September 8, 2023
Webinar With Intellix DNA’s Dr. Sharon Hausman-Cohen & Dr. Dale Bredesen
In this webinar, Drs. Sharon Hausman-Cohen, Co-founder and Chief Science Officer for IntellxDNA, and Dr. Bredesen talked about how genomics has evolved to become a valuable tool that can help identify contributing factors to cognitive decline that otherwise would be difficult to detect, including various sources of brain ischemia and how these different genomic factors can be addressed as part of a precision brain plan. They also discussed the intersection between brain health and longevity as they discussed Klotho, mTOR, and glutathione peroxidase.
For your convenience, we have included the webinar and full transcript below.
Dr. Dale Bredesen: So welcome, everyone. It’s my honor to have Dr. Sharon Hausman-Cohen, who’s done such a fabulous job with founding IntellxxDNA and really helping, as she says, a clinical decision support tool, helping to get the best outcomes. And we’ve said from the beginning, from the first patient in 2012, reversing her cognitive decline, that we’re always interested in one thing: what’s the best outcome we can possibly get? Obviously, part of that is going early, getting people more active with prevention, getting people more active with SCI treatment, and not waiting so long, as has been the case in the past. So, Sharon, welcome. Great to have you here. I look forward to our discussion today and to your presentation of some new and exciting things you’re doing at IntellxxDNA.
Dr. Sharon Hausman-Cohen: Thank you. Thank you so much for having me. I think I’m going to go ahead and share my screen because, as you and I were talking about, we have a lot of things that we want to be able to talk about today.
Dr. Dale Bredesen: Lots to cover. Okay, great. Well, again, thanks for joining us, everyone. And Sharon’s got a number of slides here to show. As she’s pointed out, this is more than just APOE4. We do tend to think about APOE4. It is obviously the most common genetic risk factor. And in large studies, it accounts for 60 to 65% of patients with dementia. But of course, that means that about a third, in some cases more than a third, are APOE4-negative. As Sharon points out here in our study, where she was co-author along with Dr. Ann Hathaway, Dr. Kat Toups, Dr. Deborah Gordon, and me, this was something where only about half the people that came through with cognitive decline, and they had clear cognitive decline by multiple criteria, but only about half of them in that study were APOE4-positive so it was really helpful.
This was published, it’s freely available online and was published last year. As she points out here, 11, actually out of the 25 were APOE3, three, and 2 were actually two threes. So that single gene, although it’s very important, is only a small part of the study and only a small part of the evaluation. And as Sharon and her team have shown, you can really improve your outcomes by looking at many other things. And as Sharon mentioned here, we saw people down to MoCAs of 19. And by the way, there were two in the study who went from MoCAs of 19 all the way back to 30 and did very, very well. I think that as time goes on, we can get better and better results, and we keep iterating and keep improving our ability. We have not seen anyone go from zero to 30 yet. That’s our goal, but that’s going to take something, some way, to build back the synapses.
And so again, getting in early is really, really helpful. So, Sharon, if you could talk a little bit, I’m sorry, go ahead. Maybe you could talk a little bit about some examples where you’ve seen improvements because, certainly, there were some in the trial where IntellxxDNA made a big difference in improving their outcomes.
Dr. Sharon Hausman-Cohen: Yeah. What I thought I would share before we get into the longevity and the talk about Klotho and some of the new genes is to help our clinicians understand some of those things that were going on in that other 50%, those 11 people who were APOE3/3 or the two people that were three twos. And that’s where you really need a clue map. When you have an APOE4, a clue map is still really helpful because just addressing APOE4 is not going to give you the same outcomes as if you can understand what else going on with nutrient carriers, detox hormone receptors, et cetera, and kind of fine-tune that plan. But with a three-three, you’re like, gosh, what’s going on? So, this, for example, is DNA from which we make a little hotspot. In addition to examining 600 different variants and giving an interpreted report, we give a hotspot.
This hotspot is a man who’s at high risk for hippocampal atrophy due to severe oxidative stress and neuronal growth signaling variants. So, I think of MSRB3 as basically your proteins in your brain tarnish if you don’t address it. They also had signalings in the WIF1, the WNT Inhibitory Factor 1 pathway, and that affects cognitive decline in a different way and interacts with the hormone pathways. And then VDR-Cdx2, which is a mast cell activation pathway in many ways because VDR has turned things off, people with these variants can’t turn off their IgE production. So that’s like one set of treatments, and we won’t go into too much detail because we have so much to cover. But then, for this person who was also an APOE3/3, it’s a completely different plan. He came in, and he was a real go-getter who was already had read your first book. He was on a lot of supplements and was doing a keto diet but was having cognition that was worse after long-haul flights.
Well, is a keto diet really the answer for him? If you look at some of the things he has going on, even with just a quick glance, you can see the topic. It’s not in the cognition and memory panel, which would be things classically associated with Alzheimer’s. But he’s got a lot going on in the brain ischemia panel. In particular, he has two variants. One in factor II and one in factor V. These are the common factor V Leiden and the factor II prothrombin gene variant that makes him have higher fibrinogen and higher risk for blood clots. So, for him, natural or prescription blood thinners are the key to brain health. And so, I think that what IntellxxDNA has done for your ReCODE to practitioners is given them the ability to go, well, what else should I not miss? What else can I address? But then also, we can’t know every single supplement and what path it works on every single medication.
And so, as a clinical decision support tool, we are able to give that referenced information and put it right in front of the physician so that they can get reminded, oh yes, this is factor II. I know that it is associated with blood clot risks and stroke risk, but even interactions, the interactions that are combined with factor V, you can have up to 20 times increased risk for VTE. That’s really important for someone who’s traveling across the country on a regular basis or across the world. Interestingly, just as a side effect, this gentleman did very well once his fibrinogen and his hypercoagulability were addressed. Exposure to the particulate matter of air pollution is going to further push that fibrinogen. So that’s why we always say that IntellxxDNA, yes, gives you their patient’s genomics. Still, it’s really an educational clinical decision support tool to allow you, as a physician or practitioner, to create a precision medicine plan for each patient.
Dr. Dale Bredesen: Let me just ask then, do you prefer nattokinase-pycnogenol? What are the things that you like to use to treat these sorts of people?
Dr. Sharon Hausman-Cohen: Yeah. I prefer lumbrokinase. That’s why we put it first if somebody is at really high risk, like with factor II or factor V, because it’s about eight times the fibrin dissolving units per pill. I also think that pycnogenol has really great studies. Pycnogenol was studied in a trial called the flight trial, and it was shown to decrease DVTs in people at high risk. They took people who had already had either previous DVTs, cancer, or swelling in their legs, and they showed a dramatic rise in their risk, but it also has benefits for cognition. And so, pycnogenol is probably one of my favorites. But in a high-risk guy like this, I would use both pycnogenol and lumbrokinase. And again, I always joke that this is the study I was talking about, the flight trial. There is no way that a long-haul flight trial like this would’ve ever gotten IRB approval in the United States because they were all high-risk people. And look, five people got DVTs in the control group, two people got SVTs, and, of course, zero in the treatment group. So pycnogenol and nattokinase or pycnogenol and lumbrokinase. But again, because this guy’s so high risk, I would kind of lean towards the pycnogenol and lumbrokinase.
Dr. Dale Bredesen: Right. So, one question: an interesting paper came out where they actually looked at vascular plaque, and then they gave people various doses of nattokinase. They either gave them about 3,600 IUs, which is a little bit, it’s about a hundred to 80 milligrams, or they gave them 10,000, which kind of surprised me, so that it would be 500 milligrams instead of the usual 100 milligram dose and then followed plaque. And what they showed was they actually saw plaques retract, plaque loss over time, but only in the 10,000. Really worries me giving people that much. What do you feel comfortable with in terms of giving nattokinase?
Dr. Sharon Hausman-Cohen: I actually do feel comfortable with high doses because we know using fibrin dissolving units, nattokinase is usually 20,000 to 80,000 fibrin dissolving units depending on the company of the pill. And lumbrokinase is 300,000 fibrin dissolving units per pill. And the company that makes the lumbrokinase, Boluoke, I spoke with their chief medical officer, and they’ve studied it up to six pills a day and have a publication showing even with people on heparin, they did not have increased bleeding risk. So that made me feel a lot better.
Dr. Dale Bredesen: Wow. Yeah, that is impressive. Very, very interesting. And, of course, people are using it now also because of the idea of getting rid of spike protein. Have you been using it for your COVID-19 people?
Dr. Sharon Hausman-Cohen: I have. I discovered that the combination of pycnogenol and lumbrokinase was great for COVID back when I had one of my APOE4/4 cognition patients with a factor V get severe change in his mental status and cognition after COVID. And I thought, well, maybe the lumbrokinase, maybe it’s your factor V causing problems. That’s how I discovered that I checked his fibrinogen levels. They were sky-high, almost 600. And within a week of using a relatively high dose of lumbrokinase and pycnogenol, he was better. I felt very comfortable using it both for the fibrinogen and the spike proteins.
Dr. Dale Bredesen: Very interesting. Thank you.
Dr. Sharon Hausman-Cohen: And a lot of this kind of information is in our tool where you can click on the links and go, let me look at these studies. You don’t have to memorize this, and you don’t have to memorize dosing because we’re going to give that all in the tool. And again, I want us to have time to go on to the other, the main talk today of longevity and some of those variants. But the key point here, why we want to do this introduction, is you’re not going to get someone well just like thinking about the 36 holes if you just think about one gene. Looking at a whole collection of gene variants that have been related to cognition and memory, hormones, homocysteine, heavy metals, et cetera, that’s going to be what helps get somebody well. And this gentleman did have other things that were looked at. Of course, in IntellxxDNA, we’re going to also include all the things that you’ve talked about in all of your publications, things that relate to amyloid processing proteins, mitochondrial membrane proteins, microglial dysfunction, BDNF, choline, et cetera, and even the hormone receptors that can trigger more inflammation. And I like to just think of genomics as kind of the window that gives us that look well beyond blood work.
Dr. Dale Bredesen: Absolutely.
Dr. Sharon Hausman-Cohen: Should we switch over to the topic of oxidative stress and longevity and other variants that relate …
Dr. Dale Bredesen: Absolutely, yeah. Let’s talk about some of the new work you’re doing.
Dr. Sharon Hausman-Cohen: Well, it was actually because of some of the Apollo Health-trained ReCODE doctors that were asking us. They’re like, “Sharon, when are you going to add Klotho?” Klotho took us a long time to figure out, which is why it took a while to add. But just to give a fun little background, Klotho was one of Zeus’s daughters. She was the spinner of the thread of life. Her sisters measured and cut the thread, so that’s why. We know that from the beginning, they knew that Klotho had something to do with longevity. And the question was figuring out why and how. And that’s what’s going to be our interesting discussion today because 30 years ago, well before we had genomics and understood it, they knew that levels of the Klotho protein and levels of that expression related to lifespan and aging, as well as to a lot of other topics, to topics ranging from stroke risk and cardiac risk to cognitive decline and MS and osteoporosis and even kidney stones, cancer. But all of these are tying into healthy versus accelerated aging.
The basic thing before we go too deep into how the genomics helped us is you need to understand that you want Klotho levels to be high. And I thought I would share this picture of mice with low Klotho levels because you can just look at that mouse and you can go, oh my gosh, that mouse does not look healthy. And that’s because low Klotho contributes to hypomyelination, losing synapses, and, of course, cognitive impairment, but just accelerated aging. Klotho-deficient mice will look the same when they’re born, but by three weeks old, they start to display signs of premature aging. They typically die at eight to ten weeks of age, which is, again, mice only live 15 to 20 weeks, but that’s still premature. And they also will have the kind of things that we have as humans as we age: thinning hair, thinning skin. Klotho levels are primarily determined by your genetics, but what we’re going to talk about is how diet, lifestyle, exercise, and supplements can affect the transcription, can affect the levels because Klotho levels naturally decrease with aging. Everybody wants to work to keep their Klotho levels high.
Dr. Dale Bredesen: Actually, the mice we dealt with in the lab for years live a couple of years. If you’re a long-lived mouse, you might live three to five years, but they live a few years and get Alzheimer’s if they have the genetics for it, typically after several months. So obviously, Klotho has a remarkable effect very early on, so that’s really impressive.
Dr. Sharon Hausman-Cohen: Klotho has a lot of effects, but I think some of the key ones so that we’re kind of all on the same page as to why it helps with memory is it’s produced, and all genes have differential transcription, meaning they’re produced in different parts of the brain in different amounts. But Klotho is produced in large amounts in the hippocampal neurons and the CSF. It helps to create those new hippocampal synapses, regulates axonal transport of nutrients, helps prevent neurodegeneration, and even affects NMDAR and long-term potentiation. And so we think of how some of the NMDAR drugs are used in cognition. In the CSF, it suppresses macrophage activation and CSF inflammation. It also relates to antioxidants because the expression of Klotho directly correlates with your ability to make enough catalase, superoxide dismutase, and glutathione peroxidase. So again, oxidative stress has independently also been associated with memory issues and aging, some of these genes in fact, and even demyelination.
Dr. Dale Bredesen: And just a point on that, I think it’s been fascinating. There’s just no question, as you pointed out, that oxidative stress is very important very important in stroke, very important in neurodegeneration, very important in myocardial infarction, list go on and on and on. And, of course, in longevity, as you mentioned. And yet, years ago, Arlan Richardson did a very interesting experiment where they increased the oxidative stress by removing some of the antioxidants genetically. And surprisingly, the mice had almost no change in their lifespan. So, on the one hand, it’s very clear there’s something very important about this, and obviously, Klotho has a big impact on it, and yet it’s not as simple and obvious as if you increase the oxidative stress; the animals are actually going to live much shorter. I think there’s a lot we still all have to learn about oxidative stress and various disease states.
Dr. Sharon Hausman-Cohen: I agree. And I think that part of that story does relate to genomics because most people can, in response to more oxidative stress, increase their catalase levels increase their superoxide levels, and you’d have to repeat those studies. And there are studies now being done, as I said, they relate. There are some studies with regard to things like MS and other disease states in individuals who genetically can’t make enough glutathione peroxidase or superoxide dismutase. In those people, they may be the ones who need a little more oxidative stress. And that’s again why I think we have to use a mixture of what we’re seeing clinically and someone’s genomics. Oxidative stress, also we know, damages proteins and reduces mitochondrial function, and I think that’s part of the story as well. It may be interactions with people who have worse mitochondrial repair, which again ties into the APOE4. There’s a lot to this story. But I think one of the things you and I were talking about over the past week is the role of mTOR in aging. Do you want to talk a little bit about mTOR and the general pathway?
Dr. Dale Bredesen: Yeah. Well, I think what’s fascinating about this is that when people have looked for what are the genes that are critical for longevity, interestingly, they’re all coming back to energetics. So mTOR, of course, is related to nutrient sensing. And so, especially things like protein and especially even methionine will trigger this. Things like rapamycin have been used as longevity drugs, and of course, caloric restriction is another way to go. But there are other pathways, obviously; your NAD, for example, sirtuin, is NAD-activated. So again, low on your energetics, you have more NAD+ than NADH. And so, this activates sirtuin. And then, of course, AMP kinase. These are all energy-related responses, and mTOR is an important one. And as you point out, he has a very interesting relationship to Klotho.
Dr. Sharon Hausman-Cohen: Yeah. One of the things to understand is that first of all, when you get older, when we’re talking about mTOR, you would think, well, mTOR is nutrient-sensing and does all these things that inhibit autophagy that you actually would want a lot of mTOR. But one of the things is the mTOR levels in a child versus the mTOR levels in a senior are very different. One of the things that happens with aging is hyperactivation of mTOR. And that’s again why rapamycin has been looked at as a treatment for aging because it inhibits mTOR and brings those levels back down. But autophagy, mTOR, normally inhibits autophagy. And so if we want to be able to increase that autophagy so that we can have our time for mitochondrial repair. And so all of this stuff interacts, but what really was interesting to me as I started researching Klotho is that mTOR hyperactivation lowers Klotho, and that is key to the aging phenotype conveyed by the mTOR pathway.
Conversely, when you inhibit mTOR, you’re going to raise Klotho, so the same kind of interventions, caloric restriction, and rapamycin that inhibit mTOR help you raise those Klotho levels. And the way that they were able to show that is in Klotho-negative mice. They knocked out Klotho in some mice. Rapamycin didn’t do anything. It could not work; it couldn’t affect or have the normal effects that would have benefited the aging and the phenotype. So whether you’re studying vascular calcification or other things that are associated with aging, we know that mTOR’s role is linked to Klotho. And so that’s why I decided that we should definitely make sure everybody understood a little more about Klotho. I also thought the other really interesting thing about Klotho, so just here, you can see Klotho downstream is really important for our antioxidants. We talked about that. But it’s also really important for our anti-inflammatory pathways and amyloid beta processing.
Klotho, if you have Klotho, it inhibits the overactivation of those NLRP3 inflammasomes. NLRP3 is a gene variant that is very involved in what kind of a response you get to COVID and other viruses, as well as even vaccines, getting a hyperactive or underactive response. But Klotho affects both of those pathways. It ties in so much to what’s going on. And you had talked earlier about when you were doing lab research, and you guys would use APP transgenic mice as an Alzheimer’s model. And when you look at them, they have these erratic EKGs, and you could probably know more about that, but they have low Klotho levels. And if you increase Klotho in these APP mice, you can improve their memory and spatial learning even though you don’t affect the APP or tau levels. So that’s why, again, I think this is a pretty important gene.
Dr. Dale Bredesen: Absolutely. And I think it’s important to just stop here for a moment because you pointed out something really important. It’s related to inflammation. What’s really cool here is that a beta has turned out; people wondered for years, why are you making this stuff? You’re not making it to give yourself Alzheimer’s, obviously. It’s turned out to be a really fascinating antimicrobial. It basically sequesters these various pathogens and also binds metals, and kills bacteria, viruses, and fungi. It’s kind of an amazing peptide, but it is part of your innate immune system. The fact that Klotho is having effects on inflammation goes perfectly with the idea that it would impact a beta, which is ultimately turning out to be part of the innate system’s memory, a long-range way of saying, I’ve been exposed to these insults that I’m going to keep this stuff around that can help me to survive. So, the idea of just getting rid of it without understanding why it’s there doesn’t make a lot of sense. But having the Klotho increase and being able to reduce this is really cool.
Dr. Sharon Hausman-Cohen: Yeah. We also started talking about the coagulation cascade and how genes that make you have higher fibrinogen also are not great for your cognition. Really, the way I describe it to my patients is if you have too many fibers floating in the blood of fibrinogen, you’re not getting as much oxygen. It’s like having too thick of blood. And another way, so Klotho, again, it’s like how APOE4 interacts with 1,700 promoters. I don’t think we have 1,700 things that Klotho interacts with, but we’ve already got the oxidative stress pathways, the inflammatory, the mTOR, but also it causes, when you have low Klotho, it causes your pY1 to go up and pY1 elevation affects fibrinogen as well. And so, I think, again, addressing Klotho is going to have a lot of downstream benefits. All of these survival curves show you that, again, Klotho animals, Klotho knockout animals, are not going to survive as well or live as healthy of lives. And now we can switch over to humans.
One of the things is just to show you a couple of studies, and then we’ll talk about how you can use genomics to determine who’s at risk for low Klotho. However, CSF Klotho levels have correlated with Alzheimer’s and MCI. I want to start to call attention; you’ll notice in this study, they talk about the Klotho vs. haplotype and the heterozygosity. That’s what we’re going to talk about because that is the genotype that conveys the risk, to have one copy of V and one copy of S essentially. And it increases Alzheimer’s risk because it affects amyloid and tau and inflammation and everything else. But if you even just look at CSF Klotho levels, again, we’re not going to go spinal tapping people. You can see those controls at about 1,200, mild cognitive impairment, 1,100, and dementia went down to a thousand. We know it’s important.
So, what is this VS variant? And that you and I, again, were talking shortly before we started, and you said that is the one question people are going to want to know without having to do a spinal tap. How do we know what the Klotho levels are? Well, in any gene, you get single nucleotide variants, little changes along the gene that can affect function. So, in the APOE gene, we know APOE4 makes you make less of the APOE protein. Well, the variants, and they’re conveyed by RSIDs, the variant that is the V variant dramatically lowers Klotho production. You would think it would be bad to be a VV, and it is. It’s very bad to be a VV. I’ll show you some studies. But because V and S interact, being a VS is better than being an SS. Because the VVs and the SS are the same people, and that’s the confusing part because they’re linked in most people.
If you get two S, you get two Vs. And the way the genes interact, you get the least Klotho as a VV and the most Klotho as a VS. And so that’s why, again, you’re going to see VS referred to as the benefit that helps to reduce the burden of tau amyloid raised Klotho. This was a study of Eastern European Ashkenazi where they studied people who were already 79 years or older, and they said, how many of those people lived five more years? And you could see the VVs very few, only about 12%. Whereas the VSs, they call it FB here, they later changed the name, and 65% of them are still alive. And that’s where they started to say, okay, if you’re going to have five times the risk of the likelihood of surviving, five more years when you’re 80, that’s why this is a longevity factor. That’s a big difference. And it’s also a huge difference in stroke risk in the elderly. And if you look at this elderly population, 30 times the risk of stroke in people who are VV compared to the VS. And that’s probably a combination of oxidative stress and the pY1.
Dr. Dale Bredesen: Again, inflammation and thrombosis, you can show exactly how they’re connected there.
Dr. Sharon Hausman-Cohen: So, what do we do about it? The same thing again that you have taught us all to do is we have to be thinking about a multipronged approach. You’ve already discussed that we don’t necessarily want to just focus on lowering oxidative stress. And I agree. I think that the first thing we want to know is what we can do to increase transcription and actually increase Klotho as opposed to decreasing oxidative stress. And then, we can also do things that lower mTOR, lower oxidative stress, lower inflammasome activation, and increase the NMDAR activity.
Dr. Dale Bredesen: Of course, NMDAR, I mean, that’s a double-edged sword, as you know. I mean, memantine inhibits glutamatergic transmission and has a very, very modest effect. So, you want the right amount, not excitotoxicity, and not too little.
Dr. Sharon Hausman-Cohen: Right. And I think there’s a difference in different parts of the brain. And so that’s a whole complicated discussion in and of itself.
Dr. Dale Bredesen: Again, it’s always great to hear about patients getting better. Tell us about Lily.
Dr. Sharon Hausman-Cohen: So, Lily, I chose her because she is somebody who would be more of a PreCODE patient. And we’re so used to advertising what we do for the patients who are already experiencing cognitive decline. But we know that many people will start to notice little things. They’ll call it brain fog. Once in a while, I get brain fog when they’re in their forties or fifties. And those people are really important to reach out to as well. She was coming a little bit, and she actually didn’t initially talk about the brain fog. She was worried about her severe dysmenorrhea, which was probably endometriosis, and things like PCOS history. But she just wanted general health optimization, and things that stood out in her history is that she had kidney stones bad enough to require surgery at age 29. She had brain fog that was intermittent starting in her mid-twenties, but she couldn’t tell what made it worse.
But she also had headaches, migraines, problems with fatigue in her twenties, and muscle complaints that she noticed were worse when her husband made her start working with a trainer and doing resistance training. She never had a problem when she did yoga or dance or more aerobic training, but as soon as she started doing resistance training. And then she also told me that she got extremely ill when she went to Mexico. In fact, she was pretty aware of the integrative world and needed to go to a rescue place and get IV glutathione. They gave her IV glutathione and vitamin C, which helped her get better. If we look at her hotspot, she’s one of these Klotho people. So, at the top of the hotspot report, we can see she’s got two copies of Klotho, but she’s also got quite a few other things that relate to her ability to detox. I thought that I would just kind of show how this ties in with her history.
Dr. Dale Bredesen: Now, you mentioned VS earlier, and here I see it on her report. If you could just go back one slide there. You’re reporting GG. Could you talk a little bit about that?
Dr. Sharon Hausman-Cohen: Yes, so the variant that she has, and I don’t have the RS number showing on this version. When you’re in the actual physician’s toolkit, it’s going to have all the RSIDs. But this is the V, so she’s a VV. The names are one of the difficulties of genomic research. There can be five different ways of naming one gene. So MTHFR C677T. And then there’s another way of naming it with an RSID, and then there are other names. And so the same thing with Klotho. And so, a GG here would be considered a VV. So, she’s in that group.
Dr. Dale Bredesen: Yeah, so this is guanine, and in this year now, so you’re getting valine from that triplet. Okay, that makes sense.
Dr. Sharon Hausman-Cohen: Yeah. So, the thing that I found really interesting was that she was actually the reason I chose her; she was the first patient in my practice after we added Klotho, where I found two copies. So, I had known some things about her. We went back to her right after we added Klotho. I just gave that look, and I go; this makes so much sense because Klotho contributes to kidney stones. So, that severe kidney stone issue starting in her twenties was very interesting. It relates to calcium oxalate sensing and phosphorus.
Dr. Dale Bredesen: Did she actually have hyperphosphatemia or not?
Dr. Sharon Hausman-Cohen: Well, I actually did not yet check it. She has been busy traveling the world lately, and so she hasn’t had a chance. Literally, we just added Klotho to our report a month and a half ago. So, I reached out to her when I saw this, and she hasn’t had a chance, but we’re going to check because it may change a little bit how we address her kidney stones.
Dr. Dale Bredesen: You made her better so she can travel the world. That’s great.
Dr. Sharon Hausman-Cohen: Yeah. And then when she felt, remember when she felt that she did aerobic exercise, she was great, but the resistance training was not so great. Well, aerobic exercise increases Klotho. So, with all of your seniors that come in, because remember, aging decreases Klotho, and they’re like, oh yes, I’m working with a trainer, and I’m doing weights. Really, that’s not going to help their Klotho. We’ve got to get them moving. We’ve got to get them walking, doing ellipticals, doing exercise, bicycles, things that are aerobic, dance, whatever they want to do. But that’s really important for them and explains why she felt horrible. And Klotho can be upregulated until it can’t. They did a muscle study where they showed you can really have your muscles go back so you can deal with the sarcopenia until you get to be the oldest of the old, and Klotho gets really low. I think that what’s really important is don’t wait till you’re 80 to start to try to get your muscle strength back. Deal with this sooner.
So, what did we do for Lily’s Klotho? Well, there are different ways to address it. You can address it with supplements, diet, lifestyle, with medications. And so, one of the things we’re going to talk about is how resveratrol works is different than giving the SOD, for example, versus the saffron. And in the tool, we explained it all; I just didn’t want to make a slide too busy. We can address it with diet, medication, and supplements. But our first choice is to affect the expression. Lily had endometriosis. We had tried pioglitazone because of her endometriosis, and we did not know about Klotho at that point. Pioglitazone in the literature is one of the treatments for endometriosis, but it’s possible that raising the Klotho, which lowered her pY, is part of what helped her pain from her endometriosis.
We added piceid resveratrol because resveratrol actually increases the expression of Klotho. So that’s one of the most direct interventions. And actually, she said that that really helped her. I spoke with her just last week, and that helped her a lot. I want to, just for fun, poke back at a couple of her other variants, the CYP2E1 and the GPX1. Remember how she got so sick with alcohol?
Dr. Dale Bredesen: Yeah.
Dr. Sharon Hausman-Cohen: CYP2E1 affects autophagy in both the liver and the brain. It’s particularly important in the liver and will affect the blood-brain barrier, and neurodegeneration is a risk. But alcohol is dramatically going to worsen that effect because, again, it’s going to affect the gene transcription. And so, when you already have overactive CYP2E1, alcohol makes it even more overactive. And then you’re going to get the flushing and the rapid heartbeat and the nausea because you’re going to have increased aldehyde levels. You’re just pushing that detox too fast, and it gets stuck at this intermediate.
Dr. Dale Bredesen: Yeah, this is very interesting.
Dr. Sharon Hausman-Cohen: And so then again, again with everything, the thing, if you’re going to use genomics in your practice, what you’re trying to do is going, okay, what are some of the key things? What can I do about it? The number one thing, as I said, you really cannot be drinking alcohol. But she did the right thing by taking vitamin C because vitamin C blocks alcohol’s ability to induce CYP2E1. And it was just the detox place she went to and said, oh, let’s try giving you some glutathione and vitamin C. But you also have to be careful. If she had taken Tylenol, that would’ve made it worse because that’s more toxic with CYP2E1.
Dr. Dale Bredesen: It’s interesting because these people act as if they’re on Antabuse, where you have that first step, but you don’t have the second step. Very interesting.
Dr. Sharon Hausman-Cohen: Absolutely. And again, you don’t have to memorize this. All of this is in the tool. This is how it’ll look under potential interventions. We’re going to say, what can you do to reduce the expression? What can you do to reduce the downstream oxidative stress? What can you do to protect against the alcohol-related damage? What can you do lifestyle? What can you do with medication? Don’t use things like St. John’s Wort and Tylenol. The last pathway that we’ll take a real quick peek at so we have some time for questions is, should we talk about glutathione peroxidase?
Dr. Dale Bredesen: Absolutely. So important.
Dr. Sharon Hausman-Cohen: So, glutathione peroxidase is an antioxidant gene, but I think that one of the reasons it is so important is because of its role in the mitochondria as well. It’s demonstrated having enough glutathione peroxidase is important in terms of helping to protect against some Alzheimer’s, Parkinson’s, epilepsy, and ischemia. And also even in things like mental health issues and stress. And so, I thought it would be fun to talk about this study done in Ecuador. There is a famous geneticist in Ecuador who has gone and followed people for over 20 years, and he showed things like who gets obese with different environmental exposures based on their genetics. As part of his study, he showed people who had two copies of this GPX1 variant, which reduced activity by up to 70%. And some of the tissues had 7.2 times the risk of Alzheimer’s when he followed the adults who had high exposure.
Now, their exposure to environmental toxicants was very high. It was on the Ecuadorian-Colombian border where they were spraying glyphosates to get rid of the cocaine. So, it was unusual exposure in terms of the amount of chemicals. And this study has not yet been repeated with GPX having that kind of an odds ratio. But I thought that was really interesting, especially since visual memory is one of the hallmarks of early cognitive decline.
Dr. Dale Bredesen: Absolutely. Especially in posterior cortical atrophy, PCA. Now, did they talk at all, or did this person talk at all about the risk for ALS or risk for Parkinson’s, or other toxin-related illnesses?
Dr. Sharon Hausman-Cohen: He looked at children and saw definite neurodevelopmental issues and birth defects. There was a different study that looked at pesticides and Parkinson’s, but GPX is involved, as well as some of these different aquaporins. ALS, I have not seen a study on GPX for that, but there have been some really interesting studies that have come out on how mycotoxins and mold are a big trigger for ALS. There are a lot of environmental exposures that are definitely something we can’t ignore in our patients with any kind of brain issue going on. One of the reasons I think that GPX is more important than some of the other glutathione pathways for brain health, in general, is because the mitochondria rely upon GPX, and you’ll get mitochondrial dysfunction when you don’t have adequate GPX production. I tell my patients if their mitochondria can’t get rid of their oxidative stress, they basically will, I say, explode. I don’t know if they really explode, but you get mitochondrial dysfunction, and you probably could explain that a lot more eloquently.
Dr. Dale Bredesen: Interesting.
Dr. Sharon Hausman-Cohen: And then this again ties this back in with memory impairment and how glutathione peroxidase knockout will cause more memory impairment in animal models. And then, if you increase glutathione peroxidase in this study, they showed they could rescue some of that memory impairment. I think it’s important in a patient like this like Lily, who has the Klotho already, that we don’t ignore glutathione peroxidase. One of the things we chose to do was she actually was Asian, and she said her mother used to give her ginseng all the time. And interestingly, people figure things out culturally that work for them in their families. Ginseng, a particular species of ginseng, can increase glutathione peroxidase activity, but also, ginsengs can help attenuate the overproduction of reactive oxygen species in mice that don’t have enough Klotho. So astaxanthin is another thing that can increase GPX1. I think that you have a great knowledge of some of the different products that have astaxanthin, but astaxanthin also helps with Klotho FOXO3 and Nrf2.
Dr. Dale Bredesen: Interesting. And, of course, yeah, also age-related macular degeneration, another one.
Dr. Sharon Hausman-Cohen: Yeah, that’s really interesting because people were initially, if you go back a couple of decades, people like eat your carrots, get all your vitamin A, but it turns out that too much vitamin A is a negative for macular degeneration because it blocks the absorption of lutein and astaxanthin and zeaxanthin, which are what the eye really needs. Science is constantly going on. We’re getting toward the end. So, we have time for questions, but I just wanted to end with a lot of the supplements that you are already familiar with and work on the pathways that we want to look at genomically. So GSTO2 is the ability to recycle vitamin C. Those CYP2E1 people need more vitamin C. Selenium, which is in this, the ReCODE type three toxic. One of the reasons that I’m sure you guys designed it, and if you want to talk about this, it’s a GPX1 co-factor. Do you want to say anything about…
Dr. Dale Bredesen: Yeah. I mean, I think it’s just that everyone recognizes that this is critical for glutathione usage, absolutely.
Dr. Sharon Hausman-Cohen: But it’s fun to go. I like to dissect backward and go, oh, for the toxic type, it makes so much sense. This helps; it has the milk thistle in it. It’s got the NAC in it. It’s got the curcumin. And so that raises the heat shock proteins. And so, I think it’s fun to go, how do we match the genes to the different things. So, for Lily, her prevention plan is working quite well. She said she feels the best ever. When I talked to her again a few weeks ago, she was on an antioxidant formula with long-acting resveratrol and astaxanthin, staying on her pioglitazone, increased antioxidant foods, and high catalase foods, which are just fruits and vegetables. And I think that’s an appropriate amount of antioxidant support for a young person. We don’t need her taking tons, but we want her to use the diet for what she can. You can also increase Klotho expression directly with omega 3s. Make sure she knows about the cardio strength training. Give her some things to address that CYP2E1.
You don’t necessarily want to start a 40-year-old on 30 different things. And she’s doing a few other things, some vitamin D and a few other things. But for her brain genomics, this is and detox; that’s what we’re doing. I’m sure that people want to know how they can learn more about ReCODE training and Intellxx training. And so just want to throw some QR codes up while people are putting their questions in and IntellxxDNA is being used; I don’t know if you want to say anything about your new study, the Evanthea study.
Dr. Dale Bredesen: Absolutely. The new study is taking place at six sites, so just getting off the ground here after over a year of planning. And we’re thrilled to be working with IntellxxDNA, just as we did in the first study. Sharon showed that wonderful result from one of the patients in the first study. So, there are six different sites. It’s Dr. Craig Tanio down in Florida. In Hollywood, Florida. David Haase, who is in Nashville. And then Nate Bergman, who’s just outside of Cleveland. Dr. Kristine Burke, who is right outside of Sacramento here. Dr. Ann Hathaway, who’s here in San Rafael just North of the Golden Gate Bridge. And then Dr. Kat Toups, who’s in the East Bay. I am so thrilled to be working with all of them. We really look forward to an exciting study. It’s already registered on clinicaltrials.gov, and you can see the Evanthea Dementia Reversal Trial. You’ll see the website there.
Dr. Sharon Hausman-Cohen: And I have something exciting to announce as well. We are working with the same IRB board that you guys are working with to get more data. And we’re doing a small study with a genomically targeted, showing that the tool helps clinicians make better decisions and get where they’re going. Our IRB person suggested, and we are moving forward for any of you as clinicians who want to pick a part in a study that we can get a conglomerate study going across the country as long as you guys are doing measurements before and after. And so we’ll be letting you know more information if you want to join in that, where you can be part of us showing across the country that we can get better outcomes together. And I think that it’s really important what you’re doing in the Evanthea study where you guys are looking at so many different parameters and what I’m going to call a center of excellence or centers of excellence.
But I think if we can partner as community physicians and also show that what you are doing, what you’ve taught us to do, of looking at all these different factors and addressing them, that genomics can help us get there. But equally and more importantly, we can get improved outcomes. The more publications we can get, the better. If you want to join the IntellxxDNA community, all you need to do is let them know that you are a ReCODE practitioner and Apollo Health practitioner, and we will give you our full mentoring training program and online training program at no charge because we need to do this together. There’s also new, exciting news that I’m going to turn it over to you for Dale about that horribly difficult thing of how you get your patients to change their eating habits.
Dr. Dale Bredesen: Yeah, that’s a great point. And from the very beginning, people have said, okay, it’s great to talk about synaptic signaling and all this stuff, but ultimately, what do we do day to day? And if you’re telling us to have a plant-rich, mildly ketogenic diet and have appropriate organic food, et cetera, how the heck do you get all this stuff? Where do I have to go? We actually worked with Nutrition for Longevity, and we are thrilled to work with them. They’ve done such a great job with literally meals for food, medical meals. Julie G. and my wife, Dr. Aida Bredesen, have worked extensively with Nutrition for Longevity with Jennifer Maynard over the last nine months or so now, refining, refining, refining. This is now available for delivery. It makes it very easy for people to get an appropriate KetoFLEX 12/3 plant-rich, mildly ketogenic diet to support cognition.
Dr. Sharon Hausman-Cohen: And of course, since this is going out to people from both of our communities, we often get asked, how did we learn so much about cognitive decline? And it’s not just the genomics. Genomics will give you a lot of a big head start on understanding some of the contributing factors. But Apollo Health ReCODE 2.0 has developed an amazing training program where you can hear from Ann Hathaway about hormones and Neil Nathan about detox. I teach genomics. Dale about so, so many topics. So, if you’re not yet ReCODE trained, you can scan this barcode or QR code and start your own self-paced program. Did you want to add anything about the training, Dale?
Dr. Dale Bredesen: No, I think that’s a good point. We had over 2,000 physicians in ten different countries and all over the US, as well as neuropsychologists, as well as nurse practitioners, as well as health coaches, and on and on, who have all trained. And I think the outcomes speak for themselves. We see many, many people who are improving. We’re hearing more every day, just dramatic improvements. And, of course, we’ve published a number of these, and we look forward to more. I think that’s critical. We’ve got, as Sharon said, some real experts: Neil Nathan talking about toxicity, Chris Shade and Cyrus Raji talking about neuroimaging. Of course, Sharon talking about the critical nature of genetics in this, on and on. So, lots of experts.
Dr. Sharon Hausman-Cohen: IntellxxDNA will be going international in 2024, which is just around the corner. If you’re listening from another country, reach out to us. We’ll let you get started very soon.
Dr. Dale Bredesen: That’s a good point.
Dr. Sharon Hausman-Cohen: And then the last sponsor of our webinar has been LifeSeasons. And so, for any of you who don’t know about all the great LifeSeasons products, you can scan here and learn more.
Dr. Dale Bredesen: Lots of great questions in these last few minutes here. Let’s talk about the questions. You brought up the going international. Kathy asks, is Intellxx available in Canada? And if not, when will that be?
Dr. Sharon Hausman-Cohen: My CEO tells me that it should be before the end of this year. So that’s what we’re saying, or first or the very beginning of 2024. Reach out, and we can make sure you’re amongst the first to be trained.
Dr. Dale Bredesen: Fantastic.
Dr. Sharon Hausman-Cohen: Someone (named) Karen asks, “Do results from this test affect the ability to get long-term health insurance or life insurance rates if they indicate risks for cognitive issues or dementia?” That is a great question. IntellxxDNA is its own platform, and we recommend that you don’t scan someone’s genetics or genomics into their EMR. Keep it in its IntellxxDNA form. IntellxxDNA is not covered by insurance. Someone asked the price. The executive report, which is all the medical and all the brain, is $1,200. The brain alone is $900 because it is a complete clinical decision support system. Again, we’ll give you a demonstration to show you. But we have our own platform where you can keep all the information. From my understanding of the law, if you are not taking insurance in your practice, you are not taking insurance to cover IntellxxDNA, and it’s not part of the medical record, then that does not have to be released. And that’s what we do in our practice.
Dr. Dale Bredesen: Karen’s also asking about hemorrhagic stroke or a brain bleed if they are using some of the things you talked about earlier, pycnogenol, nattokinase, lumbrokinase, et cetera.
Dr. Sharon Hausman-Cohen: I won’t mix things like pycnogenol and lumbrokinase with prescription blood thinners, but that’s more because the prescription blood thinners increase the risk of brain bleed. I, in the literature, could not find any studies of increased brain bleed. But that is a really good point for people to know. When patients are asking you questions about the new anti-amyloid drugs, if they’re an APOE4, you’ll see in the IntellxxDNA tool a long discussion about how both APOE4/4 or 2/4s or 2/2s are all at much higher risk for brain bleeding. And so I am a little more thoughtful on the 4/4s about not going super high on the dose. But I spoke with one of my colleagues at Harvard who’s been involved in some of the studies of the new drugs. It was a lively discussion, but I was really happy to hear that he was excluding APOE4/4s from his trial. It’s just really important to know that about APOE4/4s.
Dr. Dale Bredesen: Yeah, absolutely. And then Karen goes on to ask about pycnogenol and lumbrokinase or nattokinase with high-dose fish oil. Are you okay with that?
Dr. Sharon Hausman-Cohen: Yeah. And I think that the whole point of a clinical decision support tool is generally yes, but you take into effect we have both risk and benefit SNPs. If somebody has lots of coagulation risk SNPs, then I’m going to feel really comfortable with that. If they have the opposite, if they have more bleeding risk variants, you might go a little lower in dose. But again, usually, I had one patient where when she went up to a hundred milligrams twice a day on pycnogenol, she got some bruising, so we just backed her down on the dose. And so, there’s a lot of different options for that.
Dr. Dale Bredesen: Go ahead.
Dr. Sharon Hausman-Cohen: Somebody asked if there is a link between Klotho and mast cell disorders and histamine intolerance. Not directly, but there’s some really interesting stuff coming out with mast cells, and that will be the mast cell, and histamine intolerance pathways will be available starting in September, which is pretty soon. I haven’t seen anything about Klotho relating to that.
Dr. Dale Bredesen: Yeah, that’s interesting. There were a couple of patients recently who have responded to these anti-CGRPs, like Ubrelvy or Nurtec, who had some degree of mast cell activation disorder. So, it’s something to keep in mind for people who have mast cells. Is this contributing to their cognitive decline? And you can see a fairly quick turnaround. It only lasts a day or two, but it really tells you that this is one of the contributors to cognitive decline.
Dr. Sharon Hausman-Cohen: Yes.
Dr. Dale Bredesen Then goes on to ask about Klotho levels in various tissues. Could you talk a little bit about various tissues in Klotho?
Dr. Sharon Hausman-Cohen: So yeah, that’s a really important concept in genetics because people sometimes will try to verify someone’s genetics with blood. Remember, blood is just one tissue. And so, Klotho levels, for example, would not be something you could measure from the blood. Klotho is primarily, it’s expressed mostly in the kidneys, in the hippocampus, and in the CSF. A lot of times, again, the beginning when genetics and genomics first started, a lot of people doing nutrigenomics were like, okay, they have a gene that makes homocysteine go high, so I’m going to see if they have high homocysteine by checking their blood levels. Well, you can do that for homocysteine, but for endocannabinoid receptors, they’re only expressed in the gut and in the brain. For Klotho, we just talked about different things in the brain, and different gene variants have differential tissue expression. So that was a great question.
Dr. Dale Bredesen: Yeah. A question here from Dr. Ram Rao. My colleague Ram, it’s great to hear from you. He’s saying, “APOE4/4, so the homozygous are known to have high Klotho levels, and yet they are at high risk for cognitive loss. Any insights?” I think this is an interesting question because part of the answer comes from Ram’s own discovery. I think one of the most important discoveries made in APOE4 studies is from Ram. He’s the one who found that APOE enters the nucleus, interacts with RelA, and then enters the nucleus. And as you mentioned earlier, Sharon it interacts with 1,700 different gene promoters. It really has a very interesting kind of reprogramming of the cell. What Ram found is that one of the effects is that it has a pro-inflammatory effect.
People had known there was something pro-inflammatory about APOE4. How does that work? What Ram found is that some of the genes that it interacts with are things that normally mitigate the inflammation, turn it down, and this turns those down. So, with a net effect, you get a prolonged, more active pro-inflammatory effect. I think it was really beautiful work. He found effects on PP2A, for example, which is impacting the phosphorylation of tau. Again, a pro-Alzheimer’s sort of effect. Ram found interactions with things like glucose handling things, like the microtubule effect. So really striking and really, I think, explanatory. And Klotho obviously doesn’t do everything. It’s something important. But as you’ve shown, when you’ve got 1,700 genes that are impacted, you’re really changing the programming of the cell.
Dr. Sharon Hausman-Cohen: And I think that that is the really important point is there are different things that APOE4 downstream causes. And so, the Klotho people, so yes, in the APP mouse model, Klotho helped to rescue some of the things. But that’s a different, that’s not the main cause, that’s not what’s going on necessarily for APOE4s. I think that I brought up Klotho not so much because of the interaction for APOE4s but is one of the things not to miss in some of the people who are APOE3/3s that have other causes. I had another woman who has two copies of Klotho, and she was getting lots of leg pain, and her NutrEval® showed really bad antioxidant levels. It’s to help identify a different group of people. But we’ll have to look at the interaction. Is there something about APOE4 that actually, in response to APOE4, people who can increase the transcription of Klotho? And if they were to separate out that study based on variants, are there people who have the APOE4 Klotho combination, and is that more problematic?
Do they live less long, for example? We’d have to look and see. Is it because the two copies of Klotho are only 2.4% of the population? If the study was not done looking, kind of taking aside the VV or the variants that are the people who are at risk for low Klotho genetically, we can’t really say that those people still had high Klotho with their APOE4. We don’t know which would’ve overridden the other.
Dr. Dale Bredesen: And just we have time for just a couple more here. Arun is asking about, “For blood thinners, we test with PT and INR and dose accordingly when using fish oil, natto or lumbrokinase and pycnogenol. What blood tests can give us dosing guidelines?”
Dr. Sharon Hausman-Cohen: I’m shaking my head about the PT and INR because it won’t really help with these particular variants. I tend to look at fibrinogen levels, especially in the factor II people. There were a couple of different studies showing that the risk of stroke for individuals who had fibrinogen levels over 370 was ten times the risk for those who had it less than 310. So, it’s a tight scale. You’re going to find because of COVID, because COVID really, both COVID and the vaccine, from my experience, have increased fibrinogen levels in people in general that there’s a lot of people with high fibrinogen levels now compared to had we checked in four years ago.
Dr. Dale Bredesen: Yeah, good point. And then we’re running out of time here. You’ve talked before about TOMM40, maybe if you could say a word about that.
Dr. Sharon Hausman-Cohen: Yeah. TOMM40, if you go back to the ReCODE training, I discuss it quite a bit in the online ReCODE training and a little bit on a webinar that you and I did previously. But it stands for the outer mitochondrial membrane. It is a variant that actually doesn’t make you have less TOMM40, but it makes you have an abnormal TOMM40 that allows for the mitochondrial outer membrane to get gunked up essentially. And that is definitely part of the APOE4 story because 75% of APOE4s will have a TOMM40, and that’s just one of the many genes that interact with APOE4. But if you look in the literature, there are parts of Africa where APOE4 does not convey nearly the risk of Alzheimer’s. Well, in that population, they tend not to have Tom40, but in Caucasians, 75% of people with APOE4 will have TOMM40. You’re going to want to really work on mitochondrial membrane repair, not just giving the acetylcysteine and the ALA and the carnitine, but also giving membrane lipids, whether ATP 360 or there are different kinds of membrane lipid products out there, acetylcholine, all of those, phosphatidylserine, that help those membrane lipids.
Dr. Dale Bredesen: Fantastic. All right, Dr. Sharon Hausman-Cohen, thank you so much for your expertise. Thank you for founding IntellxxDNA. Thanks for the great work you’re doing. We look forward to working with you on this currently starting trial and for the future. And I hope a lot of people will get trained in this and hope they will get really great outcomes. Thanks very much.
Dr. Sharon Hausman-Cohen: Thank you for having me. I really appreciate it.
Dr. Dale Bredesen: Great to hear from you, and thanks for the excellent slides. All right, thanks for the great questions, and we’ll see you guys next time.