are?
Peter Williams:Because that's an interesting point, isn't it? Because Alzhemeimer's is... I suppose it's interesting isn't it cause these genes were originally set up for Okay, well, yeah, I mean, I think I learned something like even in the 19 hundred's 50 was the maximum age that you're gonna get, if we took you back right back to caveman times, I'm looking at 35 to be the maximum we get. So it was absolutely crucial that that gene was expressing itself on a daily basis, because you didn't live that long. So I suppose, you know, it's comes down, because of course, the biggest risk for Alzheimer's, regardless is your age. And I suppose that's the same with most chronic chronic diseases is that, you know, you can't, you have to always have to factor in, you know, well if you're getting older, you you're more likely to, you know, develop these problems, because living this long, although we have the capacity to do this, and we talk a lot about this, you know, you know, optimal ageing, and you know, maybe we can go to, you know, we can go to 130, maybe a little bit longer, theoretically. But the reality is for many people, and I'm in one particular, I don't seem to have those gene sets, I mean, my breeding line, if you like was clearly down highly explosive, highly inflammatory probably survived Well, for the early parts of my life, but not looking great for living to 100. Even though my grandma on my Mum's side lived to 100, so good on that side, but (well there's something there) not so good on the other side particularly with the men. Can we have some kind of numbers on this then? So we talk about lifetime risk, don't we? Because I was just looking at, I'm doing a presentation coming up soon. And I was showing a case study, and I've got a female who's an E4/E4 and depending on which literature you read her lifetime risk by the time she gets to 82, with that genotype, for developing Alzheimer's is 60%, which is pretty big. (Yeah). So can you give me some averages on numbers, because I think this comes down to the question about should you know, and what is the method that you know, that you're told? And you know, what does the research suggest, about when you have been told, is that a good thing or a bad thing? Where are we with risk?
Helen Gauche:So with your E3/E4 carrier, so that's your heterozygous genotype. You have an increased risk, it's a three fold increased risk.
Peter Williams:Okay, so it's pretty big.
Helen Gauche:Yeah, E4/E4 depending on population, group ethnicity, but averaging it out, and especially Caucasians tend to have the higher risk is 14 to 16 fold.
Peter Williams:Wow, that's, that's quite incredible, isn't it?
Helen Gauche:It's late onset Alzheimer's, but...
Peter Williams:Can you can you explain, because I think this is the other thing is that late, what we mean by that is, it's probably not going to start to show or have certainly a diagnosis until at least you're in your 60s or 70s. Would that be correct? Exactly. But we call it LOAD, don't we? That's the term we use late onset,
Helen Gauche:LOAD, late onset Alzheimer's disease, exactly. So you get your earlier onset, which is actually governed also by genes. These are the mutations that you that you would carry. But that's a really, really small percentage of the population that carry those. And that's where you're seeing an Alzheimer's disease actually manifest around your your 40s. And
Peter Williams:And they are very specific aren't they? They are the presenelin genes are Yeah, yeah.
Helen Gauche:Yeah. And so those are, those are the mutations that's early onset and Pete exactly right, late on set is around your 60s 70s. But if you carry the E4/E4 genotype, that age, the risk, obviously, for developing Alzheimer's disease is higher. And the age to actually have Alzheimer's disease starting to manifest is, is lower so it's a younger age. And that still is still considering sort of still late onset but closer towards the younger side. But then if I think about I mean, my parents, you know, and they, you know, 70s, and it's not that old, you don't think it's that old.
Peter Williams:But I suppose the key we've got to think about this is that and again, one of the key things I want to say in that lecture is and I suppose this comes down to knowing where you're at, I think we clearly for a lot of humans, we have this mismatch between we're living our lives, and actually what our genes are designed to do. And ApoE4, I think, is a classic example of an ancient sort of genotype because, because threes and twos have come much later haven't they.(Yes, I think that is correct. Yeah), they've come much later. So originally, everyone was APOE4, but we've had these mutations which have arrived, 10s of 1000s of years ago, I think, 3,3 came and then two, as well, which is, I suppose, is an adaptation process, isn't it? So that again, is sort of beneficial gene mutation, I suppose a little bit like white skin is a is a beneficial gene mutation, as the environment has changed, as you say, as humans have moved from hot countries to northern climates to I suppose classical Celtic's with copper hair, I don't think that's the prime skin for getting any sunshine on
Helen Gauche:For trying to get some vitamin D. Exactly.
Peter Williams:That's always the classic is it's just the reason why I suppose skin cancers is an issue is because it's not a good idea to take that skin to the Mediterranean.
Helen Gauche:Yeah, exactly.
Peter Williams:So let's go back on to where we were with regards to risk. Can you just talk about well, you know, why should I know? I think it's a good question. And is, because there has been some, there was always an argument about about genetic counselling and how is this done? I think this is still I still see this as potentially one of the risks of the direct to consumer tests. What has what has the literature said?
Helen Gauche:So, there is there are a lot of components I want to first start with, I mean, maybe just one of the big points around why maybe people should know, obviously, in a responsible manner, and we'll get there. But even though your e4 allele confers this great risk towards Alzheimer's disease, cardiovascular disease, it's not set in stone, your genes do not determine your destiny. And there are these great RCTs these randomised control trials coming out, and coming out quickly now, looking at how we can modulate the effect of your e4 genotype on your phenotype. So what can you do with your environment? And that was a classic example of, you know, thinking of this individual in Central Africa, you're not going to be eating a modern Western diet, and why with some ethnicities in certain areas in the world. Why are they not getting the higher risk for Alzheimer's disease? Well, we need to start looking at what is their environment? What are they eating? How much are they exercising, what are their stress levels, because all of those things make a huge difference when it comes to modulating the effect. So yes, it might be a 14 fold, but it's not a 14 fold for everyone. It's depending on what you're doing.
Peter Williams:Exactly and and I think this is the key thing that we've learned, isn't it and we talked about we also talked about the difference between some Genes that we're looking at, and other gene based diseases, there is a difference isn't there? So, you know, there are some genes that are fully mutated, that you will get 100%, you're gonna get the disease. Yeah, I can't remember whether they're called high penetrance genes.
Helen Gauche:Your high penetrance is is a very, very strong chance. So high penetrance would be something like your BRCAs, and then you get your fully penetrant as well. So fully penetrant means 100%, you are going to get that disease.
Peter Williams:And the stuff that we're looking at in practice, these genes are in a sense, in a sense, low penetrance genes, aren't they? But everything that we look at that your company looks at the APOE4 Is the standout gene, isn't it from a point of view of just simply as you say, it is talking to so many genes and so many pathways. And if it's not, your right, as you said, you're never going to get the delivery system it's always probably going to be on time it's delivering the wrong stuff. And then we've got the increase in oxidative stress and everything else that goes with it. So can you just give us a brief around just APOEs, obviously, because I'm hugely interested in I tell you what, let me take a step back, let's come to that. Can we just talk about why why I think the key message is this is probably why it is beneficial to know, I certainly think it's beneficial to know your gene result. Because then as you said, genes don't determine outcomes they are a component of outcomes. And as you say, regardless whether you're so if you're 4/4 you said maybe 14 times more likely to go on and get Alzheimer's, that's probably if you're doing nothing. So, here's the thing, you start exercising well consistently, you're sleeping, well, you know you're eating the right diet, you're absolutely not, I would say definitely not a smoker probably try not to drink at all. Can you talk about those two, because I'm drinking and smoking really stimulate oxidative stress, don't they?
Helen Gauche:They do, to another degree, it's just on another level. And with this E4 genotype, as we mentioned, these antioxidant enzymes, the communication there is not very good. And so E4 individuals have a much, much higher oxidative stress predisposition, higher oxidative stress levels, so you want to literally put E4 individuals into a lovely bubble where they manage their stress, they exercise. So these are the studies that are coming out what they're looking at as is moderate intensity exercise on a regular basis on a daily basis, good quality diet, and there's that mind diet that's looking at your blueberries, your your high fibre, plant based eating very low in any trans and processed food trans fats & processed foods. And so just a really good clean diet, lower in the animal saturated fats, good quality omega threes and DHA is and we can kind of the list goes on with certain supplements that could also be done. And so by having that information available and putting this person into that kind of bubble, we can significantly decrease the risk. A wonderful thing about what these studies are showing also is that E4 individuals tend to be hyper responsive to interventions. So they actually may see a greater drop in their LDL levels and higher changes in HDL levels, better oxidative stress changes with interventions compared to E3/E3 individuals.
Peter Williams:Well, that completely makes sense, doesn't it? Because it's a bit like, you know, if you're going to take the car to the garage that you say so suddenly your taxi is getting smartened up and the navigation system has been improved, you know the patient's experience is better, then there's so much more that you can improve on because
Helen Gauche:Exactly. Expectations completely changed. So, so that's where I think, you know, the knowledge of this being able to motivate change in behaviours. So that's a really big thing around nutritional genomics is the knowledge that an individual receives that it's their genotype, they are going to be responsive to these interventions, they have these specific lifestyle risks. And if they know all of that this is what the literature is saying that they are more likely to follow the interventions for a longer period of time. So they're more likely to believe what the practitioners saying, to actually change the behaviour to be motivated to be compliant for a longer period of time. And that's what we want at the end of the day.
Peter Williams:Well look , I think the reality is Is that knowledge is power and you give people choice. And I think what's great about this, even if you did this gene, it allows you to really start personalising the future in quite a precise way. I mean, as you say, you you sent me a very updated paper with regards to APOE4 genotypes risk of Alzheimer's and nutrition. So do you want to brief on that? Because, again, as you say, it's really interesting, isn't it? Because I think this is what I've always what I've always I've been in this industry now 30 years. And then if I go back 20 years ago, there was always that thought process maybe you're the same, Helen that I know this is right. But everyone, but conventional medicine wouldn't look at this as right. It's the way your systems thinking. But now just the literature is almost consistently full of systems thinking data. And it's like, yeah, we were right, I knew we were right. And we are right. And all the literature is right now, because it's been written in the right way, which is exactly how that paper was written. So can you give us a brief on that paper? And, you know, and I think we've got to look at people like Dale Bredesen from a point of view of his Keto flex approach and the work that he's done. But, but this is a brand new paper, isn't it looking at, here's what we definitely believe in the literature would be some of the important things to do. And I think you've outlined the basics. But can we jump into some slightly more detailed with regards to maybe basic nutrition and maybe some of the aspects of where they're looking at additional supplementation?
Helen Gauche:Absolutely. So this was it was a it was a lovely review paper published in"Nutrients". And obviously, as a dietitian, that's kind of where I like to look. And as you say, Pete, you know, thinking of what we were doing many years ago, now, it's come to be right. It's just, it's healing with food and doing a lot of Preventative Medicine, with diet and lifestyle, which is great to see this coming out and the personalization aspect of it as well. So it's a paper looking at precision nutrition for Alzheimer's prevention, and specifically in E4 carriers. And just a review of the observational and intervention studies that have been done looking both at animal as well as human studies, in vitro, in vivo, so it's got kind of everything that they've said, they've really done a great review of the literature.
Peter Williams:I was gonna say the sort of scientific naysayers may go, Yeah, but there's no randomised controlled clinical trials that are double blinded, blah, blah, blah. But the reality is, is that I think that's the poor answer, usually to discussion. And I think, you know, if you look at pioneers like, like Bredesen as a good example. I think, as a as a systems thinker, and many systems thinkers, they're looking at all the literature, but being able to put all this together and say, Look, there's no one intervention here that is going to solve the problem. So let's have a look at the literature. And let's see whether this has proof that it might work. And then let's, let's jump in with it. So go on, continue with that paper, because I think as you say there was a lot in that paper, and we'll definitely put it in our notes.
Helen Gauche:And also what's quite interesting is they more recently very recently so I think it kind of missed this paper, but there are some very interesting RCTs these randomised control trials actually coming out for cognitive decline and looking at APOE so they are in fact doing them now as well and and looking at the differences in saturated fat intake and the differences in you know, following a complete dietary pattern that is being adopted as well and E4 carriers actually showing great results. Obviously, when it comes to RCTs and Alzheimer's disease, there's always this kind of ethical issue around what can you do and what we should always intervene. So some studies you just cannot do in an RCT, it's just not feasible or practical, but you are seeing in the sort of just cognitive function area, there's a lot coming through. So what this paper was looking at is based on what we spoke about in terms of you know, these different systems in our body our looking at our cholesterol system and transport looking at oxidative stress and antioxidant status, looking at our delivery of our DHA and EPA. Other things that we haven't even gotten into is how e4 allele carriers tend to have a decrease in the the the APR E also functions within our central nervous system so it's we're also looking at you know how it controls your five yearly tangles and your tour and your plaque so that we haven't even got there. But this paper kind of tried to approach the issue of cognitive decline through all of these systems. And then thinking about the systems, what do you need to put into place to support these systems? So looking at the biological pathways, and one can you do that, and it divided the recommendations and gave kind of obviously, there's a great review of everything, but it divided the recommendations into dietary interventions. And then what could you do possibly with nutraceuticals? And this is where, you know, you can you had this question of, should people know about e4 genotype? How should they know and this is, I think, so important to understand that probably going, absolutely going to a healthcare professional, who is versed in this kind of literature versed in nutrition and lifestyle to be able to provide proper interventions, practical guidelines that can actually be used by the person who does have an E4 genotype, versus getting this information on the internet or direct to consumer, because there's a lot of information in this paper from the different types of diets you can follow whether it be you know, low saturated fat comes out as a very important point. So saturated fats and trans fats, especially animal fats and proteins do not seem to be kind of beneficial or don't don't protect against Alzheimer's disease in E4 carriers, your low glycemic index or more of a low carbohydrate diet, in general might also be protective with a large amount of greens and colours in the diet. And then your your animal protein that you are getting in should be from your fatty fish sustainably caught and responsibly. So you know, avoiding the heavy metals. And so that in terms of dietary pattern was what was recommended to be probably the best way to go. But getting that information as a consumer and saying, Okay, well, what is, you know, what is the low carb diet, it could end up being well, you know, you go on to a low carb diet, which is extremely high in saturated fats, and completely lacking vegetables and good nutrients.
Peter Williams:And this is absolutely some of the unconscious mistakes that I see in practice, all the time, I'm on a low carb diet. So what are you eating? And the diet is overwhelmingly saturated fat, and you're like, this is probably not a good idea. But fats are safe, you know, they're not going to give me cardiovascular disease, it's like, we just can't say that until we've got more data with regards to you and your lipids don't look great. And so you know, you really do need to have it. So I absolutely agree with you. And even for us that you know, and for you, you know, and I know that sometimes the data and the rabbit holes that you have to jump down and think about how you put it together is so overwhelming. That even people like me and you we've been in it 20/30 years, it's like, geez, where do I start? And how do I think about this? And if we do that, then does that off balance that? And okay, so we're going to run this process for three months, and we'll make sure we got checks and balances in and then we'll see where we go. So it's, it's really it's almost like the art of how you play it out? Unfortunately, as you say, yeah, the amount of people through no, through no fault of their own, they found something you know, and I'd say, you know, is there evidence for stuff like intermittent fasting for APOE4 or, you know, fasting? Absolutely. But when you've got people coming in, who are highly fasted with literally chronic fatigue, because they, their blood sugar's all over the place, there needs to be a compensation to say, this is probably not a smart thing to do. You know, think about how we how we work on this. So I absolutely think I think and that is because Systems Thinking is incredibly difficult to for a patient to do. And it's very difficult for us to do, let's face it, that's why you probably only just learned it now. Because there's not that many people who can really think on that level and put it all together and to say, this is probably what you need to and that's why it's so important that I believe if you are going to have genetic genetic tests done, that you can go to individuals who've been trained in understanding of say, Okay, so here's what makes most sense. Because the risk of messing it up, I think is really quite large.
Helen Gauche:Yeah, absolutely. And I mean, when you then think about in this paper, again, looking at all the nutraceuticals that are recommended, I mean, it's a long list, there are a lot of nutraceuticals that are recommended, and then you have to think well, what else is going on in this individual? What what do i Where do I need to focus as you mentioned, the chronic fatigue or, you know, if there are other, just other cardiovascular issues or an autoimmune issue, or hormonal issues, you need to take all of those things into account.
Peter Williams:Yeah, I think this is this is unfortunately, I'm gonna this is one of the problems I've come up against when using Bredesen protocol because the list of what Dale wants you to do is just probably I would say, for most people completely overwhelming with regards to, you know, you might be spending four or 500 quid a month on supplementation. And the reality is for and I would say, I mean, obviously, I'm Bredesen trained been using it been certainly using the principles of it for many years. It's a pretty, pretty damn solid template to use. But it's highly impractical for most people, and cost prohibitive for most people. And so as you say, you've got to basically be trained in that systems thinking, and then you've got to triage
Helen Gauche:That's exactly it.
Peter Williams:on where we're doing, you've got to triage and then you've got to strategically design what you're trying to do over a period of time and make sure that they're in order. So that we've got to deal with this first, because this affects this more than anything else. And there's no point for us doing those tests now, because they're going to be a waste of time. Because in three months time, it's going to look different, so maybe we put them later on. So we save you money there. So can we talk about some of the nutrients. So because I'll give you my experience of what people have done is that many people hear of this new way of resolving Alzheimer's. And what I would say on this is that I don't believe Dale's programme is a programme for bringing back people from Alzheimer's per se, because once you've had an Alzheimer's, this is very specific way you get diagnosed about times. And that can generally only be done by specific scans looking at certain things. So in my experience with the people who we've been to see who've had a diagnosis of Alzheimer's, we've not been able to bring them back regardless of the protocol because the taxi is too far gone.
Helen Gauche:Yeah. You want to you want to catch it before, you want to catch those little warning signs? Yeah.
Peter Williams:And those warning signs could be this is the whole thing about Alzheimer's, isn't it? It's a late onset disease. But it's been gently smouldering away from your 20s. So like all chronic diseases, that starting really early, but what's happening is that they don't, they don't sort of bring their heads above the parapet until you really hit your 40s and 50s. But Alzheimer's is absolutely one that's smouldering away and I know because I'm I've definitely got mild cognitive impairment, I've had it since 45. Hence, the reason why I'm so interested in this, you know, my story is a bit different from what I am, I am APOE4/E3. And I do have quite a lot of pro inflammatory genes, as you know, and I've got a bit of periodontal disease, but I'm doing an incredible job of trying to keep it down, even though I probably eat too much meat, but at least I know that okay, I'm gonna meat today, so therefore, maybe I'll do a bit more cardio. I just completely lost my train of thought, what were we talking about?
Helen Gauche:That you were saying, I mean, just in terms of the the amount of supplements and way to talk I just found what I was gonna say
Peter Williams:is that I think we've got this with what we've experienced, or certainly what I've experienced with patients, is they think they're going to come in and you're going to give them a whole host of supplementation, that's going to solve the issue. And unfortunately, it's it's so far from the truth. And I think that's sometimes how maybe the general public perceive functional medicine, if you like, yeah, it's the complete opposite. It's like, you know, this not really, these are parts of the puzzle, not going to solve it on their own, and how much your how much benefit you're going to get from an i.e, what you're clinically going to see on a day to day basis is probably way away from what you're perceiving as well. That doesn't mean to say that they're not going to be beneficial. But you know, I mean, we had this with COVID, is that, you know, these post COVID protocols came from nutraceuticals. And you've got to say to people, you know, what is your perception that the supplements are going to solve it? Because they're most likely not. Are they going to be helpful in the process of getting you better? Yes. So I've always got to be, and I don't think people quite get that story yet. There's a lot of things you're going to have to do, hard yards on a daily basis to offset some of these. And that's the tricky conversation, which is why you need an why you need someone with you, I think to help you on that side. Yeah. Let's talk about let's talk about some of these supplements that they've suggested.
Helen Gauche:I mean, one thing that you said that I think just resonates is the supplements of really can be really, really good, really important and good science behind them. But I heard it many many years ago and it was just something that stuck is that you cannot be you cannot be Superman. With a lot of supplements if you've got kryptonite in your lunchbox(agreed) and it was a really, I don't know where I was, but it's I think it's just such something that you always have to keep in mind is the diet and the lifestyle, the alcohol, the smoking. Those are number one that you have to get right and then the supplements come after.
Peter Williams:I like to say that they're the 10s and 1000s on the top of the cake. Yeah. Because otherwise it just becomes green pharmacy then doesn't it? Yeah,
Helen Gauche:absolutely.
Peter Williams:What I would say on that is that there are only a specific times when it really hits the mark. And maybe you do hit the mark, but something like when you have like a real, you know, severe deficiency, and in high therapeutic dosages, then you definitely see the difference. I've definitely seen that particularly with B 12.
Helen Gauche:Exactly, yah, B12. Especially, yeah, B 12. Magnesium sometimes,(absolutely) is one that comes through, and then with E4 carriers, you know, that we know that there are certain things that are not being delivered the way they should be. So we spoke about these omega threes, the fats and, and the DHA that comes through as being really important. So when we looking at DHA as a supplement in you know, making sure that you've got it in the right form, it's conjugated, and so that it gets to where it needs to be, that's where it becomes really important, especially in E4/E4 carriers with this cognitive impairment risk, to get DHA to the cells to help them to be nice and elastic nice and fluid, so that they can communicate with other cells and communication between cells is so important for mental well being so DHA from your your fatty fish, your krill oil, a really good option and that's where there was quite a lot of nice research done with with your DHA, other ones that came up, I mean, there's some that I think we could look at from a big cup of blueberries every day. And you know, your clients coming through your plant your plant foods, your apples, onions, things like that, but quercetin it's just the doses that become quite different your Quercitin and that's your your food sources, your apples, your onions, that also showing in some studies that you may significantly decrease your inflammation by this NF Kappa Beta pathway. So that is really, really important as well. And and Pete you mentioned earlier, before we actually started you were talking about MMP nine, why that's so important in cognitive health. And and this is where Quercitin plays a role in inhibiting or, or kind of modulating MMP nine expression as well. Interesting. Other ones, I mean, we know as we are resveratrol, that there's a bit of conflict on this one, just because of how it gets delivered into the body. And, and again, this is where you need a very high dose you need it in a very specific form. And it's a very expensive nutrient.
Peter Williams:Yeah. Which is, the problem with this, because a lot of this is, I still say a lot of this is unfortunate posh medicine, because, you know, I mean, Resveratrol is expensive. And unfortunately, there are different types of resveratrol out there that aren't going to be delivered as well. I know the that I can do you know that? Because there's quite a few different forms. And you know, people say this is the best form to deliver it with, I'm not quite up fully with the literature on all of that.
Helen Gauche:So I must say I would have to, I think we'd have to actually do a full review of just resveratrol to be able to see which is the best delivered. But there are as you say there are some that are better delivered than others. That
Peter Williams:just that leaves a question, doesn't it because sometimes when you read the back of a supplement bottle, you'll be looking at it and it'll be going, it's going to deliver 10,000 times the RDA and you're like, oh my god, am I going to be toxic. But the reality is, the reason why you need that much is because you're going to, you're not going to deliver most of it. Hardly any of it. Because it's so different. It's so difficult sometimes to deliver vitamins and minerals. So just for everyone, when sometimes you read in the one day multi, and it says, you know, some of your B vitamins are at 5000 10,000, the normal amount, you're certainly not going to be getting that it's just as you say they have to put that amount in because that will hopefully deliver a little bit hardly any. Exactly,
Helen Gauche:exactly. So that's
Peter Williams:quite interesting. Look at when you look at liposomal levels, they're much much easier delivery system. I got two more things I want to talk about because literally as I say it's my favourite gene, and we're coming up to the hour and I want to just bring in two more things. Can we talk about APOE status and Mercury because obviously this is something that number one we've worked on for a while number two, we have a lot of discussions around because it's involving mercury in the environment, but also mercury amalgams in the mouth. So what is the relationship with APOE4 and mercury
Helen Gauche:In a nutshell, it's the oxidative stress, okay, if we think of mercury, it's this major oxidative stressor on another level, it causes so much oxidative stress on the body. The other thing that mercury does, it inhibits a lot of your your lipid transport from working properly. So everything where pretty much where E4 carriers already have a problem. You're just going to have mercury exacerbating that problem. So
Peter Williams:So your worst case scenario is that if you've got a mouthful of mercury amalgams, you're a smoker, you've had a drink, and you've decided to cycle back through central London at five o'clock, while all the traffic is there, that's about as bad a situation as you can go. And the joke about that, I mean, it isn't, you know, we can have a joke about it. But I've got some patients who that's exactly, that's exactly what they're like. And I'm like mate, we've done all the data. This is the worst case scenario that you can do. So if you're going to do that, let's make some choices with regards to how we're going to do that. So because of course, and this is the problem, isn't it? And me, you and Dr. John Roberts have tried to sort of consistently chat about this, because I suppose the reality is, in theory, yes, absolutely. Let's get the mercury out of the mouth. But of course, the way the mercury is taken out, been taken out, it's not been taken out with a dentist who has been specifically trained in mercury removal, we could make the situation a lot worse. And then I suppose we've got that situation, well, what is the mercury going to be replaced with which comes into that I suppose that holistic dentistry argument with regards to well, what are you going to replace it because I know again, working with another dentist on this, as soon as you start replacing teeth, with other structures, those structures, not only maybe inappropriate to your immune system, but actually may be more problematic for pathogenic bacteria to attach to so it's easier for them to attach and then we've got the periodontal disease, which of course stimulates
Helen Gauche:on its own a risk factor for Alzheimer's disease. So absolutely.
Peter Williams:so I suppose the key the key for us is that mercury just becomes just such an oxidative stress and APOE4s are not good with oxidative stress. Is it the GSTM1 genes that also are needed for that one
Helen Gauche:It is and so they really, I mean, they're integral in managing mercury toxicity or mercury, oxidative stress. And what happens is, again, there's a decreased expression, they get tired from working. And eventually there's a full suppression of these GSTM1s to actually manage and detoxify what is coming through from the mercury.
Peter Williams:Great. So I think that that resolves that. But I think again, it has to be the dentist that that have been trained in safe Mercury removal or they have a they have a, it's called, smart, safe mercury. That's a good question. I don't want to the a is for, anyway. But they're called Smart dentists. And they've gone through quite significant training. And they use a lot of procedures to make sure your Mercury is taken out in the appropriate way. And what I tried to do over the years, is try to give patients more clinical, that's whole whole point about why we've got the add on with DNA smile, isn't it because mercury is a major part of that. And DNA smile is not just for the oral health, it is has a quite heavy tie over to Alzheimer's disease risk as well. And we wanted to be able to say yeah, you know what, maybe you are a bit of a canary in the in the minefield. And that's a whole thing about preventative, isn't it particularly with Alzheimers, that's what I want to do. And, you know, I've got a case study that I'll present at this conference where they say, Look, this patient is a canary in the minefield, and you can't suddenly get to the point where oh I've got Alzheimer's, what I'm going to do, because it's too late
Helen Gauche:You want them out of the minefield.
Peter Williams:Way way way before the they've even decided to go in the mine. For me, I started having, you know, I've definitely got some quite significant memory issues. And they started showing up reasonably early when, you know, I was mid mid 40s where just, you know, name recall is pretty horrific, really. And so I've been able to offset all of that certainly for for the last eight years or so, on that side. Let's Let's summarise them. Can we summarise with regards to because it is a favourite gene of ours, isn't it because it's so influential with it being a low penetrance gene it is talking to just a huge amount of mechanisms, biological pathways genes, can we summarise or I suppose the summarising is the genes don't determine your outcomes. Your lifestyle fundamentally determines the outcomes and that's a really important point. If you if you do have an APOE4 allele, then your risk certainly for cardiovascular disease and for Alzheimer's does go up and go up quite significantly. Let's assume we have that, one of the The most important things that we can do, if you can name over the last couple of minutes, I think that's a great place to end on a daily basis that is going to be beneficial for us to do
Helen Gauche:Daily moderate intensity exercise. Don't forget your exercise, be active daily.
Peter Williams:So as I was going to say, we're going to summarise up because obviously, this is my field as well. The reason why we're talking about moderate is because if we do high intensity exercise, it becomes quite an oxidative burden doesn't it. And whilst that's okay, occasionally, and I definitely recommend it occasionally, with APOE4 genotypes, in particular, it's something where we've got to distinguish away from physical performance, and health. And Helen, I will definitely say that I probably accelerated my problems. Because I, you know, I've come from a culture of contact sports, go hard or go home, let's get into a full on scrap, you know, that sort of stuff? And the reality is, is that's probably, you know, with hindsight that's probably harmed me, you know, because everything has to be a world record session. And it's only now is that I'm recognising Pete, this is just not smart. You know, this goes against all the data. So sometimes good. Moderation is absolutely, definitely learning that, but it really is key because the push all the time is problematic. So thanks for reminding us on that one.
Helen Gauche:I would say then plant based diet with eating, just get the rainbow look at the rainbow and get the rainbow in daily. So eat the rainbow and eat plant based. Avoid processed foods and eat your fatty fish. Yeah. I think you know if you could have it like that, I would say that's kind of a really good start. And then the last two things would be your your smoking and your alcohol. Yeah. Well, and stress management. So look at what, look at what is damaging your body, remove those and eat clean. I would say that's, that's at least a good start, then then get your practitioner to speak about personalised supplementation, because it has a really good role to play. But it's just so good to get it personalised to
Peter Williams:Yeah, I think here's the worst case scenario. you. So I always say this, I've got a couple of clients say, I say look, here's the worst case scenario for you. And it's a really nice day out there. So you've decided to have a barbecue, okay, you've gone down to the butchers, you've bought a whole host of meat, you're not the best barbecuer in the world so most of that meat's burnt. And someone, one of your mates has decided that he's going to offer you a fag, you used to be a smoker, but you know, you've had a beer, you've had a couple of beers, the sunshine and you've had a fag, and you're tucking into the barbecue with a load of burnt meat, and you've That's a fascinating field. not decided that you want to put any veg with that as well. So that for me is almost like that worst case scenario. Now, that doesn't mean to say that you can't have the Barbie. But maybe you can make some choices around that that are going to be more beneficial. And and this is for me. I mean, it's, I mean, we've been in this industry for you know, as I say for a couple of decades, and you know, you work for, for a genetics company, and it's so simple and obvious to us that you can offset the balance anytime that you would like to about okay, so it still means you can live a life in the way you you may want to but at least you've got the detail to be able to make some some just more informed and personalised choices. Yeah, absolutely. Great. All right. Brilliant. Let's, I think that's a brilliant place to stop at. Thank you so much again, for your overwhelming knowledge on this it's absolutely fantastic. I'm gonna be coming back, I was thinking I've got a couple of other really good ones that I think we should do. I think the I think that that's going to be that's going to be the next one ones around taste preferences and being overweight and satiety, I think would be interesting that I'm talking to people all the time because people why do we Why do we have these behaviours, particularly around food or alcohol where we know we shouldn't have them, but we do, again, has a very strong gene influence to it. of Helen and Pete's conversations because I just think again, that's just a really interesting field because I think what's interesting about that field is is that it's almost out of your conscious control. You know, you don't choose the time you don't choose to go into the fridge because you're choosing to go into the fridge, is that you know there's quite a profound gene push there to why you did. So again, I think that would be really informative. Helen, I really appreciate your time.
Helen Gauche:Thank you. Always appreciate being on, thank you for inviting me again Pete.