What Should Your Homocysteine Level Be (and why it matters)?


Welcome to Better Brain Fitness, hosted by doctors Josh Turknett and Tommy Wood. In this podcast, we will explore the frontiers of how to keep our brain fit and healthy so that we can perform at our best and do the things we love for as long as possible. Let’s go. Hello and welcome to another episode of the Better Brain Fitness Podcast. I am joined once again today by my always illuminating cohost, doctor tommy Wood hello Tommy.

00:37 : Hello okay so as usual, we have a great question that one of you guys submitted for us today by the way, if you do have a question that you would like for us to answer on this podcast, send it our way at Brain joe dot Academy forward slash questions. There’s also a link in the podcast description. So today’s question which Tommy will be fielding comes from Mike in Pennsylvania, who asks is a 9 0 homocysteine level concerning for my risk of Alzheimer’s? If I have one copy of APO e, four i eat three to four whole eggs daily but have the MTRR gene and found that I may need to supplement with choline to reduce homocysteine further.

01:26 : I have an omega three index over 10 %, take B vitamins, exercise daily and eat a low carb, higher fat and protein diet Okay there is quite a bit of jargon in that, quite a bit to unpack. Easy, easy to get lost in the weeds here and I think this is a perfect doctor Tommy Wood question because Tommy knows these weeds, but he’s very good at helping people navigate and not get lost so Tommy, what do you have set to say about Mike’s question? Well, thanks very much both to Mike and to you i will try to be illuminating today and I actually picked this question after somebody else slid into my Dm’s on Instagram and asked me what do I consider to be a high home assisting level so hopefully answering both of those questions at the same time today.

02:22 : Lots of things that we can unpack here, but we can talk about genetics, obviously related to APO E genotype, but then maybe we’ll touch upon some of the genotypes associated with high levels of homocysteine or impaired 1 carbon or methylation metabolism. And then also talk about absolute homocysteine levels and dementia risk. And some, you know, other related diseases like stroke and cardiovascular disease, which for which homocysteine is important as well supplements and dietary strategies to lower homocysteine and then he also mentions the omega three index and we’ll talk about the interaction between Omega 3S and homocysteine so if I get to the end of my screen, I haven’t touched upon all of those things.

03:06 : Let me know and I’ll fill in any gaps. So let’s start with a brief revision on some of these things so APO e four or apolipoprotein E genotype 4, you can have two different copies of your apolipoprotein E genotype. It’s related to lipid or cholesterol metabolism and also can affect some vascular things and inflammation in the brain and in general. There are three types Apolivic protein two three and four. You can have one or two copies of each. So for a total of 2 copies of the APO E gene and in those who have one or two copies of APO e four.

03:57 : In Western populations they have an elevated risk of Alzheimer’s, dementia or age-related dementia. This is about maybe two to six fold increase in those with one copy and then you know somewhere between 5 and 20 fold higher in those with two copies. As ever, there are several caveats to that one is that your APO E genotype only contributes about 5 % of your total risk of Alzheimer’s disease or dementia. So even though it does contribute, it’s a small contributor within the big picture and Mike is ticking off several boxes as part of the big picture, but there is some risk there.

04:47 : And then the other parts of it, as I mentioned very specifically that the risk is elevated in those in a Western setting, and you know it a lot of the evidence comes from those who are of Northern European ancestral descent. There are other groups where Apple e four does not seem to be associated with an increased risk of dementia. 3 populations that have been studied and published recently are the Bolivian Chiminee, the Nigerian Yoruba and then some indigenous populations here in the United States. And in those three groups, Apple e four is not associated with an increased risk of dementia. There are a number of reasons why that might be it could be in the context of other genetic factors that are associated with those groups living in that area.

05:39 : That’s possible or it could be the fact that they are eating and living a lifestyle that is more consistent with their more recent sort of ancestral development and evolution could be a combination of the two. But it definitely seems that outside of a traditional western lifestyle, Apple e four has less of a connection to dementia risk doesn’t mean it’s not a risk factor but just it’s context dependent. And I think that the fact that it’s context dependent means that there are gene environment interactions that we can then take.

06:17 : You know we can leverage, we can say you know if we are reducing a whole bunch of other risk factors for dementia, it’s possible that the any additional risk that we have from our before is going to be diminished i think that’s a hypothesis of this stage, but it’s a fair one to make because it’s not a consistent effect across all populations. So that’s the starter. And then my specifically asks about homocysteine. So homocysteine is this output from our methylation system and elevated homocysteine levels are associated with higher risk of dementia when you look at the interaction between homocysteine level and Apoe foil genotype and that’s specifically his question and I think what the question is saying is I’m at, I believe I’m at higher risk because I’ve one copy of Apple V4 Do I need to lower my homocysteine even further than anybody else would in order to get the benefit where I’m at greater risk for a given level of homocysteine? The answer here, as much as I can find, is that for a given level of homocysteine, having one or two copies of apple e four does not increase risk of dementia any further so there is no interaction between homocysteine level and apple e four genotype.

07:44 : There are several studies that have shown no interaction or that the risk does not of from elevated homocysteine does not differ across apple e four genotypes so in general, any target for homocysteine for disease risk does not. That target does not change across genotypes. There are some studies that have shown that those with Applebee 4, or at least you know when you grab a random selection of the population, those with one or two copies of Applebee 4 had lower homocysteine there are others where they had higher homocysteine but in general, and this is just what happens by a random chance but in general there does not seem to be a significant effect.

08:25 : You know that more homocysteine is worse if you have one or two copies of Apple e four there was one study that showed the homocysteine had the stronger effect on a marker of Tau, one of the sort of classic hallmarks of Alzheimer’s disease in the CSF in individuals with apple with one or two copies of apple e four however, in that same study, it did not correlate with any measure of cognitive function or clinical dementia rating so it’s probably just another spurious correlation to a pathological marker of unknown significance so in general, I don’t think you need to have a different target for your home assisting depending on your app or genotype.

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09:42 : All right, now back to the show. So then the next question or the customer that is the target level of nine, is that a good target or is that level concerning? So that level is not concerning and I think that it’s just fine and it would be regardless of who you are so when you look at cystine levels and different health outcomes, so but in particular dementia, cardiovascular disease or atherosclerosis and stroke risk in general, the risk tends to be highest if your homocysteine is about 15 in like depending on the study, often to do a certain type of statistical test, you kind of dichotomize or you like create this artificial break in the home Assistant level that you’re measuring like what’s what do you call high homocysteine? And across studies it’s usually somewhere between 11 and 15 when we look at dementia risk.

10:53 : A lot of this work has been done by David Smith who ran the Vicerock study out of Oxford and he’s written a very nice review paper on homocysteine and lots of different disease risks including dementia will add it to the show notes. But essentially you see benefit in terms of brain atrophy and cognitive function if you lower homocysteine below 13 and then some smaller but additional benefits if you lower homocysteine below 11. And those are based on his randomized control trial so below 11 seems to be the target in general people ask me i use the target of 11.

11:35 : In his paper, he suggests a target of 10 just because that gives you a little bit of a buffer outside of a Gray area and there are some studies that suggest a homocysteine below 10 is associated with a lower burden of coronary atherosclerosis if you write about cardiovascular disease risk. However, I will say that there are also several other studies that suggest homocysteine is not correlated with atherosclerotic burden so that’s a little bit of it. That’s a little bit of Gray area.

12:05 : But it certainly seems that lowering homocysteine below 11 is associated with decreased brain atrophy and cognitive decline. And then there’s also a good amount of evidence to support that will decrease the risk of stroke. And then it’s a little bit more new one, still bit more of a Gray area for heart disease. So then I think that target is kind of relevant to everybody.

12:32 : Mike then mentions his genotype, so he has a polymorphism in the MTRR gene. Other people would have heard about polymorphisms in the MTHFR gene being associated with home assisting levels. And I even wrote a little paper a while back which showed that in general your MTHFR genotype, which has long been suggested to be associated with home assisting level, isn’t really unless you have multiple polymorphisms that result in very significant decreases in the function of the MTHFR gene or in the protein.

13:13 : And in that setting you can overcome almost all of it by supplementing with a little bit of riboflavin or B2 just getting your recommended daily amount of riboflavin if you have some kind of the more sort of notable MTHFR polymorphisms, a little bit of riboflavin pretty much does everything that you need, just it’s to do with how the mutation affects the binding of the gene to FV DH2 and FD H2 is made by is made from ribaflamin, so just a little bit of ribaflamin does the trick there. Then a lot of other things are mentioned so in general in clinical trials where they decrease homocysteine with B vitamins, they use a little bit of folic acid, some B6 and some B12 So the B vitamins, those three plus riboflavin, just ensuring you’re getting enough of those could be a small supplement and in general you know they’ve used the cheap off the shelf any pharmacy B vitamins so nothing fancy, although others would suggest that not supplementing with cyanocobalamin, which is the cheapest form of B12 but instead something like hydroxycobalamin or methycobalamin or adenosolcobalamin could be could be better but again, with a reasonable quality B vitamin complex, you’re going to get all of those things and that’s probably going to be more than enough for more for most people if they’re not getting enough B vitamins from the diet and they still have elevated homocysteine, other things that can be important so Colline is part of this whole system as well mike mentions that he gets Colline from his eggs, and that seems to be keeping his home assistant level or helping contributing to keep his home assistant level at level of nine.

15:05 : That’s great. You can supplement choline, CDP choline or cytic choline i’ve mentioned this on the podcast before because that’s actually been used as a supplement in those with cognitive impairment and then also in those with traumatic brain injury and it’s shown benefit in those who were who had inadequate levels of choline previously. And it can also help with some things like fatty liver disease or decrease in the risk of fatty liver. So coven is 1 and the last one of course is creatine. Creating creatine or you know generating your own creatine is one of the most methylation intensive processes in the body and that may be one of the reasons why creatine is beneficial.

15:52 : And there are some supplements with creatine can be beneficial and there are some studies that suggest that supplements with creatine may help to decrease homocysteine. So another reason to think about supplementing with creatine, the final, I believe the final part of this question or the what I expected from it is related to the omega three level and there’s this very interesting interaction between omega three level and home assisting level on cognitive function and promises decline.

16:24 : This comes again from David Smith studies, but also some other trials that have been run where they’ve done these secondary analyses and they’ve looked at who benefits the most either from supplementing with omega three or from supplementing with B vitamins to reduced homocysteine and what you see is that when you’re supplementing with B vitamins to decrease homocysteine, the benefit is the greatest in those who have adequate omega three status. And then the opposite has also been seen, which is that if you’re supplementing with Omega threes, you only see benefit if you have low enough home assisting.

17:05 : So there’s definitely an interaction between the two other studies. You know, swathes of work by Bill Harris and Cogley colleagues who developed the omega three index have shown that Omega threes are very important for brain health and function as well as volume if you’re looking at different areas of the brain on an MRI scan. There was a recent study they published last year, I think, which showed that there was this interaction between Apoe genotype and Omega threes on different parts of brain function and brain structure. However, in reality the main takeaway is that you just need to have adequate Omega threes in that study the way they separated the groups.

17:50 : You did best if you were in if you had an omega three index above five or six, though in general I think that they recommend above 8 as being the lowest risk across all sort of related diseases, you know, particularly including like cardiovascular disease and other things. When I say there’s an interaction between omega three index and apple e, four it doesn’t mean that you need to have a higher level or anything like that it just means that there were different fats were relevant for different areas of the brain and different apple E apo E genotypes, which makes sense because that has different effects on vascular things or information or elements of information in the brain.

18:36 : But in general, if you just ensured that your omega three index was adequate, none of that really matters anymore because you’ve kind of ticked all those boxes so that’s why it’s sort of interesting from a scientific perspective, but from somebody who’s just trying to make sure they’re covering all their bases, just getting you omega three index above 6 or 8 %, you know you’re in good shape. And Mike’s mentioned that his is above 10.

19:01 : So or so he’s in that low risk group both from his omega three status and from his home assistant status. And I think everything he says he’s doing exercising daily. So he’s eating a high quality, high quality diet that’s nutrient dense. Essentially i think that he’s mitigating all of the potential risk that he can from his apple E for genotype and in general, it’s even possible that may have no impact on him long term because there are plenty of people who live with an apple E for genotype and don’t get dementia and I think he’s taking care of all the risk factors that he can on that front so nothing that I would, I would add to that, it all sounds great.

19:49 : Well, thank you for that tour through the weeds And I think that that’s given probably a lot of people some good context. Imagine if you’ve not familiar with you know all of these terms that it may take another listener to kind of get the get the big picture there, but that’s a good overview of all of these things. So one question I had was. Related to the testing for the methylation genes like m t h f r and m t r and, this is not to like pile on to like you know, the value of genetic testing but just generally curious, do you think is there anything that a test like that can offer above and beyond what you can get by checking things like home assisting levels and omega three? No, I don’t think it’s useful because I am going to go based on the Homo system level rather than the genotype.

20:48 : And often, you know, and whenever I say that to people, they’re like oh, but I tested my methylation genes and it found this and my Homo system was high and the answer is, well, yeah, but your homo system could be high regardless of your genotype. And we know what the intervention is it’s nutritional and the first step is basic replacement of folate B6B12 If you need to lower it further or it doesn’t respond then riboflavin and codeine will do the trick in the vast majority of people so I in general, I’m not a big fan of genetics testing because I think it adds stress without changing what you’re going to do about it.

21:34 : And in general that makes it a net negative for me. Yeah, I think that’s a great point there are two things is A is the thing that’s being test, is the genetic test. You know what it’s a marker for? Is that thing something we can influence at all? And then B is that is that influence going to change based on the what the result of that particular test or what you do going to change so yeah, I think that the they have to meet those criteria to in order to be valuable, valuable beyond an academic standpoint.

22:09 : And you know who knows things could change where you do find oh this particular variant, you know it is factor does make a difference in how you might manage it but until we’re there probably it’s just an added stressor without much additional value probably, right. Yeah, I in terms of the methylation ones in general, they may exacerbate the effect of nutrient deficiencies or insufficient insufficiencies, but it’s still driven by the nutrient elements so it doesn’t change what you would do and this is my main issue with sort of genetic driven interventions particularly in nutrition is that the there is pretty much no study that says for this genotype this specific intervention is better than generic advice.

23:03 : And until and I am hopeful that one day we’ll be able to do that would be great like we can have more impact faster. But that evidence doesn’t exist yet and until it does i’m not sure there’s any benefit there. And so then we could go broader like Apple e four that’s really personal from like individual to individual there are some studies where they gave people their APO E genotype and for those who are APO e four it just increased stress like they wish they’d never known. And in general, you know this is this is going to change depending on your perspective because depending on your genotype you may respond less or less well or better to some pharmaceuticals that are coming onto the market or in different ways and if your neurologist may want to know that and act on it in that in that way.

23:59 : But in general I would argue that I would do all the same things to minimize your dementia risk regardless of your alpha genotype so it doesn’t really add that much in my mind so if you’re somebody who you think that knowledge is going to be stressful, I wouldn’t test, I would still do all the same stuff and you’re still mistigating as much of your risk as possible so just be we have to be really careful about how people respond to information and it’s very different from person to person so we shouldn’t just say everybody should be tested because it would just depend on how that person’s going to respond to that information.

24:35 : Yeah, absolutely. So I think one of the key takeaways from the from your conversation unpacking all that was is that homocysteine is clearly something of that is relevant for with respect to dementia risk something to be aware of and mindful of as well as omega three and a lot of the OR part of the reason why Mega 3 matters is that it influences how that how almost homeless is deem impacts us so you want to be you wouldn’t want to pay attention to 1 without being mindful of the other because of that interaction okay well, that was a great question.

25:21 : A lot of brought up a lot of important topics and if you guys have any followups related to that, feel free to send them our way. Or if you have any other questions about brain health and fitness for us to try to tackle, you can send them to brainjo.academy/questions and we will be happy to take a stab at it. Ok i was just going to, I was just going to add one thing that I didn’t mention i was I was just going to give the dosages from this paper from David Smith for those different B vitamins that have been used in trials just in case people you know want to apply that for themselves so folate 4 to 8 milligrams per day, B six ten to 20 milligrams a day and B12 5 to 1 milligram per day.

26:07 : That’s what’s been used in trials to decrease home assistance and then have benefits so in case anybody didn’t want to go diving through that paper, right, that’s kind of those kind of like general recommendations. Do you know are there any existing supplements that combine all of those at the, yes, there are plenty. There are those numbers yeah most like most B vitamin supplements will it will include them at those levels and you and I would probably take one that includes a little bit of Riboflavin just like 1 to 2 milligrams.

26:42 : Right, exactly. Because more you’re just going to pee out. I don’t need it. You’ll get rid of it so there’s at normal dosage levels there’s not much risk of taking extra okay well, thank you Tommy, and thank you everybody for listening and we will see you in the next episode.