Episode 63: Best Strategies to Prevent Cognitive Decline with Grain Brain Author and Neurologist Dr. David Perlmutter

Almost six million Americans live with Alzheimer’s disease and one in three seniors dies with Alzheimer’s or another form of cognitive impairment.

Dr. David Perlmutter is a board-certified neurologist and four-time New York Times bestselling author who specializes in a functional medicine approach to preventing Alzheimer’s. He is a Fellow of the American College of Nutrition, a member of the Editorial Board for the Journal of Alzheimer’s Disease, and has published extensively in peer-reviewed scientific journals.

His books have been published in 34 languages and include the #1 New York Times bestseller Grain Brain, The Surprising Truth About Wheat, Carbs and Sugar, with over 1 million copies in print. Dr. Perlmutter’s new book Brain Wash co-written with Austin Perlmutter, MD will be published in January 2020.

In this episode of New Frontiers, Dr. Fitzgerald talks with Dr. Perlmutter about the best strategies for preventing and slowing cognitive decline, and how his thinking about preventive lifestyle strategies has evolved since he published his first book Grain Brain.

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Dr. Perlmutter is a Board-Certified Neurologist and four-time New York Times bestselling author. He serves on the Board of Directors and is a Fellow of the American College of Nutrition.

Dr. Perlmutter received his M.D. degree from the University of Miami School of Medicine where he was awarded the Leonard G. Rowntree Research Award. He serves as a member of the Editorial Board for the Journal of Alzheimer’s Disease and has published extensively in peer-reviewed scientific journals including Archives of Neurology, Neurosurgery, and The Journal of Applied Nutrition. In addition, he is a frequent lecturer at symposia sponsored by institutions such as the World Bank and IMF, Columbia University, Scripps Institute, New York University, and Harvard University and serves as an Associate Professor at the University of Miami Miller School of Medicine.

His books have been published in 34 languages and include the #1 New York Times bestseller Grain Brain, The Surprising Truth About Wheat, Carbs and Sugar, with over 1 million copies in print. He is the editor of the upcoming collection The Microbiome and the Brain that will be authored by top experts in the field and will be published in 2019 by CRC Press.

Dr. Perlmutter’s new book Brain Wash co-written with Austin Perlmutter, MD will be published in January 2020.

Dr. David Perlmutter

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• Effects of a medium-chain triglyceride-based ketogenic formula on cognitive function (Study out of Japan MCT oil for 12 weeks)
• Neurology: Midlife insulin resistance, APOE genotype, and late-life brain amyloid accumulation

Dr. Kara Fitzgerald: Hi, everybody. Welcome to New Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine, and today is no exception. I am so excited to be having a … Actually, already, we’re jumping into a sit-down, fabulous conversation with Dr. David Perlmutter. You know who he is. He’s a board certified neurologist.

Dr. Kara Fitzgerald: He’s a four-time New York Times best-selling author. He’s on the board of directors and is a fellow of the American College of Nutrition. Of course, he’s a long time IFM faculty member. He received his MD from University of Miami where he was awarded the Leonard G. Rowntree Research Award and he is on the editorial board for the Journal of Alzheimer’s Disease.

Dr. Kara Fitzgerald: He’s published extensively in peer reviewed literature and he lectures all over the world and again, of course, with IFM. His books are … They’ve been translated into many different languages and he’s always up to really, really cool stuff including a lot of really lovely self-care that we’ve been just conversing on and we’ll talk about so welcome, David, to New Frontiers.

Dr. David Perlmutter: Well, thank you, Kara, and I’m really looking forward to our time together.

Dr. Kara Fitzgerald: First of all, I just want to ask you. You’re on the editorial board for the Journal of Alzheimer’s Disease. You’re straddling two worlds. You’re firmly in the functional medicine space and you have been. You’ve been a leader in our world for a very long time but you’re in a mainstream setting as well. In fact, you guys have a documentary coming out soon that we’ll also talk about, “Alzheimer’s: The Science of Prevention.”

Dr. Kara Fitzgerald: You’re interviewing a lot of folks who are firmly in the mainstream camp. How is the greater neurology community receiving what you have to say these days?

Dr. David Perlmutter: It’s a very good question. A great place to start and I would say that, first of all, as it relates to the Journal of Alzheimer’s Disease, there’s no neutral exclusivity. That is a journal that I think is very forward-thinking and open to ideas that are not necessarily based on standard Western medical model of pharmaceutical intervention so that’s certainly not counter to our mission. As it relates to our upcoming documentary, “Alzheimer’s Disease: Science of Prevention,” I will say that the people we selected are more in the IFM mindset. Many of whom our IFM audience would know Jeff Bland, Dale Bredesen, David Ludwig, so people that are really willing to embrace the notion that (a), we don’t have a cure for this disease and (b), it is, to a significant degree, preventable.

Preventive medicine has been around a long time, at least the notion of preventive medicine, at least since the time of Hippocrates so that antedates or predates rather, the formation of IFM by a few years.

Dr. Kara Fitzgerald: Right.

Dr. David Perlmutter: There’s been the notion that we should be looking at how we can prevent disease and as it relates to what I do in this world, the brain has been pretty much the last frontier to come to the table for whatever reason.

Dr. Kara Fitzgerald: Right.

Dr. David Perlmutter: People have really had a tough time getting their arms around the notion that our lifestyle choices are so fundamentally important as they relate to the brain and the more I do what I do in this world, that is to vet this information, the more I realize that … Of course, I’m taking a perspective here, but it looks like the brain might well be the most receptive organ in the body to lifestyle modification as it relates to disease prevention. Who knew?

Dr. Kara Fitzgerald: Really? That’s pretty extraordinary statement like underscore. You’re clearly still a disruptor but your pond is getting a lot bigger and there’s some pretty impressive folks swimming in there and there’s a lot of data support in what you’re saying.

Dr. David Perlmutter: That’s right. I’d say that we’re really reaching, I don’t think, to the point but again, maybe I just have a certain perspective but for example, when the Journal of the American Medical Association, November the 2nd of 2018, publishes an article, a meta-analysis of 10 studies with over 2,700 participants looking at the effectiveness or lack thereof of the two main classes of so-called Alzheimer’s drugs meaning drugs based on memantine or drugs that are cholinesterase inhibitors to treat Alzheimer’s…finds, not only are they not effective but they actually are associated with increased rate of cognitive decline on a standardized, what’s called the ADAS-Cog study, Alzheimer’s Disease Assessment Scale. That is published by, again, JAMA and for them to tell us that these drugs that are being sold in America for the treatment of Alzheimer’s, the Alzheimer’s patients that you would put your faith into that your doctor is giving you for mother or father or husband or wife.

Finding out, we’ve known for years that they’re ineffective but find out that they’re associated with worsening cognitive function over time of your mother or your father and yet, it’s still on the market, still a standard of care so last year … Actually, it’s 2017 in February in the Journal of Neurology, they published some practice parameters and trying to answer the question.

What should a neurologist recommend when he or she sees that patient coming to the office who now has gone beyond subjective cognitive impairment and now fulfills criteria for mild cognitive impairment. In other words, beyond the patient thinking that here she is having issues actually doing neuro psych testing and demonstrating that this person does indeed, is now on the continuum for cognitive decline. They vetted 14 different interventions, the cholinesterase inhibitors, memantine, a bunch of other drugs and they came up with only one recommendation as to what a practicing neurologist should recommend for their patient and it was a drug called exercise. Physical exercise was the only thing sanctioned by the Journal of Neurology. That’s the governing board that, for example, determines that you are a board-certified neurologist. First of all, not like we didn’t know that. We did know that. The relationship of exercise to neurogenesis turning on BDNF to grow new brain cells, increase synapses, synaptogenesis, neuroplasticity was so wonderfully described by Dr. Kirk Erickson at the University of Pittsburg who is one of our participants in the upcoming docuseries.

It is breathtaking that a journal underwritten by pharmaceutical companies would publish this, oh my gosh, that’s just fantastic. I saw that. I thought, “Well, great, here’s data. I have to make slides. Wonderful. It would be great for the presentation,” but we take a step back and say, “My gosh, this journal saying exercise, what a world we live in.” Dr. Perlmutter was out there talking about this years ago and people were saying, “Yeah,” but others, no real whatever data. Now it’s a recommendation for practice parameters.

Dr. Kara Fitzgerald: Right, right but the other side, the flipside of that coin so for you and your world, it’s an extraordinary … Well, not you and your, it’s for our world. It’s this just like from the rooftops, aaaah. Just powerful validation but then the visual. When you were talking, for me, was putting my hand into a conventional neurologist’s toolkit and there is nothing there. There’s no room. I put my hand into the toolkit and how heartbreaking that is and what a crisis these physicians must be in.

Dr. David Perlmutter: Well, it’s not that they can’t avail themselves of this information. There are neurologists who come up to me and say, “I read your book, Grain Brain and it helped me.” Last night, it happened. I gave a lecture at a medical school last night and it was happening and there are some people who are going to not be satisfied with status quo. Like you say, there’s nothing in that toolbox to treat the disease process itself. There are certainly some things to help with symptom management. For example, in Parkinson’s. Yeah, we have medications that can reduce tremor. Medications to counter rigidity but in terms of targeting the underlying disease process, there’s nothing that exists in that toolbox.

Having said that, we fully understand that this situation is a mitochondriopathy. It is an acquired mitochondrial issue and therefore, what do you and I and integrative type, functional medicine type healthcare providers recognize is a powerful way to improve mitochondrial function and one of the things that’s certainly invoked today is the ketogenic diet.

Why don’t we talk about? Let’s design a study to use a ketogenic diet in an acquired mitochondriopathy which we call Parkinson’s disease for which we have no cure, no meaningful treatment as it relates to an ongoing disease and it turns out that that study was … There was a study in 2005. It’s more of a proof of concept.

It was only five participants, but it was dramatic and more recently, a study appearing in the Journal of Movement Disorders clearly demonstrated. It was 38 patients, eight weeks long, looked at some of the things people get concerned about with respect to a ketogenic diet, high fat, low carb so they looked at things like lipid parameters, hemoglobin A1C but also looked at what is called the Unified Parkinson’s Disease Rating Scale.That looks at a variety of issues, motor activities of daily living, motor complications, medication complications, et cetera, and virtually, across the board, those individuals who got on a ketogenic diet, mitochondrial therapy, if you will, all had dramatic improvements in their Unified Parkinson’s Disease Rating Scale targeting the fundamental issue here which is mitochondrial failure.

Giving these neurons in the substantia nigra the ability to do their thing again and people get better. It’s more of the substantia nigra issue. That’s what people say. Anyway, for your neurology boards, you got to get that one right. Pars compacta of the substantia nigra but there are a lot of projection areas from the substantia nigra to the basal ganglia, et cetera, that are affected. The truth be known, it’s a pancerebellar event. Parkinson’s patients have constipation and extracerebral things like seborrhea and all kinds of other skin issues. Typically, they can become arthritic so it is a classic manifestation of inflammation. What is the most worrisome downstream effect of inflammation? Free radical mediated stress which, to all of us, means mitochondrial damage. Here, this was published in the Journal of Movement Disorders. How many people have read it? Not a lot. It was front page on the…

Dr. Kara Fitzgerald: Right. Right, right.

Dr. David Perlmutter: … MedPage today or something. No, it wasn’t but that’s our mission. We make this information available through our outreach for those who are interested in learning about it.

Dr. Kara Fitzgerald: Right. Yeah. It’s just really, that’s very inspirational. It’s just really, really exciting to hear about. Just jumping around a little bit here, just talking about Alzheimer’s because you’re putting a lot of attention there. Fundamentally, mechanistically, is this an acquired mitochondriopathy as well? How would you articulate that, the fundamental, the molecular, I guess, pathophysiology?

Dr. David Perlmutter: Kara, I’d say that that is the million-dollar question here and I think what we’ve clearly come to understand is that it’s a multifactorial event. It is not a thing. It is not the cholinergic hypothesis. Years ago, it was noted. Postmortem in the brains of Alzheimer’s patients that there was less in the so-called Alzheimer’s areas of interest. There was less acetylcholine. Well, therefore, deficiency of acetylcholine, that must be the problem. Let’s fix it like low levels of dopamine are characteristic of Parkinson’s as if that were the problem. The fundamental problem, so what happened was based on the cholinergic hypothesis, medications were developed that could inhibit the enzyme that breaks down acetylcholine.

We call them cholinesterase inhibitors and that’s where pathogenesis was and it’s really a reductionist mentality that ultimately manifests as monotherapy, which doesn’t work. We have to abandon the notion that there is a single cause of Alzheimer’s and with that that there is a single remedy for this situation. There are many ways that you can jump on this carousel.

It takes a lot of work to slow this carousel down. And the goal, of course, is to stop it. That said, if we recognize that fundamental here is the mitochondrial dysfunction which has been demonstrated for years. One might expect that targeting mitochondrial function might be worthwhile as part of the puzzle. If you know Dr. Dale Bredesen, he leverages 36 different points. He calls them holes in the roof to kick the rain out of the house. I am certain, some of the holes are bigger than others and are letting more water in. I think, probably the biggest hole, the biggest area of leverage would be recognizing the powerfully damaging effect of dietary sugar and we find carbohydrates on the brain through the mechanism of development of insulin resistance.

We’ll talk about that in just a minute but even simply wanting to target the mitochondria, Dr. Bredesen does it with a ketogenic diet but even targeting the mitochondria as we learn in the Journal of Neuroscience Letters in November of 2018, using something like a medium-chain triglyceride oil, MCT oil in order to increase the production of ketone bodies…Allow ketone bodies to be present to power-up the brain cells of Alzheimer’s patients has been proven effective so in one study, giving 50 grams daily for 12 weeks of a ketogenic formula, demonstrated to increase ketones in individuals, Japanese study, showed significant improvement in both immediate and delayed logical memory compared to base sign. These are in individuals who were already well on their way to cognitive and who were declining cognitively and so in 12 weeks, you would have expected them to be worse, even neutralizing them so they didn’t decline would’ve been a great accomplishment but they actually improved so what are you doing with that? You are increasing the provision of ketone bodies like beta-hydroxybutyrate which the brain loves but I’ll also tell you something that many of your listeners may not know and there is when you give MCT oil, the capric acid which is the 10 carbon part of MCT, C8, C10 and C12. Capric acid has been noted in Leigh’s syndrome, L-E-I-G-H syndrome which is a specific deficiency of mitochondriopathy, inherited mitochondriopathy of complex I. It’s been demonstrated in Leigh syndrome that giving C10, medium-chain triglyceride dramatically and directly upregulates complex I of mitochondrial activity so I think that’s really something to think about in terms of treating, in this case, Alzheimer’s disease but I would also say that would be definitely something on the menu for Parkinson’s patient as well.

Dr. Kara Fitzgerald: Right.

Dr. David Perlmutter: Really, across the board as it relates to neurodegenerative condition so what we’re looking at, what becomes so important is the notion of augmenting brain energetics. The inability of the brain to utilize fuel source and to do its job. What literature now tells us is that there is a deficiency, a bioenergetic failure, if you will, of the brain that is detectable 20 to even 30 years ahead of time prior to the onset of cognitive dysfunction. That’s a pretty compelling thought. What is even more exciting is the newer research by Dr. Stephen Cunnane, who has demonstrated that when you look at a glucose PET scan in an Alzheimer’s patient and you see dramatic reduction in glucose utilization in the temporal lobe regions, the areas of interest as it relates to Alzheimer’s disease.

You look at these scans and you see. Wow, look at that profound decrease in glucose utilization. The notion was that those are neurons that are failing. They’re not functional anymore and they’re not using glucose because they didn’t start their motors, right? Well, that is a flawed idea because what Dr. Cunnane has demonstrated is that when you administer ketones to these patients and then do a different kind of scan it’s still a metabolic scan but it’s using C-11 as acetyl acetate so this is a brain scan that’s measuring brain metabolism of a ketone. These brains light up in a normal fashion. My gosh. What is it telling us? These are neurons that are…

Dr. Kara Fitzgerald: They’re still broken.

Dr. David Perlmutter: Yeah, they are functional but not functioning and they just need to be powered by the right kind of fuel and they’re going to go on their merry way and what does that explain? It explains the study I spoke of a moment ago.

Dr. Kara Fitzgerald: Yes, yes, yes, yes.

Dr. David Perlmutter: Where are these people and proof? That’s where the rubber meets the road.

Dr. Kara Fitzgerald: That’s…

Dr. David Perlmutter: Then, the other study says, “Yeah, okay. I get. Let’s prove it and proves it. What more do we want here?”

Dr. Kara Fitzgerald: Boom. Mic drop. Mic drop.

Dr. David Perlmutter: Yeah. I’m wearing a headset so I’m not going to drop the mic.

Dr. Kara Fitzgerald: Listen, I just want to circle back to that original, the study out of Japan you just mentioned. That was 50 grams of MCT for 12 weeks, per day for 12 weeks. That’s what it was.

Dr. David Perlmutter: I don’t want to say proprietary formula but it was … Yeah, I’ll give you the study.

Dr. Kara Fitzgerald: Okay. Yeah. Yeah.

Dr. David Perlmutter: I’ll put it in the notes but it was 50 grams of their so-called ketogenic formula and it contained 20 grams of MCT oil and what they did was they compared study. They compared it with an isocaloric formula of individuals but they didn’t have the added MCT oil so a great control. They measured plasma levels of both acetyl acetate and beta-hydroxybutyrate. In the MCT group, you would … as expected, these levels increased.

What does that tell a practitioner about treating the next patient who comes in who says, “You know doc? I want to do the best I can for my brain.” Or what might … The advice might just be for the practitioners, for themselves? It would be that we recognized the powerfully salubrious effects of being in ketoses or however you want to define it. At least having those ketone bodies available to power ourselves. Ketone bodies use some really important things. We know that ketones historically have been fundamental for our ability to survive. We know that the ATP production and utilizing ketones is far more efficient in comparison to glucose and both on a milligram promoter in basis in terms of the number of ATP molecules produced.This ATP is produced with less production of damaging free radicals, i.e., reduced oxidative stress. We know that beta-hydroxybutyrate in particular as one of the ketone bodies though, in truth, we know it’s not under scientific definition, a ketone. Who knew? Nonetheless, it’s like quinoa as a grain but it’s not. Anyway.

Dr. Kara Fitzgerald: Right, right, right.

Dr. David Perlmutter: We know that this beta-hydroxybutyrate that is produced when we are fasting, when we are on a ketogenic diet, when we’re taking supplemental exogenous ketones, et cetera, is powerful in terms of its histone deacetylase activity. As such, it’s changing gene expression. It stimulates cellular function because it acts powerfully through those G protein receptors on the cell wall and from my perspective that beta-hydroxybutyrate is yet another way to turn on the production of brain-derived neurotrophic factor. Like exercise, like turmeric, like DHA, it is enhancing the growth of new brain cells specifically where we need them most, in the hippocampus and at the same time, enhancing neurogenesis so we … I mean enhancing neuroplasticity so that our neurons can reconnect and that’s fundamental for memory function.

Dr. Kara Fitzgerald: Let me ask you a couple of questions. You’re saying a lot of really cool stuff here and I just want to … I had the privilege of talking to Valter Longo and I know that you know him. I’ve spoken to him and we were waxing philosophically about … Well, he was. I was interviewing him about the idea of exogenous ketones. Using exogenous ketones and putting them in a milieu of high sugar. That could be metabolically cacophonous and I’m curious about…

Dr. David Perlmutter: Cacophonous, I love it. That’s a great word.

Dr. Kara Fitzgerald: Well, what’s your opinion? I just want to throw that out there and get your opinion so if I’m a standard American diet person and I go to GNC and grab some exogenous ketones and start supplementing with them, is that a good thing? All in all, is it better than just eating my standard American diet or is there any concern around that? Just thought I…

Dr. David Perlmutter: Well, I would say that first, Dr. Longo’s work is really just exceptional. He’s actually in our upcoming documentary as well. I would say, I guess, the comparison then here is standard American diet unchanged in both groups. One group takes exogenous ketones. I think that the exogenous ketone group would probably be better off.

Dr. Kara Fitzgerald: Better outcome.

Dr. David Perlmutter: Because, I think, if they do raise levels of beta-hydroxybutyrate, they may be able to benefit from aspects of it, whether it’s G protein aspects of it, BDNF, et cetera. Increasing insulin sensitivity but the degree of offset, I think this is where you’re getting. The degree of offset is not important so if you’re eating this diet high in refined carbohydrates, that is the worst thing you could be doing. If it was a choice between changing your diet or doing a standard American diet and adding exogenous ketones, there’d be no choice. Clearly, I would offer the former. In other words, dramatically cutting your simple carbohydrates, refined carbohydrates, eating more fat. Whether you’re in ketosis or not and whether you’re taking exogenous ketones or not, that would throw the biggest net in my opinion.

Dr. Kara Fitzgerald: Okay, yeah. That makes total sense. That makes a lot of really good sense. Yeah. That, I want to talk to you about your whole prevention thinking and some of the things that you’re doing. You’ve been very open about your family history of Alzheimer and I know that you and your family are really, really mindful around your lifestyle and how you’re walking the walk as you’re talking about that so I want to talk about. Also, within this, because I know that you eat … You’re fully in a ketogenic diet and maybe that fluctuates but how … Yeah, how ketonic do we need to be to be getting, reaping the benefits of prevention…

Dr. David Perlmutter: That’s a great question. I think, Kara, it’d be how ketonic are you in the context of your degree of hypoglycemia as well.

Dr. Kara Fitzgerald: Perfect.

Dr. David Perlmutter: Last night I spent giving a talk. I was with Dr. Dominic D’Agostino who is really just so dialed in on this. He had so much wonderful information and he talks about an index that looks at those two parameters. Your fasting blood sugar and your ketone level cell. What I would tell you, I’m sitting here at my desk and my Precision Xtra-ometer and beta-hydroxybutyrate-ometer is right here. I just look forward to pricking my finger each day and then hoping I can still play guitar afterwards but that said, I think that my blood sugar runs about 65. Many would say, “Wow, that’s too low. How do you tolerate it?” I tolerate it because I’m running a ketone level. In my case, a beta-hydroxybutyrate of about 0.8 or slightly higher so I can have conversations with you that hopefully are somewhat meaningful but that said, I think that the notion of a normal blood sugar being up to 90 to 100 is pathetic.

When you look at the most well-respected literature that is already correlating increased risk for dementia at 105. I spend a lot of time obviously in how all of this relates to the brain and its destiny. I think that we should really make it our goal to redefine where we want our patients’ blood sugars to be. Of course, every patient is different and no one’s going to jump from a blood sugar of 150 and be great in a blood sugar of 70 overnight. They can absolutely work to that end as Dr. Sarah Hallberg has wonderfully demonstrated with her studies, Virta Health but I think that … Actually, it was a question I was asked last night: if suddenly, we drop our blood sugar especially athletes who are trying to do keto all of a sudden. They drop their blood sugar and have no…Well, I think there’s a lot to be said about the notion of keto adaptation and that is the facilitating of that pathway to utilize free fatty acids that are mobilized for fuel to power, first and foremost, your brain and then your body. If you start crashing amply, you’re not going to be continuing being a runner or weightlifting. I think there’s a lot to be said about, yes, let’s get the blood sugars down to high 70s, 80s. Maybe perhaps, 90 although I’m starting to wonder about that.

Dr. Kara Fitzgerald: Yeah.

Dr. David Perlmutter: Maybe don’t pay so much attention to fasting blood sugar but look at the A1C or fructosamine. Also, the fasting insulin levels and get surprised. That said, looking simultaneously at whatever marker you choose to give your senses to what is now supplanting that glucose level to power your brain and power your body. I.e., how keto adapted are you?

Dr. David Perlmutter: I’m not talking about pushing yourself into ketosis via exogenous ketones or even MCT at this point. I’m talking about enhancing lipolysis and the whole process of ketogenesis in your body, i.e., keto adaptation, which does not happen overnight. It may take three, four, up to six weeks of diligence to become flex-fuel adapted.

Dr. Kara Fitzgerald: Right. Right, right. Okay, so just allowing yourself to move into it relatively slowly. Well, let me just ask you out of curiosity with the numbers that you just described. You’re in pretty rich ketosis and your blood sugar is really low. Yeah, you’re quite lucid. You’re pulling study after study off the top of your head.

Dr. David Perlmutter: Who is this? Who are you? What are you talking about?

Dr. Kara Fitzgerald: That’s amazing. What does your diet look like? Are you just eating fat bombs all the time? What…

Dr. David Perlmutter: Not at all. My diet is and it sounds in contradiction to what I may have perceived the Grain Brain diet to have been or be. My diet is mostly vegetarian, mostly above ground, colorful vegetables. I will, maybe once a week, have … Probably once every two weeks, have some meat, more fish and some chicken. Probably like, no, without a doubt, my biggest source of animal protein is wild fish. Typically, almost exclusively salmon and that’s really … those are the fundamentals. I drench everything in olive oil whenever I eat which is typically twice a day but actually, either once or twice a day. I’m becoming more of a devotee to time restriction in terms of the amount of time I’m allowing myself to eat during the course of day and doing my very best to not eat within three hours of going to sleep.

I typically, though most people who are talking about this do have breakfast and I’m not a big breakfast person so I will go ahead and do my work out before I’ve eaten anything and typically eat by around 12 or 1:00 in the day. Everybody has to find where they function best, what’s comfortable for them. I find that there’s various ways that you can assess is it working? One of the ways is your athletic performance. For me, yes, it’s athletic performance. It’s also cognitive performance and it’s also the quality of my sleep I find is significantly, this revelation. Significantly related to my adherence to the program or making changes in the program and so I use an Oura Ring to determine my quality of sleep, the amount of time I spent sleeping, my sleep onset. How much REM I’m getting, how much deep sleep, i.e., lymphatic, cleaning my brain type of sleep. How much of that is going on and I make variations in my program and try to see in these various parameters what those variations do? Recognizing that I’m an N of 1, as is everyone listening to this and their patients.

Saying that, where I’m going with that is it’s good to make the broad sort of recommendations and certainly, we have done that today and we ought to continue to do that today. In addition, there is plenty to be said about then. We understand lower refined carbohydrates, physical exercise. Making sure to sleep, et cetera. What does Kara need specifically based on her genome, her microbiome, her current medical situation, her current biometrics across the board, what would be best for you?

Dr. Kara Fitzgerald: Yeah. We’ll, I do consider coffee to be a vegetable.

Dr. David Perlmutter: I’m there. I’ve never heard that said before but I am now going to incorporate that. I love that. Honey is not. Not that I would recommend it for anything because it’s sugar but I think that’s a chance to come clean here, honey is an animal product.

Dr. Kara Fitzgerald: That’s interesting. Yeah, yeah.

Dr. David Perlmutter: Made by animals.

Dr. Kara Fitzgerald: Yes, so thus far in my journey, coffee has been a part of my world in the morning.

Dr. David Perlmutter: Yeah, I presented a study last night demonstrating how ketones within four hours of coffee consumption are definitely upregulated and it’s a cup of black coffee. It’s not a Frappuccino. A Frappuccino is not drinking coffee. A Frappuccino has 72 grams of sugar. That’s 18 teaspoons of sugar so again, that’s the … Well, coffee upregulates ketones but is that all set? Eighteen teaspoons of sugar, hard to imagine.

Dr. Kara Fitzgerald: Let me ask you a question too. Just considering, right before we hopped on the call, you were actually working out. Not a lot, but if you did anything high intensity, if you moved into phosphocreatine. If you did any burst training, we tend to need, at least my experience, and maybe this is my N of 1 versus your N of 1…Physically, I do better in a ketogenic diet. I think I could actually do a lot better if I turn the volume up on it. Like currently, I tend to be just doing a urine strip like maybe in small… and honestly, I think if I measured my sugar, which I should do because I do have my precision kicking around here, it would probably be higher than I’d like it to be.

There’s actually, as an aside, there’s a cool study from the early 2000s, the San Antonio Heart Study where they really looked at those numbers in relation to cardiovascular disease and saw anything, I think around 85 or below … Eighty-five or above is being associated with increased risk. They sorted the data into quintiles and also, with insulin so insulin five or above was associated with increased cardiovascular disease.

That is definitely on the low side of normal in a standard insulin range so those have been my numbers that I worked with personally in my practice and then David Ludwig. I actually pinged David Ludwig on what he thought an optimal insulin was and he put it at around two of somebody who’s metabolically optimal. Not…

Dr. David Perlmutter: I would agree with Dr. Ludwig. He is yet another participant in our program.

Dr. Kara Fitzgerald: It sounds like you guys are really putting together a cool program.

Dr. David Perlmutter: It was really very, very exciting. Just to hear, when you let these, when you take your foot off the brake and let these people go, wow, that’s great stuff so it’s up to us now to figure out how the heck … Do we parse this out? How do we edit it? That, we have people for that, but you’re right. Let me get back to you I think where you’re going with burst training.

Dr. Kara Fitzgerald: Yes, yes, yes.

Dr. David Perlmutter: Again, it’s all about the individual and people should learn what’s best for them based upon, in this case, what type of exercise they gravitate towards and I think some of that has to do with genetics in terms of energy, their body’s ability towards energy. Keep in mind that we’ve got 12 miles running worth of glycogen at the ready.We can power both with that and glucose just from the mobilization of glycogen stores. Then again, if somebody thinks they do better on a specific supplement during training, we have plenty of anecdotes and some of them have some pretty good scientific underpin.

Dr. Kara Fitzgerald: Let’s talk about that. I want us … Sorry. I want to start to just tease out some of your thinking and I know you’ve evolved since Grain Brain. You actually published it up to … Yeah, right. Yeah, and you published it. Yeah, you’ve been conversing on this arena but I want to talk about prevention and I want to just talk about … We’re broad stroking in here about your prevention protocol.

We know we’re looking at getting into a ketogenic program, whatever that looks like for the individual. I get that you’re underscoring that quite a bit and I appreciate it. It sounds like MCT but exercise, you’ve spoken about sleep. You’ve spoken about … What else?

Dr. David Perlmutter: Let me amplify that for just a moment and talk about why really and mechanistically, what else may be going on that is really fundamental. It’s not just that we’re trying to power the brain with a more efficient fuel source. I’ve listed a few of the other attributes of beta-hydroxybutyrate, the histone deacetylase activity that you put in a simulation, et cetera. I think the main goal here is to look at improving insulin sensitivity. Now, why do we want to do that? We want to do that because insulin is a fundamental player as it relates to long-term potentiation. That’s the way we consolidate activity into memory. It also is a trophic hormone for the brain. We also know that we need good insulin functionality of blood-brain barrier insulin receptors to allow the brain to absorb glucose from the bloodstream.

The whole notion of developing insulin resistance is really important as it relates to the brain and that is yet another target of getting on to ketogenic diet right? There’s been no effective way for example for the pharmaceutical realm to help rid the brain of beta amyloid. Every attempt to do so has actually really been associated with worsening cognitive function for whatever reason. Even efforts to reduce the production of beta amyloid via enzyme manipulation and even vaccine, vaccinated people to develop antibodies against beta and while these have all been forth with complications and all of these trials 100% have come up empty handed. There is a very interesting study that was appearing in March of 2018, I don’t know the date, I apologize. The study looked at having insulin resistance during your midlife time and what did that do to your risk for amyloid accumulation considering people who are APOE4 positive and APOE4 negative.

What the study found was really very, very remarkable that just in looking at the insulin resistant versus people who are not insulin resistant by whatever definitions they used a HOMA-IR findings. There was a dramatic increase risk of having a positive amyloid scan if you were insulin resistant in the person who is insulin sensitive or not having insulin resistance. Then, they did it in looking at those individuals who are APOE-4 positive. We know that individuals who are APOE4 positive homozygous more than heterozygous accumulate beta amyloid at a higher rate and would be more likely to have a positive amyloid brad scan.

When you look at this even in the people who are APOE4 positive, there was much more risk of amyloid accumulation if they were APOE4 positive and insulin resistant. So take home message here, you’re not going to change whether you’re APOE4 positive or negative, you get back your 23 and me and you see your results pretty much end of story. You sure as heck can determine whether you’re insulin resistant or not and that’s a lifestyle choice. Primarily based upon a diet secondarily based upon things like quality of sleep and exercise activity.

Diet, being by far and away the most important leg of that stool. It’s been often said that you can’t exercise away a crummy diet and I truly believe it. All of these efforts to build a brain with less beta amyloid need to take a look at this study published in such a respected journal that says “Hey, if you’re insulin resistant look at your risk of having a positive amyloid scan.” Now, that’s not the end all, but it’s certainly very important as people consider this amyloid hypothesis.

Dr. Kara Fitzgerald: Right. Okay, so you hit that home.

Dr. David Perlmutter: Okay. Are we going to the bonus round now?

Dr. Kara Fitzgerald: Yes. That’s so great. It’s very, very, very elegant and eloquent and focused. We’ll circle back to all the citations from Dr. Perlmutter and we’ll just tap him on his…

Dr. David Perlmutter: Good luck with that.

Dr. Kara Fitzgerald: I know, we’ll do the best that we can. I was going to say that actually but we’re going to really…

Dr. David Perlmutter: I’ll make it work. I’ll make it work.

Dr. Kara Fitzgerald: Yeah, you definitely have given us a lot of really juicy content and I know everybody wants to check it out. Okay, so supplements they’re kind of like maybe the icing on the sugar-free yet tasty and safe icing on top of this. What are you thinking about and are you considering medications? Remember, we’re still over in the prevention camp.

Dr. David Perlmutter: Yeah. I’d say that supplements are exactly what their name implies and that they are supplemental too. Supplemental to fill in the gaps that might be created. I think one of the biggest gaps that is created in the modern diet is created as we look at this ratio between Omega-6 and Omega-3, which is perversely elevated in favor of Omega-6.

I think we’ve got to work on that first through diet and recognizing where this Omega-6 is coming from but also adding in some good levels of Omega-3 and certainly DHA is one very important supplement as it relates to the brain, Martha Clara Morris at Rush has called our attention to this relationship between lower levels of DHA and increased risk for dementia for a long, long time. I think that’s very important information we recognize DHA is an anti-inflammatory through, it’s effective COX-2 inhibitor.

A DHA is a DBA or gamma activator and as such also reduces inflammation. DHA serves as a precursor interestingly for endocannabinoids that can block endocannabinoids like 2AG and anandamide which would otherwise stimulate the CB1 cannabinoid, endocannabinoid receptor and would have otherwise increased the production of inflammatory mediators, appetite, reduced lipolysis so that’s…

Dr. Kara Fitzgerald: That’s basically offsetting the impact of 2AG is what you’re saying?

Dr. David Perlmutter: Well to some degree but understand that anandamide and 2AG are made from arachidonic acid.

Dr. Kara Fitzgerald: Right, that’s right.

Dr. David Perlmutter: As such they are higher, they are derivatives of an Omega-6 diet. We fire up and lower ourselves up with Omega-6’s from eating grocery store oils, safflower, corn oil, et cetera, sunflower oil ultimately elevate our arachidonic acid production. We are setting the stage for increase ultimately CB1 activity which is especially as it relates to adipocyte activity is increasing all the things we don’t want to increase and reducing things like adiponectin. We can offset that then by having higher levels of blocking endocannabinoids that are produced from higher levels of Omega-3.

I think it’s kind of interesting in this day and age of people beginning to understand the endocannabinoid system to understand that it leverages our diet in terms of its endogenous activity significantly we can manipulate our endocannabinoid system based upon food and supplement.

Dr. Kara Fitzgerald: Very cool. Thank you.

Dr. David Perlmutter: Choosing a DHA supplement, I would look for a phospholipid DHA that’s on the market. I would look to the future for fish derived oils that may provide these pro resolving mediators that are so important in resolving this process of chronic inflammation. A DHA is absolutely on the list I think…

Dr. Kara Fitzgerald: How would you dose it?

Dr. David Perlmutter: I think a 1000 to 1200 milligrams of the DHA part of the fish oil pills so look at the EPA but I think if you’re just going to focus on the DHA, I think phospholipid DHA is the way to go. There are a lot of other things, I think whole coffee fruit extract or concentrate that has been demonstrated to augment BDNF production as much as exercise, or depending on the degree of exercise. I would leave that on the list, good old vitamin D which has got to be on the list. I think that there’s a lot of magnesium deficiency around.

I think we need adequate amounts of magnesium for utilization of a variety of enzymatic pathways that would be on the list. I like turmeric because of its anti-inflammatory activity, it’s NRF2 activation activity and the whole cascade there as it relates to reducing inflammation augmenting its antioxidant function and has to include some transferase so they roll them in with detoxification. That’s probably the bare bones list beyond that, I think you cultivate a list based upon testing, based upon what you’re finding either directly measuring things or looking at downstream effects. Measuring a homocysteine as a marker of availability of methylated B vitamins for example or even standard B vitamins and those individuals who don’t have an MTHFR polymorphism as to why for that matter, so there you go.

Dr. Kara Fitzgerald: Okay, so then yeah. You mentioned homocysteine any other big labs that you’re going to be thinking about like what are the first ones you’re going to be checking off with most of your …

Dr. David Perlmutter: As far as labs go, I’d say there’s huge merit in understanding someone’s fasting insulin, fasting blood sugar, A1C, homocysteine, C-reactive protein. If you want to start looking at AOHDG as a downstream marker of inflammation and then generation of oxidative stress that would be good. I think they would be the key players for everyone. Then again as we move to more of a personalized approach, I would say that a genetic profile is very good to have to then recognize where further deficiencies may exist, recommendations in terms of further supplementation based upon understanding of an individual’s cytochrome P450 activity or you name it, vitamin D receptor, polymorphisms as mentioned, MTHFR.

A variety of things more than you will then learn about an individual’s ability to metabolize fat and risk for certain things that you would then want to look at further laboratory studies. To throw that broad net in terms of what I believe should happen when somebody goes for their annual physical at their family practitioner, I would love to add to the fasting glucose, A1C and at least the fasting insulin level. We reserve A1C for diabetics and hey, we’re already seeing correlation of brain shrinkage at an A1C of 5.6, 5.7. This is a powerful correlative marker as it relates to risk of brain shrinkage. Now, that’s probably not a good thing.

Dr. Kara Fitzgerald: Yeah, right. One of the really interesting things I’ve just observed in my clinical practice. I’ve never seen it published although I haven’t even looked for it, it’s just something that I’ve observed in pre-menopausal women and particularly there’s a few with PCOS coming to mind. Normal A1C even in A1C that we would consider great but a very high insulin actually within normal limits but up in the 10, 15, 19, just maybe just above the normal limits of the reference range. I mean what I see is this insulin working just overtime to control blood sugar in A1C and you would not know that if you didn’t get a fasting insulin.

Dr. David Perlmutter: Of course, if you don’t look for, you’re not going to find any. It really brings up a very, an interesting part of this discussion that might explain to some degree why there is a two to one representation in Alzheimer’s patients women to men. We know that PCOS which may affect as many as 20% of American women and is the number one cause of infertility in America and is something that effects men and women though men don’t get cyst on their ovaries, they get all the other metabolic stuff and it goes around that goes along with this.

Skin changes the metabolic issues etcetera, but what is interesting about PCOS is vis-a-vis our earlier discussion of early brain changes in terms of glucose utilization that it’s been demonstrate that in women with PCOS there is between a 9% and a 14% decline in brain glucose utilization in women average age 25 years with PCOS. That translates to a brain energy pattern of a seven-year-old. So, this becomes an issue for us to be concerned with today that needs attention right now because my sense is that unchecked, the brain glucose utilization is going to further decline and that’s not a good thing.

Dr. Kara Fitzgerald: Yes, yes.

Dr. David Perlmutter: I think that’s really very important data.

Dr. Kara Fitzgerald: Yeah, it’s just this observation I’ve made time and again, I would never not get a fasting insulin and there would be… not that many women have ovarian cysts who are metabolically PCOS…

Dr. David Perlmutter: I agree and it’s an unfortunate term, it’s like the term progesterone. It’s for gestation.

Dr. Kara Fitzgerald: Right. Yeah.

Dr. David Perlmutter: Gosh, I mean that kind of locks you in to this mentality or like testosterone level or how does it relate to women. We make cholecystokinin, acts in the brain, 90% plus of serotonin is active in the gut, not the brain. Another 9% is in the platelets and 1% is in the brain, yet we call it a neurotransmitter. The names that get attached to these things really compromise our ability to have a broader view of their activity.

Dr. Kara Fitzgerald: Absolutely, well and we just end up missing. We just miss women all of the time unless you’re willing to cast the wider net like if you would pick it up in the labs that you just articulated. I mean you would pick up those imbalances in a lot of individuals regarding what you end up labeling or coding the mass.

Dr. David Perlmutter: What has to happen then is that doctors need just to add this to the list and before they will add it to the list, however, they’re going to have to answer the question as to why. That then begins the whole discussion as to the fundamental importance of insulin sensitivity well beyond just lowering blood sugar. The fundamental long-term consequences of insulin resistance throughout the body, immune dysfunction, cardiac dysfunction, and certainly as it relates to the brain.

That then requires taking the course or listening to the lecture or something, just some way to get tuned in. I would say that even if doctors could check fasting insulin and A1C on their non-diabetic patients, they start to make discoveries and then begin to ponder, ‘Wow, I don’t know what this means.’ Let me just say parenthetically that as it relates to A1C and this is extremely, extremely powerful because first of all A1C is an indication of right, elevated persistent, elevation of glucose as an average, that’s what people understand.

Well, what does that mean? It means then that that person is at risk for insulin resistance. It correlates as mentioned with increased risk of brain atrophy, but beyond that what is actually happening when hemoglobin is glycated. This is a post translational conformational change of that protein and it’s appearance. It’s three-dimensional configuration is altered and that is huge. The functionality of the proteins is totally linked to how they appeared to their shape. Suddenly we changed the shape of a protein, and I want your listeners to right now be thinking at the same time multi-tasking, of the notion of misfolded proteins in the brain.

Anyway, and we talked about misfolded proteins as it relates to the things in the brain outputs, amyloid, et cetera, and it’s changing the shape and therefore the characteristics of proteins and by far and away the biggest issue here is changing the shape of our proteins when they glycate. Believe me, just because we measure A1C and its hemoglobin, it’s not the only protein that gets glycated. Proteins throughout the body are susceptible to this change in the three-dimensionality and that creates issues as it relates to inflammation and autoimmunity.There’s a lot going on with hemoglobin A1C that I think people should be aware of.

Dr. Kara Fitzgerald: Yeah, without question. This just circles me back to your comment and I know unfortunately we have to wrap up. Your comment a handful of minutes back, when we are originally dialoging around prevention and the bioenergetic failure that is initially perceived 20 to 30 years out. I mean when we’re talking about these early perturbations and insulin resistance. The early onset of insulin resistance and…

Dr. David Perlmutter: Well, let me just say that and this is a great place to wrap it up and to look also at the literature that correlates markers of inflammation three decades out as being predictors of brain shrinkage specifically in Alzheimer’s areas of interest as well as memory dysfunction, markers of inflammation that were measured three decades ago and then come back and see these patients. Now, you see a perfect correlation between brain atrophy as well as functional changes.

Those markers back then with things like Von Willebrand factor, fibrinogen, total white count, et-cetera, more recently a study that was post in February of 2019 looked at similar factors and also added C-reactive protein but extended the group that was evaluated to individual’s even in their mid-20s and again  found a dramatic increased risk of developing cognitive dysfunction based upon having elevated inflammatory markers 30 years ago.

My point is it’s all well and good to see patients with mild cognitive impairment, already established Alzheimer’s disease. I think to really throw that net as wide as we can early on in life to get the word out that research is demonstrating that inflammatory markers that looking at waist to hip ratio 30 years prior are powerful predictors of Alzheimer’s risk. That’s a message that’s kind of hard to sell because yeah, I know if I wear my seatbelt today, my risk of being hurt in an accident today is reduced. You tell me, my diet today I’m going to think about this 30 years from now? Yes, that’s exactly what we’re saying because when it gets to the point that you suddenly are beginning to experience measurable cognitive decline with all due respect there is not as, there is very little that can be done.

Dr. Kara Fitzgerald: Right.

Dr. David Perlmutter: That’s the message that we yell from the mountain tops that it’s a preventable situation and this is how to do it and it’s very straight forward. It’s not like this is going to put you at risk for other things while at the same time reducing risk of Alzheimer’s, no. This is the best diet lifestyle program you can be on. It’s the same thing you should do for your heart, for cancer risk, et-cetera. It’s all about inflammation and insulin sensitivity.

Dr. Kara Fitzgerald: I just had to pull up a 13-year-old patient who came to me with PCOS, I just have to look at her labs and it’s right, she’s 13 and her fasting insulin is 23.5. I mean so we think about our adult patients but indeed, this is what pediatricians, these are kids, this is when we’re seeing it all.

Dr. David Perlmutter: I hear you and my heart right now is saddened to hear that news about this child. It’s saddened in the context of very likely 98%, I pull that out of a hat, pediatricians are going to think that the answer here is simply a medicating this child that Metformin is going to fix those problems end of story. It really is just one part of the story or gastric reduction surgery or something like that. Then, birth control pills, that’s not the answer here.

Dr. Kara Fitzgerald: That’s right. Well, her A1C is 4.9 so they had missed it anyway and they would…

Dr. David Perlmutter: Yeah, anyone use it that’s right.

Dr. Kara Fitzgerald: Right. At least not at this point until she was….

Dr. David Perlmutter: Well interestingly, and now so she’s an individual who doesn’t glycate as readily but nonetheless it’s clear that … What’s her fasting blood sugar?

Dr. Kara Fitzgerald: It’s 100. Actually, initially it was 121 and then I’m just sort of scrolling over her course of time.  Well, let me tell you the really amazing piece of the story. I mean now, her last insulin I think she was down to single digit. I just have to pull it up. The most important part of the story is that actually and I see her A1C is now down to 4.7. Is her own embrace of what’s happened with her own empowerment…

Dr. David Perlmutter: Don’t you love it?

Dr. Kara Fitzgerald: … of how pulling these carbs that yeah, how these carbs have been making her feel lousy in this little 13-year-old with a complaint of brain fog.

Dr. David Perlmutter: That was her initial complaint what do you know?

Dr. Kara Fitzgerald: Yes, it was one of them, one of the handful of issues. I mean PCOS is what originally brought her but yeah, just not feeling good, being irritable, not thinking well et-cetera. Just right there, but also it’s just really lovely to change the course of someone’s existence of have them learn. Actually, I didn’t change the course, she adopted this, and she got it from her own experience by doing this.

Dr. David Perlmutter: How beautiful for you though that you’re getting to experience this with a child whose destiny has been changed? No question.

Dr. Kara Fitzgerald: Yeah, that’s right. Not only her destiny but then those she’ll go out and influence by it. Having this information at such a young age.

Dr. David Perlmutter: Yeah, for sure.

Dr. Kara Fitzgerald: We have to do a part two for sure. Maybe after the documentaries out, I’m so looking forward to it. I know you’ve got another book coming out as well. You’ve got lots of stuff going on but as you said to me before, you’re going to leave for four months and practice what you preach by sailing in a boat to Alaska with your wife.

Dr. David Perlmutter: Yeah, that’s right. What can I say? It’s a lifelong dream.

Dr. Kara Fitzgerald: Beautiful.

Dr. David Perlmutter: What’s nice, I’ll be reading along the way and writing and still remaining engaged. Thank you for our time together, we really seemed to cover a lot of ground and it was a lot of fun.

Dr. Kara Fitzgerald: Yeah, it was great. Just a real honor to be able to talk to you today. Thank you.

Dr. David Perlmutter: Yeah, me too. Bless you. We’ll talk soon.

Dr. Kara Fitzgerald: And that wraps up another amazing conversation with a great mind in functional medicine. I am so glad that you could join me. None of this would be possible, through the years, without our generous, wonderful sponsors, including Integrative Therapeutics, Metagenics, and Biotics. These are companies that I trust, and I use with my patients, every single day. Visit them at IntegativePro.com, BioticsResearch.com, and Metagenics.com. Please tell them that I sent you and thank them for making New Frontiers in Functional Medicine possible.

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