049-Sharon Hausman-Cohen MD and Carol Bilich: DNA, Genomics and Dementia Risk
Our knowledge of DNA and genomics continues to grow as genetic testing becomes more widespread. Genetic risk for Alzheimer’s disease is no longer limited to the ApoE4 allele. By fully understanding our genetic profile we can better implement prevention strategies with lifestyle and supplements when indicated.
Dr. Sharon Hausman-Cohen, received both her master’s degree and medical degree from Harvard Medical School. She is board-certified in Family Medicine, a Fellow of the American Board of Integrative and Holistic Medicine, and board-certified in Integrative Medicine through the American Board of Physician Specialties. She is Co-Founder and Medical Director of Resilient Health and IntellxxDNA.
Carol Bilich, received both her Bachelor’s and Master’s degrees from the University of Texas and her certification in Business Entrepreneurship from Texas State University. She is co founder and CEO of Resilient Health and IntellxxDNA.
#longevity #wellness #Ketones #lifestylemedicine #younger #ketosis #biohacking #intellxxdna #RobertLufkinMD #rapamycin #metabolic #metabolism #carolbilch #sharonhausmancohen
Thanks again for your support of this video podcast. We appreciate any reviews that you provide which help us to spread the word of the work that we do. As a thanks for your review, we will send you a copy of one of our most popular guest’s book, The Path: Mastering the 9 Pillars of Resilience and Success by Dr Stephen Sideroff (while supplies last). To receive it , just email a screenshot of your review along with your name and US address, and include the title ‘the path’ to email@example.com. We are sorry that we can only ship to US addresses at this time.
***Rapamycin Longevity Registry***
*** CONNECT WITH ROBERT LUFKIN MD ON SOCIAL MEDIA ***
*** MEMBERSHIP ***
*** SPONSORSHIPS & BRANDS ***
We do work with sponsors and brands. If you are interested in working with us for your health industry product or service, please contact us at: https://robertlufkinmd.com/contact
NOTE: This is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have. Never disregard professional medical advice or delay in seeking it because of something you have seen here.
Robert Lufkin MD may at any time and at its sole discretion change or replace the information available on this channel. To the extent permitted by mandatory law, Robert Lufkin MD shall not be liable for any direct, incidental, consequential, indirect or punitive damages arising out of access to or use of any content available on this channel, including viruses, regardless of the accuracy or completeness of any such content.
Disclaimer: We are ambassadors or affiliates for many of the brands we reference on the channel.
Robert Lufkin 0:00
Welcome back to the health longevity Secret show and I’m your host, Dr. Robert bluff, Ken, our knowledge of DNA and genomics continues to grow as genetic testing becomes more widespread. The genetic risk for Alzheimer’s disease is no longer limited to just the APO e4 allele. By fully understanding our genetic profile, we can better implement Alzheimer’s prevention strategies with lifestyle and supplements when indicated. Dr. Sharon Hausman Cohen received both her master’s degree and medical degree from Harvard Medical School. She is board certified in family medicine, a fellow of the American Board of integrative and holistic medicine, and board certified in integrated medicine through the American Board of physician specialties. She is co founder and medical director of resilient health and Intel x DNA. Hero village received both her match bachelor’s and master’s degrees from the University of Texas and her certification in business entrepreneurship from Texas State University. She is co founder and CEO of resilient health and intellects DNA and now, Dr. Sharon Hausman Cohen and Carol billige
Sharon Hausman-Cohen 1:17
Hi, I’m Dr. Sharon Hausman come the medical director of intellects DNA,
Carol Bilich 1:22
and I’m Carol billige, the co founder and CEO of Intellicus. DNA. Intelligence DNA is a genomics interpretation tool designed for physicians, it helps them to create personalized medical plans using a patient’s DNA, and more specifically, their genome. This tool can be used for the prevention and the reversal of chronic illnesses such as Alzheimer’s. Today, we’re going to talk about genomics, the study of an individual’s genome, and how it can be used to guide you and your physician as you work together to prevent or possibly reverse cognitive decline. In addition to Intel, its DNA, Sharon and I have a practice called resilient health. Sharon.
Sharon Hausman-Cohen 2:04
This genomic approach we’re going to talk about today is something we’ve used in our practice as part of our reversal of cognitive decline program. Knowing that prevention and reversal of cognitive decline is an option for you and your loved ones, is one of the most important things that you can get from this summit. In my opinion. The landmark paper you see above was published to show that a system can be developed and replicated across the country and even across the world, utilizing a framework to identify and respond to the many contributing factors of cognitive decline, and that this can lead to improvement and sometimes even reversal of cognitive decline. I in another physician from my office, Dr. And Stephanie, are one of our some of the authors that participated in this study. As we worked with our patients, we use genomics as one of the tools that helped our patients get well. We are proud that Dr. Bredesen and many of the other co authors of this paper have added Intel x DNA genomics to their toolboxes. It’s been an incredible journey leading us to today. And we’re happy to participate in this summit focusing on the prevention of Alzheimer’s. Carol, before I go on to some cases, can you talk more about what genomics is? Sure.
Unknown Speaker 3:22
It’s my pleasure to speak with you today as the prevention of cognitive decline is an important topic. And it’s not just about seniors, changes that may be related to cognitive decline might be noticed as early as age 30, or 40. I actually noticed some small changes in myself in my early 30s. Of course, I had two little kids to boot. But I did start to notice that sometimes I had to really hunt for my keys. How many of you are not into yourself that this is absolutely true. We’re going to pair this topic of cognitive decline with genomics. Many people will say genomics is not yet quite useful for medical decision making, and that it’s still the future of medicine. But we and many of the 1000s of people who have benefited from genomics can assure you it’s very much available and is most certainly the present of medicine. Absolutely. Let’s start by talking about DNA and the genome. You might remember from your high school classes that we each start from a single cell which is created by the fusion of a single sperm and egg. And from that single cell we grow into mature human beings comprise to somewhere around 30 trillion cells, and many hundreds of cell types. Each of these cell types have different functions. For example, some make up your skin. Others make up our intestines, and still others help us absorb nutrients from food. The number of jobs that our cells do is really incredible. Now what does that have to do with our DNA? Our DNA is the instruction manual or recipe book as I like to call it for guiding the process by which we develop from that single cell into a complicated human being with many different cell types. In the picture here, you’ll see a chromosome chromosomes lie within the nucleus of each of our cells. And inside the chromosome lives our DNA, which is organized into genes. In each chromosome, you’ll find about 1000 genes wrapped together in that beautiful package. And your DNA is the recipe collection of everything that makes you you, from your skin color to how your eyes process light, to how our brains think and communicate. These are just some of the recipes that are all within our DNA. You may remember that your DNA is organized into 23 pairs of chromosomes. Everyone has 23 pairs of chromosomes, you get half of them from your mom and the other half from your dad. And your collection of DNA is called your genome. Genomics is the study of an individual’s genome. So essentially, your genome is your code or user manual that allows you to understand how your body runs. This code is very specific to you, and differs from person to person, and even from mother to child. Until recently, we couldn’t understand that code. But with the development of genomics, we can not only see the code, but we’re starting to be able to read it and learn what it needs to function at its best. Let me give you an example of how it works. We all know that if we were to buy a car, and we read in the user manual that it says to use only premium or unleaded fuel, but we put in diesel, that car is not going to work so well. It’s the same thing with your body. With genomics, your user manual, we can learn about you and whether your body needs more vitamin D than typical for optimal brain function, we can find out if you are more prone to clotting or calcification of the arteries, or even if you’re more prone to inflammation in the brain than average. And thanks to the groundbreaking work, during the past 60 years, we can now use this hugely untapped resource of our knee genome to improve our health, from deciding what medications vitamins and supplements might benefit us to learning how we can grow old gracefully with vitality, and hopefully avoiding the chronic diseases such as heart disease, Alzheimer’s strokes, and osteoporotic fractures that we’ve seen happening with our parents as they aged. Let’s talk about what information is stored in your DNA. Your DNA is a polymer made up of four constituent parts. And it acts like your blueprint for all of the molecules that make up your body. Everything that makes you function as a human is in your DNA, it kind of looks like a foreign language or a code. If you were to unravel those chromosomes and look at your DNA, you would see that it’s made up of what are called base pairs. And you might know from computer code that it’s made out of ones and zeros. And you can do amazing things with just those two numbers. But your DNA is made up of four letters A, T, C, and G. These letters they pair off with each other a pairs with T C pairs with G and then these pairs combined together in groups.
Unknown Speaker 8:03
What makes each of us unique are the very slight changes in those groups or DNA sequences. People actually differ from one another by several types of DNA sequence changes. And the most common difference between individuals is created by a very small change called single nucleotide polymorphisms, or snips. Remember those letters we talked about the A, T, C and G that make up your DNA code. But when you change one of those letters, kind of like a typo, you create subtle or sometimes not so subtle changes in that recipe of the gene. Again, think of a snip as a one word change and a recipe. If you change the word stir to blend, it might not make too much of a difference. But if you change bake to broil, it can make a major difference. snips, they determine things that are easy to see, like whether or not you have blue eyes or brown eyes. But they also contribute to factors that are less visible, such as how we enter and interact with the environment. Our snips tell us incredible things like whether or not we’ll be sensitive to certain foods, to chemicals or pollution. It’ll tell us how we will derive nutrition from our food and how we will manage stress. All the different things coded for you by your DNA contribute to your risk of chronic illnesses. And genomics can give better insight into all of them heart disease, macular degeneration, osteoporosis, and Alzheimer’s our topic of today the groundbreaking work to uncover and learn about DNA began in 1953 before I was born, around that time that some of your parents were getting married or maybe others of you were being born. This is when Crick and Watson discovered the DNA helix in 2003. Only 50 years later, the human human genome was sequenced. And that was a huge achievement. The price tag That was a cool $2.7 billion. through the decades, the technologies available to look at DNA have dropped down in price to anywhere from a few $100 to a few $1,000. But it really depends on the technology being used, and what’s being looked at today, in 2021, we’re at the point of uncovering so much information about health, that personalization of medicine, the ability to use your DNA as part of medical decision making is a reality.
Sharon Hausman-Cohen 10:30
It’s really is amazing that if you think about it, because, you know, obviously, nobody would have thought when they sequence the first human genome that in such a short time, we’d be able to have genomic information. You know, it’s not necessarily for everybody, but it’s getting to be such an affordable thing that you can use as a decision, right? I think for us, really, I find so amazing it is.
Unknown Speaker 10:55
So with that short timeline, and the major series of events that have led us to be here with you today, we’re going to talk about root cause medicine, or genomic medicine as I like to talk about it. So let’s talk about the topic of how genomics helps us to get to those root causes of cognitive decline. One really important factor in understanding all chronic illnesses, including cognitive decline, is that it’s not due to having one gene being disrupted. Chronic disease are always multifactorial ride sharing, I
Sharon Hausman-Cohen 11:27
think that is a really huge, huge important factor, because so many people go, Oh, my gosh, I looked and I saw I have the gene for diabetes, or I’ve got the gene for heart disease, or in the case of cognition, they’ll say, I’ve got the gene for Alzheimer’s. And one of the really things we want to dig into in this talk is help you understand there is no one gene. Chronic diseases are combinations of slight changes in the DNA that have combinatorial effects. So when we’re talking about the brain, for example, you know, I think sometimes when I explain things, it’s a little too sciency. But you continue, I think you do a great job of explaining things.
Unknown Speaker 12:05
Okay, so let’s talk about how those combinations of factors work to make the changes in our health. So for instance, with cognitive decline, we know that mitochondria play a big role or getting oxygen to the brain. What are some others? Yeah,
Sharon Hausman-Cohen 12:21
so and we’re gonna talk more about mitochondria, they’re kind of the energy source, the nerves can degenerate, sort of, if you think about when things get old, like plastic gets old or anything in our house gets old, you know, we have to go replace it. But our nerves are supposed to have the ability, our body has certain regenerative abilities, but some people have more disabilities, some people have more tendencies to have amyloid, which is this gunk that can build up in the outside of the nerves build up more in some than others inflammation, you talked about hormones, things like estrogen, testosterone can be really important. You mentioned vitamins already. And there’s a whole lot of them. I mean, there’s B six, there’s, which is needed for a lot of the brain chemicals and neurotransmitters, there’s b 12, zinc, and magnesium and some of the minerals, there’s just so many things, even your gut and gut inflammation can be a big source.
Unknown Speaker 13:13
So all of these things provide us with input regarding cognition. So before I turn it over to Sharon, I want to put the incidence of cognitive decline in perspective for you. During the past year with the COVID pandemic, approximately 30 million individuals in the US have been affected. If it had only been half that number. Would we still have called it a pandemic? Yeah, I 16 million 60 million. So with 16 million people affected by cognitive impairment, what do you also think of that as a pandemic? I do? Absolutely. How many people do you know that have gotten COVID? Last year? How many people told you that they are others they knew got COVID? How many loved ones 1020 30 people. Yet? How many people told you in the same year that they have cognitive decline? Or that they noticed their memories just not working? So well? Probably not too many. Why? Because they’re embarrassed, I would imagine. But some don’t realize that there’s something they can do about it. But what if there is a way to reverse this decline and help individuals and their families? What if the memory problems could be prevented in the first place? Or reversed if we identified them early on, Sharon, and I believe that in many cases, even in most cases, that with early awareness and early action they can
Sharon Hausman-Cohen 14:38
and the reason we believe this is because it’s something that we have been doing for and with our patients in our practice. But additionally, hundreds of clinicians across the country have been using this approach of root cause medicine, often with genomics, to look at an individual identify these factors and improve their care. admission for both the prevention and reversal of cognitive decline. Now, we are going to do some prevention cases. But the first case I want to talk to you about is a really exciting case, because it’s both a case of reversal and prevention. So this is Mackay. And of course, all the patient’s names have been changed and identities protected. But Mackey is a 61 year old homemaker who has a college degree, she comes in with her husband, because she’s been noticing memory problems over the past few years. So that’s that means she started in her 50s. And it’s worse over the past 18 months. She isn’t AP four, four. And she knows this, because she actually had a family history of cognitive decline and enrolled initially in a trial, which she dropped out of to come work with us. So she found out she was the AP for four had another gene that we’ll talk about later called the MTHFR. And she even had a PET scan, and it showed that she was positive for amyloid, which is basically a testing Yes, you have early Alzheimer’s. And she had an MRI in her brain of her brain that showed some white matter changes. And that’s kind of where you lose a little bit of the coding on the outside of the brain. And it’s kind of like little small strokes for lack of oxygen. So that’s not good either. And that can be associated with things like worsening memory, and even urinary frequency at night. So all kinds of changes that we see in the elderly, she had a couple of different tests for her cognition ones called California verbal learning, which depending on the part of the test, she was in the 25th to 63rd percentile. And you might go well 25th percentile 63rd, that’s not so bad. But remember, this is a college educated woman. So for her to be in the 25th percentile, that is abnormal for verbal learning. And so and then slumps, which is a more tests on a lot of different pathways. I’m going to show you an example of a slump test, she got a score 21. And this is on the range from zero to 30. Where you know, a score of one is you don’t even know what city you’re in or your name or anything like that, you get points for that, and 27, or more as normal, and 21. And below is dementia. So she’s on this borderline between dementia and normal. So that is obviously quite quite concerning to her. She did not have any exposures to anything like mold or toxins that she knows of that would have contributed to this. She does have a family history for cognitive decline, which is not surprising because we already said she’s an AP for for her mom developed Alzheimer’s, and Parkinson’s in her 60s. So again, another reason why Mackey wants to be so proactive. And she also had a maternal aunt with Alzheimer’s in her 70s. Her dad has heart disease, which started it’s 50 in his 50s. She is noticing and her husband’s noticing some decline in her father. But he has not yet been diagnosed with actual Alzheimer’s. We mentioned the slump test. Borderline dementia is you still many people with slumps at 21. They’re still driving, they can do a good job of faking things. But it’s kind of like you ask them to draw a clock. And this clock, they were asked to draw at 10 minutes to 10 minutes after 11. And you go okay, well, they’re in the general vicinity, but you can see the spacing of the numbers is off. So that’s kind of the typical kind of mistake they might make. If you ask them to name as many animals as they can in one minute, they might only get to five or six, because they’re just having trouble kind of collecting that memory pathway. So we did her slumps. And again, that’s pretty significant for 61. And so then we dug into her DNA, we’d like to say the answers are in the code. The DNA is your code of view. And if you can look at someone’s genomics, you can find things that are modifiable. And that’s why we go looking in the first place. So of course, we already knew that Mackay is an AP for four. But for many of you, you might have heard that term of AP four. And you might be like, Well, why is that one gene such a big deal, right? And it is a big deal. Each copy of a billy four is a significant one copy increases the risk of Alzheimer’s on average, because it’s not for an individual but on average about three and a half times. And if you have two copies, you can have approximately 12 times the risk. So yeah, so he’s at high risk. But the reason she’s so high risk is genes talk to each other. And AV four is one of those genes that goes and talks to over 1700 other genes. And so that’s incredible. Yeah, it there’s these things called promoters and think of them as kind of the on off switch for your genes. And a billy binds to the 1700 promoters turning on and off things throughout our genome that relate to inflammation in the brain that relate to how you have a processing that sugar as an energy source and lots and lots and lots of other things. So growth factors that
Unknown Speaker 20:00
AP for gene is actually talking to these other genes saying do this and do that.
Sharon Hausman-Cohen 20:05
Well, the AP for gene would code for the AP for protein, which is a lipid protein, which just means a fatty protein, a lipid carrying protein. But yes, that lipo lipo protein goes and binds on the gene kind of like the little assembly line and says, I’m going to turn on this gene, I’m going to turn on that gene. Wow. So those kinds of genes that regulate each other, tend to have bigger effects. Estrogen is one of those genes that can with its its receptor, go into the nucleus and turn on and off other genes. Wow, vitamin D does that. So there’s a lot of these ones, that she had some other genes, she had tons of other genes. So again, most people don’t start to have Alzheimer’s due to HIV for if they’re going to have it until late 60s At the earliest and more often seven days, maybe even early eight. So this was
Unknown Speaker 20:52
pretty early for her really early.
Sharon Hausman-Cohen 20:53
So one thing that was really remarkable about her is she had all these detox genes. There are in fact, a couple of these pathways and glutathione. Don’t worry about the names of things, you guys. But glutathione is this molecule that we make kind of I call it the ultimate quicker picker upper like a paper towel. It picks up all these toxins and helps you carry them out via glutathione transferases, via the urine via your stool via your sweat. And we’ve got about five of these major glutathione transferases, two of hers were completely missing. We call it a
Unknown Speaker 21:27
null so that she didn’t have any garbage collectors. She
Sharon Hausman-Cohen 21:30
didn’t have the garbage collectors. And you know, we think of toxins is like something that 21st century word because we’re like, What do you mean by toxins? Why would we even genetically have these, but before there were pesticides and mercury and all the toxins our body has to clear now, even in the foods we eat, even in basil, for example, there are parts of plants that aren’t good for us that we have to remove. So our detox pathways are designed to remove things that aren’t good for us. The problem is if you have parts of these detox pathways missing, and now you live in a world full, you know, it’s full of all these chemicals and petrified mercury and all this, you can overwhelm those detox pathways. So that was a really big issue for her. And in fact, when you combine this gstn know that missing gene, right with a buoy for four, it’s been shown to give five times the risk of Alzheimer’s. So she has a tremendous risk then, right, so we knew we had to address her detox. There’s also another transporter detox pathway that helps you take the toxins in your brain and kind of kick them out kind of like a bouncer at the bar. And she had this bouncer essentially was affected. And so she couldn’t remove toxins well from her brain. So we knew we had to address that. She also had quite a few things going on with her gut. So it’s sometimes it’s fashionable to go, Oh, I think I need a gluten free diet. And some people do, and some people don’t. And it depends on your genetics. But for Mackey, she really did. She had a couple of genes that made her hold on to gluten and show it to her immune system is a foreign invader, with a lot more affinity than typical, that gave her 13 times the risk of celiac disease. Yeah. And that also can contribute to brain fog, even if you don’t have full celiac. And so she didn’t have classic celiac with a gastroenterologist would have tested her, they would say no, you don’t have celiac. But if you really dig into those studies, gluten can be a cause of brain fog and individual who’s in individuals who have these different genetic contributing factors, right, so we got her on a gluten free diet. Now the next one she had is a little more complicated to understand, but it’s a pathway called nos three or nitric oxide synthase. The best way to think about is, we don’t want our blood vessels clamped down really tightly. We want them to be able to open and relax and deliver blood flow. It’s important for your heart. It’s important for your brain. It’s important for other parts of your body guy in particular. And she had problems where she clamped down too tightly. And remember I said on her MRI, she had those little white matter changes. So those white matter changes are classic in people who have problems with two copies of NLS. Three, they have about four times the risk of having that. So we also knew we had to get more blood flow to her brain. And so one of the ways that we did that was we gave her Pycnogenol and Pycnogenol it comes from pine bark, right and it’s been shown to improve cognitive function. Partially because it increases blood flow, your brain works better with more blood. So we did that and Pycnogenol can increase nitric oxide and lower oxidative stress. So Pycnogenol has been shown to improve cognitive function because it helps to kind of open up those blood flow the blood vessels and get more blood flow. And oxygen is really good for the brain. That’s one I take Yeah, it’s it’s good for a lot of different reasons. And we always use supplements that relate to whatever topic we’re talking about. So we wouldn’t use Pycnogenol in her. If the studies were only for people who had erectile dysfunction, that wouldn’t make sense no. So, but nos three can relate to cardiac disease, it can relate to, again, sexual function, EQ can relate to brain function, and Pycnogenol has good benefits. But beets and leafy greens also increase nitric oxide. So my favorites Yeah, and so we always also with our patients, work with their genomics to help let them know foods that would be better for them. Now, another factor that Mackay had was a bunch of mitochondrial issues, and mitochondria, the kind of classic phrase for them is that they’re the powerhouse of the cell. And if you think about energy sources, you wouldn’t want a shoddy energy source for your home. So if you have a really important computer that controls everything at your office or in your home, you don’t want a bad electric supply. Well, food is not a great energy source for us as individuals, because you might go into starvation mode and not be able to find anything to eat evolutionarily. At night, we don’t have food, hopefully. So mitochondria take oxygen, they take some of the nutrients in our body, and they convert them to extra energy for our nerves in our brain. So if you have good mitochondria, that’s good for your brain function. And if you don’t, it’s not great. She had a lot of problems with getting the things her mitochondria need into the mitochondria, which put her at risk for bad mitochondrial function. That becomes really important and a force because they don’t use sugar well as a brain energy source. So the combination of mitochondrial disease and empathy for is not only part of her history of Alzheimer’s in her family, but mitochondria are also really important for Parkinson’s.
Unknown Speaker 26:56
So the powerhouse of the cell, that’s the mitochondria, hers weren’t getting what they needed to be as effective as she needed them to be to function for her brain,
Sharon Hausman-Cohen 27:06
right. So you have these little pores in the outside of the mitochondria that let the CO Q 10 and the Alpha Lipoic Acid and all the nutrients that mitochondria need inside. And her pores in her outer mitochondrial membrane weren’t working well. So that was an issue. She also had other mitochondrial problems. She also had a bunch of nutrigenomics snips, snips relating to choline and vitamin D and other nutrients. So we looked at all those things. And we gave her a protocol. And this may look like a lot, and it is, but she’s a four, four. So we had to be aggressive. If we gave her Oh, start on this, I want you to exercise and I want you to even you know, cut down your sugar in your diet and just try two or three things. There’s no way we
Unknown Speaker 27:46
would have gotten sure she was motivated because she was in that study in you know, looking for solutions, right? And so
Sharon Hausman-Cohen 27:53
she was very compliant. So we started her on quite a long protocol. As you can see, mild ketogenic diet, we had our work with our dietician, because the ketogenic diet helps those mitochondria come back, but it also gives her an energy source for her brain that’s different than sugar, intense exercise, right? Good for growth factors, a bunch of different supplements and nutrients. And then we basically said, let’s try this for a few months and then circle back. Okay, so then she didn’t circle back in terms of being retested for cognition till six months later. So I’m going to jump ahead six months, we usually, we usually give people four to six months before we retest their cognition is we don’t want them to get worried, you know that, you know, it sometimes takes a few months. And so six months later, in December of 2019, we retested her and she got four points and that, yeah, that’s real big difference, because it meant that her husband was saying she wasn’t asking the same questions over and over many people who if you have a relative with Alzheimer’s, sometimes it can be tiring that they ask the same question. Where are we going today? Or what is this for things like that. She was able to do the household chores, go grocery shopping, keep a grocery list, and it was really much improved. We did some tweaks. And again, this is actually not my patient. This is one of my colleagues in my office is patient and I purposely wanted to choose a patient that’s not mine, so that you can see that it doesn’t have to be me doing the genomics. This is again, a colleague. And so a couple tweaks were made. Every time a patient comes back, we tend to go a little deeper into genomics, kind of like layers, like you would be peeling an onion. And we looked at her brain ischemia pathway, which is a fancy word for stroke, and found that she had some genes that can increase her stroke risk and a fib, atrial fibrillation, and that for that particular gene, it was better to use something called DPA, which is a different kind of fish oil, as opposed to just EPA and so we and other omega threes so as you add it, or did you switch it, we just switched it because he was on an Omega three We also because we really kind of every time we open up for genomics for a detox pathway, it’s like just completely red. So we said, are you willing to try intranasal glutathione, to get more to the brain than just kind of a sublingual? And she was, and we even switched the type of coke you tend that she was on. Because we looked back at her genomics and thought that would give some added benefit. So let me we ended up being giving her some estrogen replacement as well. Again, let me kind of show you, we’ll circle back to the genomics because people can only take in so much information at first. Sure. And she had a gene that related to the recycling of CO q 10, into his active form. So he said, You know what, let’s even go to a little higher CO q 10. Level, and let’s switch to this one that is even a little bit stronger, essentially, doesn’t need to be recycled. So six months later, so she would have followed up in three months, but then COVID hit. So I’m sure many of you guys had people, you know, had times where you didn’t do everything you planned on doing in the middle of March, April 2020. So in July 2020, she came back and it had now been 17 months of treatment. And her physician redid the slums. And you might say, well, she might learn the slumps. But if you have dementia, and you can remember a test you took 17 months ago, good for you. Got a perfect score on it. And there are other tests that you can use where there’s different versions, but in this case, we’ve done slumps. She’s got a perfect score. That’s just wonderful. Yeah. So that was really exciting. This is a case I presented to Dr. Bredesen, when we were doing a town hall meeting together. And one of the things he commented on is she got a perfect score. But then we told her that during COVID, we had added some more inflammatory genetics to the panel, because people were asking us about, do we know, you know, which genes affect lung inflammation, and we started told her just add more inflammatory genomics. And she, of course, wanted to look at them. And she’s like, What we discovered is she had too much TNF alpha. And anything alpha is like Alpha Dog, alpha male, and that can affect your brain with inflammation. And she’s like, well, give me something for that, too. And so we wanted to keep going, yeah, she wanted to keep going. And we’re going to talk about Lion’s Mane with another case, so I won’t go too into it. And then we also added something called resolve. And she was like, just keep going, because for her, she was like, I love feeling better. I love having my brain back. And so that was really important.
And inflammation, huge contributor to Alzheimer’s, not surprising. The last slide I’m going to show you about her is really a fun one, she came back three months later, because in our practice, we do tend to see people every three months, if not sooner. And again, she saw my partner, and I looked at the note is I was preparing for this. And there was under cognition, there was no need to discuss, I’m doing great. And so it really was Yeah, it really was great. She did get a little blip, of doing worse right after her COVID vaccine. And I don’t think that that’s a coincidence. But again, she’s doing well now. So it was good. It we’re gonna have to always that was just a reminder that when she gets things that create more inflammation, she’s gonna have to be careful. And we just kind of upped things for older. That’s great for her to know. Yeah. So the next case, you’re gonna do it wonder another case? Yeah, let’s do it anyway. So this one’s really different. As we said at the beginning, I’m sure there’s many of you watching that are equally force. But there are probably also many of you at this summit that want to prevent cognitive decline that don’t have an AP for an AP threes are amongst my favorite reason to use genomics, and we use it for all of our cognition patients, but it’s so fulfilling to use it with an APR three, because there’s so many things that can contribute to cognitive decline. And if you can identify them, you can come up with a much smaller preventive strategy or a smaller protocol. So this is Rachel. And again, her name has been changed. She came to us at age 48. And she is a professor so she uses her brain for a living. She came in saying that she wanted preventive measures her blood sugar was a little high, things like that. But as we started talking, she talked about that she was having some mild word finding difficulties. She also mentioned that she tended to feel stressed and anxious with frequent migraines. She has a family history of what she was calling Alzheimer’s at first. But really, it sounds more vascular because she has a father with heart disease starting in his 50s. And she is starting to notice worsening cognition and her father who was at this point in his late 70s. So what do you do when you say there’s not the classic risk factors you dig into the genomics? And Rachel had two genes that increased the risk of both Alzheimer’s 2.5 times the risk when in combination, but 3.7 times the risk of vascular dementia. Wow. So vascular dementia means its effect if you have heart disease, diabetes, stroke risk factors, and the blood vessels aren’t in as good of shape, or even high homocysteine, those are all vascular risk factors, you can have worse blood flow to the brain and again, worse cognitive problems. And so these two genes, the first one is MTHFR. And the second one is il six. So MTHFR, it stands for methyl tetrahydrofolate reductase. Or some people thought it stood for Mother Father, some people thought it stands for, you know, other things. But what it really is, is this, the ability to take one of your B vitamins, folic acid, get it into a form that the brain can use. And this is so important because the brain uses this enzyme to make not only norepinephrine, which you need for attention and focus, but also acetylcholine, which is that big memory neurotransmitter. So there’s a lot of things that the brain uses MTHFR for really, really easy snips to overcome, it’s kind of one of those pop snips, but it’s in like 45% of the population. So it’s, it’s important to address because it does do a lot of things. But it’s not the only reason. I’ll fix it in about 20% of the population. And il stands for interleukin and just think of it as inflammatory, and it relates to brain inflammation. And there’s a lot of ways that you can lower il six, and Rachel we ended up choosing a combination of sulforaphane, which comes from three, the old broccoli sprouts, and curcumin, and we use the form of curcumin that can actively get into the brain, but also the joints to she have a little bit of crankiness.
Now she also had another combination of snips that is pretty rare. It’s only found in 4% of the population. And when we start with genomics, we actually look through their 600 Different snips that we’re looking at are 700 snips, and we look for these ones that are only in 4%, or 5% or 10% of the population, because those are sometimes the most important clues. And this was a really important growth factor. That was very important to Rachel’s success. Because when you have this combination, even if you only have one copy of this combination of three BDNF snips, you have 2.7 times the risk of Alzheimer’s, it’s a lot. And then if you have two copies of it is presumably higher than that, because but because it was only 4% of the population, we don’t even know exactly a number, but it’s getting up there with a bogey. So that was really important. Think of it is if you have a plant, and you don’t fertilize the plant, or you don’t give a water, it’s not going to grow well. So that’s what kind of a growth factor does is it keeps the young neurons growing so that the Connect, your memory Center has to constantly make new connections, because you don’t want the memories only of when you’re 10. And so for her to not be able to kind of remodel and establish new little neurites new little outgrowths was important. How do you deal with BDNF because we know it’s associated with Alzheimer’s? Well, not everything is a drug. One of the things that increases BDNF most effectively is high intensity exercise. And when I talked to Rachel, she wasn’t against exercise. She definitely liked to run and exercise. But what I found is she put her work above her exercise. And, you know, it’s like if she had papers to grade, if she had a talk, she was going to be giving a reading traveling. So she wasn’t consistent them. Yeah. And so just telling her that you have to go and tell your department chairman, that you’re there a lot of times late, you’re doing all these other things that you are coming in late at least two days a week and then adding exercise on the weekends. And then there are also some supplements and some dietary things we gave her that can increase BDNF. Now, I don’t want to go through all of Rachel’s genomics, because I think we have one other really important topic to talk to about sure, as well. But I just want to say so we went through her genomics. And the list really wasn’t that that long, it was really that BDNF and the MTHFR, interleukin six, and then some choline, which was easy to do with a combination of diet and supplements, addressing her estrogen pathways for B 12 pathways, she didn’t transport B 12. well into her brain. That’s a big deal because you could have normal B 12 levels in the blood and still not be getting enough. And then her thyroid, her blood levels were okay. But it was similar to with her be 12 Where she wasn’t able to convert thyroid hormone into the active form in her brain. So we just kind of tweaked some of these little things. She kind of said I’m willing to take things but can we keep it to one one little pill box that I can do all at once at night. And we were able to do that. So how did she do? She did really really well. She is still a patient at our practice and she said I always check in with her when we’re doing everything else. And she said her cognition has remained Got back to baseline remained at baseline. She doesn’t have a problem teaching. She’s not having to do work arounds when she is coming up with words for lectures or talking to people. She’s involved in research. And the bonus was one of the things we gave her because she wasn’t good at clearing amyloid was something called ashwagandha. Oh, yeah. And yeah, I love ashwagandha. Ashwagandha helps lower cortisol. And she also has some pathways that made her have higher cortisol that contributed to her anxiety, and even that thyroid issue contributes to anxiety. So she said her anxiety and her sleep are better as well. Really great. Yeah. So, you know, you and I have always talked about, there’s a lot of direct to consumer products. And now there are so many people who know their genetics, right. And they know that they’re an ape boy for. And I think we should use the last part of this talk to talk about why you and I both very much believed, knowing APA four is kind of like too much or not enough that you’re looking at it right.
Unknown Speaker 41:03
So for the last section of our presentation, I want to focus on that and extremely important discussion about the APA for status. So many of you who are watching this presentation likely have innate belief for gene variant. If this is all you know about your genomics, it really isn’t enough information. And that’s because it’s enough to scare you. But it’s not enough to help you make great decisions about supporting your brain health. So for some of you preventing cognitive decline may be very simple like it was for Rachael, but for others, there may be extra steps. And how do I know this, because I’ve seen the genomics of a lot of people with a belief for statuses. And Sharon and I are going to show you what we mean as we discuss the final few cases of this presentation. But for the last part of this talk, let’s circle back for a moment to prevention, prevention, especially for a belief for individuals, you’ll soon understand that knowing much more than a belief for status has helped clinicians and patients throughout the US to create optimal and highly individualized prevention plans. Sharon and I have a practice together. We call it resilient health, where we as a team take care of many patients with concerns of preventing cognitive decline. And I want you to meet two of our patients, Sandra and Martha. They both have an A belief or gene variant. But what’s really surprising is that Martha has two copies of a belief for making her ably status four, four, and she came to our practice without any noticeable cognitive decline. She didn’t even know she had a belief or variant. She didn’t even know what an add for variant was. She doesn’t have a strong family history of cognitive decline. So she wasn’t even really worried about it. But if she had only known or her physician had only known about her a belief or status, and not all the information that we’re about to show them, how do you think that physician would have counseled her 10 years ago, or even today, because the medical literature will say that a belief for for individuals have up to 12 times the risk of Alzheimer’s, which is what we talked about earlier on. And I think that we would all say that’s pretty scary news. But Martha is doing so incredibly well. And what we need to know next is why and how can we keep her that way. And then we’ve got Sandra, and she’s got one copy of a belief for and generally speaking, folks with only one copy, don’t start to have any signs of cognitive impairment until they’re at least in their mid 60s. And
Sharon Hausman-Cohen 43:31
usually, actually, again, as I said, you think that’s a definition of what’s called late onset Alzheimer’s, which is what a boy for contributes to is Alzheimer’s after age 65, but more typicals in their 70s or even later,
Unknown Speaker 43:43
because she was 52. I’m I know that because she was our patient that we did that testing. Yeah, we actually
Sharon Hausman-Cohen 43:49
sent her for formal testing for early onset Alzheimer’s to make sure that she didn’t have some of those genes, the HPP and pre Centrelink related genes, which if you have heard of those great If not, don’t worry about it. But yeah, we were worried. I have early, all
Unknown Speaker 44:04
right, and she didn’t have those genes. So we’re wondering why Sandy starting to have problems. So early. Well, Martha at 77, is doing incredibly well.
Sharon Hausman-Cohen 44:13
And I think this is a great example. And so what do we need to know in addition to a boy four status is what this is really about. So
Unknown Speaker 44:20
what’s important to know, in addition to a billy status, well, there are a few other genes on the same chromosomes that can dramatically affect risk. Some of this other genes that are useful for a belief for individuals to know about relate to the ability to clear amyloid beta. That is the stuff that builds up in the brains and contributes to the plaques and tangles found in the brains of individuals with Alzheimer’s. Other genes relate to mitochondrial health, like we talked about, and again, mitochondria are the backup power source that’s crucial for optimal brain function. Remember when we talked about that mitochondrial function in the case of Mackey right, and still There are other genes on the chromosome and when found along with a belief, or they cause additive problems with memory due to that brain inflammation. But there’s one more category on that slide, Colin esterase. So let’s take a look at that particular gene butyl, Colin esterase gene, or B, ch, E. So B, CH e normally helps to suppress amyloid beta strands. You
Sharon Hausman-Cohen 45:25
might wonder why I’m having Carol explain this. Because I did a practice round for some people. And they were like cheering, we have no idea what you just explained. And so we decide to have Carol explain the science, because I’m great at explaining it to physicians, but it doesn’t come out of English.
Unknown Speaker 45:43
So I’ll try my best here. So going back to that BCA Qi gene, we know that that helps to suppress amyloid beta strands from joining together to form those fiber like structures that gunk up the brain, that’s the technical term gunk up. So people with the BCG snips are less effective at blocking the accumulation of those amyloid beta fibers or fibrils. And just in case you skipped medical school and haven’t looked at any brain tissue under a microscope recently, I’ll walk you through this picture. On the left side, where you see letters A and D, those are slides of brain tissue from the normal brain, a and a and a and d. And those are the same brain. But in the D, the brain tissue has been treated to remove some of the water and fat so we can better see those purple specks, which are the nerve cells. The slide C and F are from the brain of a person with Alzheimer’s, and the same treatment was done on that slide F. So you’ll notice less of those healthy purple nerve cells and C and F compared to those that A and D. Now focus in on the red spots of C and the purple meatball shape tangles on F. Those are the amyloid fiber tangles that build up in brains that are sick with Alzheimer’s. And these tangles chunk off the ability for nerves to send signals to each other. So people with this BCA T variant have less ability to block that formation of those purple tangles. Now a good question to ask yourself is this one, how does the presence or absence of this gene affect the likelihood of getting Alzheimer’s?
Sharon Hausman-Cohen 47:21
Well, this is really exciting because it didn’t come out till 2017. So this is a really cool slide to share
Unknown Speaker 47:26
on this graph, you’re going to notice four colored lines and staying close to the top of the graph means you have less of a likelihood of getting Alzheimer’s, you’ll notice that most of those four colors are clumped pretty close together for people in their 50s. And in even into the early 60s. But by age 65, that red line is starting to separate and be lower meaning there is a higher rate of Alzheimer’s in that group compared to other groups. Now focus in on an interval from 70 to 85. When most people with Alzheimer’s develop symptoms, you’ll see it appears to be best to be in the blue or black group. These are individuals who have zero copies of the AV 4g Gene, then take a look at the difference between the yellow and red lines. Clearly the red line is significantly lower than the yellow line and it drops down very quickly by age 80. The yellow line represents individuals with an equally for snip, but who have no BCA CI, the red line represents individuals with snips in both a Billy and BCG. So by age 85 75% of the people who carry both of those genes have Alzheimer’s, but only about 37% of those individuals who have a belief or alone have Alzheimer’s. Martha is one of those lucky a belief were carriers without a BCG snip, she 77 She’s going strong and has an incredibly wonderful normal memory test. So why does your doctor need to know about all these other gene variants? I think it’s because having as much information about you in front of them as they can, will help them to create a truly unique plan for prevention or reversal of cognitive impairment that’s tailored just for you. Just like in Goldilocks and the Three Bears. You don’t want to plan it’s too big or too little. You want one tailored. That’s just right. Sharon, can you tell us a little bit about Sandy?
Sharon Hausman-Cohen 49:30
Yeah, I’m gonna go through these two cases you just mentioned really quickly, just to kind of show you just to kind of highlight what you said, because you’ve really done a great job of explaining it. So Sandy was this engineer, she came to us with cognitive decline at 52. And she was finding that even doing math was difficult for her. He was thinking of actually trying to find a different job. And so her slump test wasn’t bad. It was 24 which is not dementia 24 for an engineer that’s kind of in the middle of mild cognitive impairment, that is a big deal. And it was very noticeable for her. So what we did is we got her genomics and she had many dozens of snips that were important. But there were a couple that I thought I should highlight, because they were really ones that I think were paramount to address. One, she had a mitochondrial snip. It was different than the one that Mackay had. But it was a snip that made it difficult for her mitochondria to reproduce, to make their own DNA and make everything they needed. And that is nothing you could have guessed, it’s in about 10% of the population, you have to give more of things like folinic acid and betchain, and choline. And without it, your mitochondria just become, you know, lack of fun, have lack of function, and then your brain can’t, can’t make those synapses. Now. She also had TNF alpha, which we mentioned a little bit before, right as that really important inflammatory mediator that alphadog. And that causes so much higher levels of brain inflammation. But it’s really problematic when it’s combined with a boy forks, it has an additive effect. So kind of like we talked about MTHFR R and interleukin six in Rachel. So in one study that was done, and nobody’s repeated this study, because it’s hard to find enough people who have both because they’re not that common. Right. It was shown if you have both this an APB for that you had over six times the risk of Alzheimer’s. So that was
Unknown Speaker 51:30
a big deal. And how does that TNF alpha snip affect those purple meatballs?
Sharon Hausman-Cohen 51:35
Yeah, good question. So high levels of TNF alpha, make it so that you have difficult processing that amyloid those purple meatballs are the amyloid, so then you get more of those amyloid tangles, which lead to kind of that gunking up that you mentioned, which causes the nerve cell loss and nerve death. It’s kind of crowds them out. And just it’s it’s just all this extra junk there. So it is absolutely affecting it, not only because you have more inflammation in the brain, but also it leads to more amyloid and gunking up with the brain. So what do you do for that? Well, that’s a great question. And there’s a lot of the prescription TNF alpha drugs are injectables, and they don’t cross the blood brain barrier. So they’re, they’re used for things like rheumatoid arthritis and autoimmune disease. But you can’t just go give a injection into the spinal cord every three days for
Unknown Speaker 52:27
for that probably not.
Sharon Hausman-Cohen 52:28
So this came out of studies in Japan, there’s this beautiful mushroom called the Lion’s Mane mushroom. And these Lion’s Mane mushrooms, create nerve growth factors and lower TNF alpha. So they not only help lower the inflammation in the brain by lowering TNF alpha, but they actually help repair the nerves that were damaged. And so this, it’s been shown to reduce that amyloid burden, reduce the number of plaques and animal models, you have to cut open the brain to see the plaque. So they don’t that study was animals. Humans don’t volunteer for studies where you have to do biopsies of the brain. And in even affects things like insulin degradation and affecting blood sugar. So there’s a lot of great things. It even affects anxiety and depression. Because when you’re growing more nerves in the brain and getting rid of inflammation, it does a lot of great things. And so the some of the nerve growth factors can go up more than 100%. This is a one of the studies that was done in Japan. And it was done with 58 year old 80 year old seniors who were like Sandy, they had mild cognitive impairment, they got Lion’s Mane mushroom 500 milligrams three times a week. And that the it was a 16 week study. And at the end of it, and it kind of slowly went up with improvement because you can’t grow nerves overnight. I just had a patient this week who said, I tried it for three weeks, I don’t think it helps. So I stopped. But she was only taking one pill. And you really need, you know, quitting material day and time. But what you’ll see is that the end of 16 weeks, 72% of the people went up on their score on there. This is a Japanese version equivalent to mocha by, but it’s still a 30 point scale, three points or more. That’s huge. And it’s really in the placebo group, only 7% of what three went up three points or more. And then another 21% went to increase by two points or more. So you get 93% of individuals in the study, not even looking at their genomics had improved cognition. So that was a really important crucial thing for her. And then we addressed other risk factors as well. We addressed her homocysteine and her thyroid and all these other snips. And Sandy’s had a pretty big plan. Because she was again already having cognitive impairment. 52. Right. But she’s doing great. Wonderful.
Unknown Speaker 54:53
And what about Martha?
Sharon Hausman-Cohen 54:54
So Martha is also doing really well. As we said Martha was doing well even when She came with to us, she came to us not really saying that she had cognitive impairment, she had high blood pressure, and a little bit of high cholesterol, and just wanted to optimize your health and was having a little bit of nerve type symptoms in her legs, numbness and tingling and a little bit of fatigue. I didn’t know her genetics. So I did put her on a mitochondrial supplement because nerve, things like that are often mitochondrial and senior that she was very curious about her genomics, right. So we did it. And when her genomics came back, we were shocked to find out she was a boy for four. And in fact, I didn’t test her cognition. Yet, because we all think of AP four fours is these people that buy 60s really can’t think straight. And she is very, very, very clear. So I tested her now at this point, she was already on a mitochondrial supplement and vitamin D, because she was having some symptoms that were suggestive again, and mitochondrial issues to me and some bone pain and wasn’t on vitamin D. But with those two simple interventions, she scored 28 out of 30. That’s great. That’s 77. So that’s great. She was doing things that really contributed to her health, it just out of
Unknown Speaker 56:11
her own doing whatever I’m doing. Yeah,
Sharon Hausman-Cohen 56:13
she’s a healthy person, she walks for a minimum of three miles every day. And we know that that affects growth factors. And so that’s good for her. In fact, it’s real fun that, that she and her daughter kind of refer to it, her daughter refers to it as I’m going to go walk mom as if she would they walk every day. And so that was good for her. But it’s not just about the walking. The point that I wanted to make is Martha is doing a lot better as an AP for four than Sandy was doing without our help as a three, four. Because when you look at the like top 10 variants that we look at a variant is another word for a snip, that contribute to cognitive decline. She didn’t have those BCG variants. She didn’t have the choline problems. And choline is real important. She’s another TNF alpha problems are the inflammation problems. So this is really important. But she also even had benefits that helped her clear amyloid. I think the bottom line here is don’t get scared. If you’re trying to have a preventive plan for keeping your brain healthy, good for you. We all want that. I want that you want that I want that. But get as much information as you can so that you can look at the whole puzzle, or you might over or under treat or choose the wrong things. And so the X information is just really powerful. Martha’s plan was really pretty simple. Sandy’s was a little more complicated, even though Sandy was the younger, the two, right, but the important thing was they both had the knowledge to understand themselves, so that they could do well. And that was really the bottom line is that they both wanted to be able to expect to live a long and fulfilling life with a good lifespan, but also a good health span, one arm into the retirement years. And that’s really what genomics is about. Because it’s you know, a lot of people again, they get these long lists of snips, and they’re like, Oh, look at all these snips I have and I’m like, What are we gonna do with that, because you can’t just look at snips, you have to understand what the gene does. And what you’re going to do about it. Genomics is like any other lab test, in medical school, we’re taught don’t order a test unless you know what you’re going to do with the results. And that’s why Carol and I created, along with the help of our wonderful team, Intel x DNA is because we felt like there wasn’t a genomics tool that gave us that information as clinicians. So the goal of genomics no matter what tool you use, is you need a tool that’s going to help you to identify the snips and variants that you have, but also help you or help your clinician know how to address these snips. Our tool was designed to be used by functional and integrative medicine trained clinicians in particular. And so it’s only available through trained clinicians.
Unknown Speaker 59:12
Understanding genomics is a lot like learning a whole new field of medicine. And it’s really important to realize the many nuances of how it’s best use, I like to think of what we’re doing is genomic medicine. And it’s important to realize that this information, that part of your Genomic Health is just one component of medical decision making, and your global health. You need your family history and all the things that are going on with you. And we believe Sharon and I believe that this decision making is best made in collaboration between you and your physician.
Sharon Hausman-Cohen 59:48
Everybody wants better health for themselves and their loved ones. And think of genomics as a detective tool that allows you and your physicians to identify underlying root causes to will allow you to have the benefit of personalized medicine.
Unknown Speaker 1:00:04
The ability to use your DNA as part of your clinical decision making is the future of medicine for sure. But it sure is the present too.
Sharon Hausman-Cohen 1:00:14
And I think that one final thing is a lot of people again, they go, Oh, I’ve got AP four, I’m gonna get Alzheimer’s, it’s really, really important to remember that genomics is exciting. It allows you to better preserve and optimize your memory. But your DNA is not your destiny, it either roadmap to health and vitality. We always like to say it really is a roadmap. So you can call it your GPS sequencing your roadmap whenever your user manual. But we hope that if you use genomics, you use it in good health to help optimize your own brain function.
Unknown Speaker 1:00:51
Thank you for joining us today. If you’re interested in learning more or finding provider training and genomics of cognition, feel free to reach out to us through our website until it’s dna.com.
Unknown Speaker 1:01:02
No, this is not intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have. Never disregard professional medical advice or delay in seeking of it because of something you’ve seen here. If you find this to be a value of you, please hit that like button and subscribe support the work we do on this channel. Also, we take your suggestions and advice very seriously. Please let us know what you’d like to see on this channel. Thanks for watching and we’ll hope to see you next time.