David Perlmutter, MD, FACN, ABIHM
I’m so delighted to be here, thank you for having me.
Heather Sandison, N.D.
So we met in person briefly at a recent conference, and it was hard for me to pin you down because you kept taking off to go hiking, which I love. There is something really compelling about taking advice from someone who actually lives it. The things that you and I talk about, they’re not always easy to implement, right? We’re asking people to get more exercise and make better decisions around food and diet in the face of a culture that has sugar, and alcohol, and sitting on your butt. It’s really easy to just do that, right? What do you think are the most important lifestyle choices that you make every day, or at least most days, right? We’re not all perfect.
David Perlmutter, MD, FACN, ABIHM
Well, I think it’d be great just to let your audience know that where you and I had that conversation was in the parking lot in the Venetian Hotel in Las Vegas, Nevada. So when you talk about alcohol, and sugar, and sitting on your butt all day, what else could come to mind, and you’re right. My wife and I decided and son, he visited as well, that we were gonna get out of town and we went hiking at Red Rock. So the point is, it’s really important. We are kind of inculcated with the notion that we should live our lives, come what may, and then once things start to happen, there’ll be a magic fix, no matter what it is. Yeah, you cannot take care of yourself and ultimately have degeneration of your hip, and you can get a new one or a knee or whatever. But you can’t really get a new brain. And it’s really so important that we realize there’s nothing pharmaceutical available as you and I have this conversation right now.
And we think back of what happened in February of 2021, with this Aduhelm drug it was the rave, but actually it didn’t work . So we have nothing in the Pharmacopia, to treat this incredibly pervasive situation called senile dementia of the Alzheimer’s type. Now affecting some 6 million Americans, highly it’s 50% of people who are age 85 or older. So in that age group, you couldn’t call it an epidemic it’s way beyond epidemic. And yet no one talks about it. And no one talks about it until a loved one is involved, or it’s your choice of profession or in my case, both. We have the data and we’ve had it couple of decades, that lifestyle choices that you bring up are exceedingly valuable in choosing a more appropriate destiny for our cognitive function. And it’s the mission then to get that information out to people.
And that’s why you and I are doing what we’re doing today, it’s because there’s powerful scientific research that supports exactly what it is that we will talk about. The idea that physical exercise can preserve the brain, the idea that keeping blood sugar under control, reducing inflammation, reducing stress, getting a good night’s sleep, involving a ketogenic diet from time to time. There’s so many areas to explore. And yet again most people ask themselves, “Well, why bother?” Well, you begin to wonder why you bother when you’re faced with Alzheimer’s for, or cognitive dysfunction for yourself, or your loved one. And then you wish you would’ve heard this information. So there’s a lot to talk about that’s for sure.
Heather Sandison, N.D.
Yeah, there are so many people who are still told that there’s nothing you can do for dementia. And yet there is so much that you can do that it can sometimes get a little overwhelming. And especially if you’re in the position of being maybe the loved one or the child of someone with dementia, potentially there are genetic predispositions that you may have. At that conference I heard you mention that you think almost 100% of dementia can be related to genetics. Can you explain how you got there?
David Perlmutter, MD, FACN, ABIHM
Yeah, and that raised a lot of eyebrows and I’m glad, I always like to do that. Traditionally we have said about 3 to 5% of Alzheimer’s may be genetic or have a strong genetic component. And I think traditionally that’s valid. We know that there are certain genes, presenilin gene, the APOE array have a role to play in terms of risk, no question. They predispose, they don’t determine, they’re not determinants. But through the lens of how we are currently challenging our highly refined genome that has served us well for millions of years, how we’re suddenly challenging that genome and all of its downstream attributes with our current lifestyle. That’s where I make the statement, that the issue relating genome to Alzheimer’s or diabetes or obesity or any of the chronic metabolic issues, is this inappropriate relationship between our current environment and our evolution. In other words, what our genome wants to see or should see, and what it’s actually seeing based upon the lifestyle choices that we are making.
And what I was speaking about, and I’ve been speaking about this in terms of blood sugar for quite some time. But what I was speaking about at the conference where we ran into each other, was the idea that humans were put under environmental pressure, actually primate, our primate ancestors long before they were humans, 14 to 17 million years ago with a time when the earth became cooler, and there wasn’t as much food available. And it was a very powerful selection input. In other words, it tended to select those individuals who could make a little more body fat and who could raise their blood sugar just a little bit and might have even had a little bit more inflammation to help protect them against infection. Not a lot, but just enough that they were the ones who survived and the others perished. So whatever gene changes this group was experiencing would be passed on.
And ultimately we’ve determined that one of the gene mutations that happened some 14 to 17 million years ago in our primate ancestors was the gene array that deals with the formation of an enzyme called uricase that breaks down uric acid, such that it became less functional. Meaning that these ancestors had higher levels of uric acid. Now, most people have heard of uric acid in the context of gout, sure. But now we know that uric acid is a central player as it relates to our metabolism. That uric acid is playing a major role in our blood pressure control, our lipogenesis, how much fat we produce, how much fat we burn, our metabolic state, even the production of new blood sugar called gluconeogenesis and insulin resistance are all highly influenced by our uric acid levels. Those of our ancestors who had slightly higher levels of uric acid survived and passed on to the next generation, that mutation, the uricase gene, there are actually several of them, mutations.
And each human today walking the planet has that mutation such that we are predisposed to make more fat, to raise our blood sugar, to raise our blood pressure when we consume certain foods like fructose, fruit sugar. The consumption of fructose millions of years ago, and continuing on to our paleolithic ancestors allowed them to survive. They’d find the berries in the fall, eat that level of fructose, they would make it through the winter when they couldn’t find food. So it’s been a wonderful adaptive genetic scenario. Nowadays with the incredible change in our diets with much higher levels of fructose, higher levels of other chemicals that make uric acid like purines, and higher levels of alcohol. We’re making uric acid left right in center, and it’s telling our bodies to make fat, make blood pressure higher, make blood sugar higher.
And so in a very real sense then these metabolic diseases like cardiovascular disease and Alzheimer’s and some forms of cancer, and certainly type two diabetes represent a genetic issue, they relate back to these changes in the human genome that were for 99.9% of our time survival mechanisms. Now, when they’re challenged by our current environment, they’re leading to these metabolic issues, these chronic degenerative conditions that are ranked by the World Health Organization as the number one cause of death on our planet right now, not some kind of infection, it’s actually the chronic degenerative conditions. Good news is, but these are it to our lifestyle choices and we can reign them in when we make better choices, and that’s what the messaging is all about.
Heather Sandison, N.D.
That’s really exciting that we have control over a lot of this. I know that you get into this in the book, but I wanna give our listeners some of the kind of tangibles, what is the ideal range for uric acid? And how frequently do you suggest testing that, especially if you’re gonna make one of these lifestyle interventions? Can you start reversing this in 12 weeks? Can this be resolved months?
David Perlmutter, MD, FACN, ABIHM
Oh, much sooner than that? You can reverse your uric acid or begin to institute change within days, that’s the good news. One study actually in England looked at 22 young men who had slight elevation of uric acid and put them on either quercetin 500 milligrams a day or a placebo, and in two weeks their uric acid levels came down 8%, that’s dramatic. So when you coupled to that, of course, then you coupled to that lowering your fructose consumption, making other dietary changes, you can really have an impact on uric acid very, very quickly. So I generally check my uric acid, not that frequently because it generally is remaining low. I check it at home with a uric acid monitor happen to have it right here on my desk, and there it is. And my last level was whatever that says 4.7. And so to answer your question about what it should be? When you go to the doctor’s office and you have your uric acid level checked. The lab that it spits out, will tell you that the normal range is seven or below. And I have a problem with that on two counts. First of all, I don’t like normal range for my patients. Normal is lame, I want optimal. I want tip top Tony.
I want people to be really achieving extraordinary health, not just average, which is what normal is, right? And the other thing is that number 7.0 was derived based on gout, based on risk for gout. And based upon the level of uric acid in the blood where it begins to form crystals, which is what gout is all about. Although now we know that people who have elevated uric acid actually have crystals forming in their blood vessels, in their heart and even in the prostate gland. So it it’s something beyond just your great toe, for example. So we’re targeting a level of 5.5 milligrams per deciliter, or lower that’s the level below, which we begin to really have an impact on risk for cardiometabolic issues, risk for neurometabolic issues. I know that’s not yet a term, but I’m gonna throw it around and hope that it gains traction neurometabolic, you heard it first. And so it’s certainly a lot lower than what was determined to be the cutoff in the past, and rightfully so.
Heather Sandison, N.D.
What I love about the us as a provider is that it’s so simple, and cheap, and easy. If a patient walks into my office, I mean, we can get this done through lab request it’s widely available, usually covered by insurance, very inexpensive. As you know I work closely with Dr. Bredesen and have been implementing it protocol, doing a lot of the testing, which is very, very extensive, and it’s not accessible to everyone, but something as simple as uric acid that gives us so many insights into this neuro metabolic state, it’s just doable, right? It’s that simple ability to do it and take action and use that data to some lifestyle changes and then get the feedback that makes all the difference in the world.
David Perlmutter, MD, FACN, ABIHM
The feedback, especially, I mean, I am really very much enamored with the notion of having data on myself and others that allow them to know what is the effect on my blood sugar today based upon the fact that I stayed up too late last night, or I ate dinner too late, or I didn’t exercise? How is my blood uric acid level doing lately? ‘Cause I’ve had a little bit more, whatever the food may be, aged cheese, for example, whatever it may be. And how did I sleep last night? What does my aura ring tell me? How much heart rate variability am I having? What’s my oxygenation? What’s my performance based on my Apple Watch? And all these things are really incredibly valuable, and there’s certainly a move amongst mainstream medicine to reign this in. There was an interesting editorial appearing in the Journal of the American Medical Association last year, really saying that if you’re not diabetic, why would you want a continuous glucose monitor? You shouldn’t have one.
But my point would be, if you don’t wanna become diabetic, then you should have a continuous glucose monitor and you can figure it out out right away. You’ll learn real quickly, what foods are particular for you that are raising your blood sugar, or how your blood sugar might respond to the fact you didn’t sleep well last night, or you didn’t exercise, or you have a lot of stress. All these factors play into blood sugar long before the doctor says, “Oh, it’s time to pop you on medication “’cause you’ve got diabetes now.” Diabetes is not like being pregnant. Being pregnant is you either are or you are not, diabetes should be looked upon as a continuum from having normal blood glucose, though the blood insulin level is now elevated.
That’s already getting to a situation that is paving the way for diabetes. The pancreas is working overtime, creating higher levels of insulin to bring the blood sugar back to normal. In that case, your blood sugar is not really that valuable in comparison to looking at the insulin level. So I’m all for people really knowing what’s going on in their own bodies for crying out, and being able to make these changes. The argument was, “Oh, people are gonna become neurotic.” When maybe that wouldn’t hurt a little bit to become a little bit more involved in understanding your personal physiology.
Heather Sandison, N.D.
One of our favorite games to play at my office is the providers say, “Okay, if we had our levels app “testing cortisol for our patients and for ourselves, “and blood sugar, and ketones.” We just start adding this wishlist of all the things that we would love to get real-time information on. And certainly my experience with wearing a continuous glucose monitor, I changed my diet completely. I didn’t realize how my blood sugar was spiking with my morning matcha. And so I had to switch that up a little bit, but certainly the per similarly I’ve seen it, I’ve seen the benefits with my patients. So I thank you for being, I think you’re involved over there, with some continuous glucose monitors and having people like you suggesting that our patients take the reigns, right? Modern medicine isn’t doing the trick, we’re not getting healthier people. We’re actually having a population that’s less healthy, and if we can get the power and the information in the hands of people who can then respond to it and use it, we’re gonna get a healthier population.
David Perlmutter, MD, FACN, ABIHM
Right, and basically modern medicine is focusing on the smoke not the fire. I gave a lecture a couple years ago to, I guess, it was a group of doctors in a large medical group up in New Jersey, I think 400 under the same umbrella. And I asked the audience, what is your go-to treatment for type 2 diabetes? And some talked about this medication, sulphonylureas, Metformin, whatever it may be, that’s the best thing we can be doing. And then I said, “Okay, great, great, great answers.” Though I didn’t believe it . But I said, “What happens when you stop the medication?” And uniformly they said, “Well, the blood sugar’s gonna go up.” And then I said, “Did you really treat the underlying problem? “Did you really treat the diabetes “or just managed their blood sugar?” They realized they weren’t treating the problem, they were treating the manifestation. They were treating the smoke and not the fire. And then I presented the work of Dr. Sarah Hallberg using a ketogenic diet in diabetics and getting people off of their medications and keeping them off their medications and allowing them to maintain normal insulin levels, normal blood sugar levels. That’s treating the problem. That’s putting the fire out, and not just fanning away the smoke.
Heather Sandison, N.D.
Right, you have a book called “Brain Wash.” And a lot of what you’re talking about there, the pattern that comes up is that modern society doesn’t really support the healthiest humans. Your current book is also called “Drop Acid,” so before I leave this, what do you think about psychedelics as a neurologist?
David Perlmutter, MD, FACN, ABIHM
Now, because of the title, “Drop Acid?”
Heather Sandison, N.D.
Yeah.
David Perlmutter, MD, FACN, ABIHM
And you were at probably the same lecture that I was at at that last event, which was interestingly given by our son, Austin Perlmutter, MD. And I think that as he well explained there is huge, huge potential here. And when we recognize historically what got in the way of this research and the clinical research, and how that sidetracked us for 30 years, at least, and now the pieces are being picked up. I think there’s really incredible potential to reconnect us. We wrote “Brain Wash” about this idea that we had called disconnection syndrome, whereby inflammation brought upon by in the various metabolic things that you and I are talking about right now. Inflammation tends to segregate our brain away from being able to tap into the prefrontal cortex and kind of locks us into more primitive, impulsivity type thinking, which is self-centered not thinking about others, not thinking about the future, as opposed to being able to use this prefrontal cortex and bring the adult back in the room.
And I think that one thing we see with meditation is that it tends to light up that prefrontal cortex and psychedelics as well. So I think that moving forward, we’re gonna see that there’ll be a lot of empowerment derived from the appropriate judicious use of specific psychedelics in certain circumstances. Austin talked about how of various psychedelics or things that are somewhat characterized as being psychedelics are proving useful in certain clinical issues. So I think we’re right at the very beginning of understanding where clinically that can go, but I think overall I’m very, very bullish on it thinking it’s gonna be a huge, a positive way of really unwinding a lot of issues that people have with respect to brain functionality.
Heather Sandison, N.D.
Yeah, and with dementia in particular that disconnection, not having that social interaction can be, and then that leading to depression, anxiety, those are all risk factors for dementia. So using whatever tools we can to combat, and especially after a pandemic, or going through a pandemic like the one that we are in right now with COVID. These things are all a bigger and bigger problem that we need to find solutions for. And so thinking outside the box and especially hearing it from a neurologist that psychedelics might be something to delve deeper in terms of the science, and certainly doing that in a safe way with somebody who’s well trained, ketamine it tends to be something that’s sort of in that category that’s relatively accessible. Do you have any thoughts on ketamine in particular?
David Perlmutter, MD, FACN, ABIHM
Yeah, and again, talking about ketamine, one could argue the fact that well, it’s not really a hallucinatory psychedelic per se, but I think the data coming out with major depressive disorder is really profound. I mean, far more successful than any pharmaceutical intervention currently approved for use SSRIs or other forms of antidepressants. So I am very, very excited about the role that ketamine might have in that regard. But there’s a unifying feature, I think, amongst many of the things that you just mentioned and it’s inflammation, whether it’s dementia, or depression, anxiety. Inflammation is always hanging around and whatever it takes to reign inflammation may prove effective. I read an interesting article this morning proposing the use of helmets or small worms in eggs, giving eggs of small worms to people to help reduce neuroinflammation in that it may prove helpful with these particular issues that we’ve just talked about. So I think the bigger issues relate to diet, and elevated blood sugar and obesity, and changes in the gut bacteria, and how those all play into augmenting this, the inflammatory cascade that seems to underlie many of these problems.
What we described in “Brain Wash” was this fundamental role of upregulation of inflammation, separating or disconnecting, the term we used, the prefrontal cortex from having influence over the more impulsive, shortsighted amygdala. So we can bring that connection back online and I think that’s the real mission that will then allow better decision-making, thinking about the future instead of just today. We are given this notion that, just do whatever you want and we’ll fix it. And we really need to bring that prefrontal cortex online and embrace the fact that the future is coming, and there is no treatment for Alzheimer’s from the pharmaceutical industry and it’s really up to us. So we really have to leverage that ability we have to embrace the idea that first we are responsible. And second, that we’re choosing our cognitive destiny in a very real way.
Heather Sandison, N.D.
Aging versus dementia. So is there some normal thing about cognitive decline as we age, or do you think that people should be able to maintain and maybe even achieve higher levels of cognition as they get older?
David Perlmutter, MD, FACN, ABIHM
I think dementia is a pathological state. There’s nothing supportive, nothing good about dementia. There’s no attribute about becoming dementia. So I think it’s pathology. I think it’s not just part of growing, it’s just not old timer’s disease, as it were. Or acceptable senior moments. There is no such thing as a senior moment in terms of writing away this notion that suddenly you don’t remember your grandchildren’s names, that’s clearly a pathological. We are living longer than we ever had, that’s for sure. And our bodies and brains, one and the same, manifest the accumulation of various things over time that are not necessarily supportive of structural or functional continued activity compared to younger, reproductive years. But there is an interesting idea that the dementia that we have is characterized by kind of shortsighted risk-taking, not leveraging prefrontal cortex, cognitive function, as much as you should as possibly being adaptive. And let me walk through this, ’cause it needs a little bit of unpacking.
When the brain activates what’s called the polyol pathway, so it’s converting glucose into fructose. Ultimately that leads to a situation of compromising functionality of various parts of the brain and reverts the brain to what is called foraging activity, a situation whereby we act impulsively. We’re not thinking about the future, we’re just looking for food right now because the brain thinks the body is starving by virtue of the fact that the fructose level is higher. And that could have been a survival mechanism obviously to be in that forging behavior. It’s more characteristic of rodents in the laboratory setting when you give them higher levels of fructose, for example. But nonetheless, we know that the Alzheimer’s brain is a brain that is characterized by much higher levels of fructose, as much as fivefold increased fructose produced within the brain.
How do we know that? we know that because glucose to fructose has an intermediary called sorbitol. And sorbitol levels are very high in the Alzheimer’s brain as well. So the fundamental here of Alzheimer’s may be that it was, I hate to say designed, but was preserved as a way of enhancing foraging activity, limited activity, less thinking about things, less being able to cogitate as a survival mechanism. So of course, in today’s world world, the higher levels of fructose in the brain ultimately lead to things like insulin resistance, even higher levels of glucose, upregulation of uric acid production, therefore more inflammation. And as such, our fundamental towards this notion of a bioenergetic defect or a defect in the way brain cells are able to utilize energy, why? Because their mitochondria have been disrupted by the higher levels of uric acid and also by fructose metabolism, which is an energy consuming ATP to AMP activity that ultimately results in defective mitochondrial function as does uric acid by its augmentation of free radicals, challenging the mitochondria.
And what happens when mitochondria become not as functional, a couple of things happen. First of all, they replicate those dysfunctional mitochondria A. And B, mitochondrial dysfunction is sensed by the nuclear DNA to trigger caspase enzymes that ultimately leads to pre-programmed cell death. So that defective mitochondria ultimately leads to neuronal death. So this is the downside consequence of this bioenergetic defect whereby brain cells are seen on these PET scans that look at glucose utilization, that the brains of Alzheimer’s patients show areas where glucose can’t be utilized, why? Because those neurons have dysfunctional mitochondria, and insulin isn’t working as well as it should. And so this gets back to the so-called bioenergetic defect that I think is very, very fundamental as it relates to Alzheimer’s and can be bypassed by a ketogenic diet as was recently demonstrated by Dr. Matthew Phillips.
Demonstrating cognitive improvement in mild to moderate stage Alzheimer’s patients on a ketogenic diet. And you can show that on brain imaging that looks at radionucleotide labeled acetoacetate versus glucose. You can show that whereas these areas are utilizing glucose, they can utilize ketones really well. So they’re functional, but not functioning to a certain extent. So it speaks to then mechanistically what has happened over millions of years, if you will, in terms of something being adaptive versus something now in the face of our current environment, being threatening. Similar with respect to the APoE-4 predisposition for brain degeneration. Well, there must have been an upside, or we wouldn’t have perseverance of APoE-4, 25% of our population carrying at least one allele. Why would it be there if it’s always gonna make people demented, and that wouldn’t be a good thing? Well, why would it persevere? First if it’s going to cause dementia generally that’s past our reproductive years, so that’s one explanation.
But the other side is that it may confer upon us an increased level of inflammation, which traditionally was probably a good thing, because it would help us fight infection against bacteria and parasites. We know even now that there is strong a representation of APoE-4 being protective, when parasites infest individuals in certain equatorial tropical regions, and offering them protection against dementia, carrying the APoE-4 allele when they have parasitic infections. So it’s time to take a step back and really take a deep breath, and look at all this information that we have, and look at it in the context of all of these things, possibly offering us a survival mechanism now in the form of these individuals living in these tropical areas, but certainly all of us historically when the world was much different.
Heather Sandison, N.D.
Right, right, I’m so glad you mentioned that keto study because what’s happening, what you’ve described is that the fuel isn’t being used efficiently in the brain. And so what can you do? You can switch the fuel.
David Perlmutter, MD, FACN, ABIHM
Right.
Heather Sandison, N.D.
And that can be, you get almost the opposite of this foraging response that you were describing, where you’re just thinking about right now, you just need to eat. And a ketogenic state, many people actually have mental clarity, they stop being hungry, they’re not as desperate to find that sugar rush. And they are able to think more clearly, of course, and that they have less anxiety, they start to sleep better. So you see a lot of things resolved. Now, I wouldn’t argue that people should be in ketosis forever, probably just as bad as burning sugar for fuel would be always burning fat for fuel. But some mix of going back and forth and getting the brain healing benefits. When I think about ancestral diets, what was consistent about them was inconsistency.
David Perlmutter, MD, FACN, ABIHM
Absolutely, flexibility.
Heather Sandison, N.D.
Flexibility, adaptability. And this kind of goes to that hormetic effect, right? A little bit of stress on the system can actually increase our ability to respond to changes in the environment. And so wherever we can do that, we find that the brain responds to that. So with calorie restriction or fasting-mimicking diet, like the ketogenic diet. With hot and cold therapies, with oxygen sometimes even, of course, in the right context in a safe place. But there are ways that we can, exercises a phenomenal example, one of the best. Where we stress the system a little bit and then get this response that’s so good for long-term health.
David Perlmutter, MD, FACN, ABIHM
That’s right, but it all requires action. And here’s the big divide, is my action going to the doctor and getting a prescription? Or is my action utilizing the very things that you are talking about today? And that’s the great divide. And I think people need to come upon that intersection and ask themselves, two roads diverged in the wood here. And by and large, it’s a lot easier to say, “I’m gonna continue to live the life that I want. “And it’s my life, I’m gonna choose “to do the things I wanna do.” Then when the time comes and I’m having a problem, then I’m hoping that there’s gonna be something out there for me.
And we see that play out quite a bit these days in terms of how people make certain decisions and do certain things. And then when they they don’t play out exactly right, they’re suddenly requiring an intervention. So that said, in the context of Alzheimer’s affecting now 6 million Americans for which there is no treatment, yet we know that lifestyle choices are powerful levers to pull in terms of reducing a person’s risk for an incurable situation. I think we need to present it like that. We need to let people know this is an incurable situation, it’s a one way street. But you don’t have to go down that street.
Heather Sandison, N.D.
Well, and I would like to differ a little bit because I’m seeing dementia reversed in my office regularly.
David Perlmutter, MD, FACN, ABIHM
No, I’m talking about from a pharmaceutical perspective-
Heather Sandison, N.D.
From a pharmaceutical-
David Perlmutter, MD, FACN, ABIHM
There is no pharmaceutical fix. Now, to be sure, I mean, we talked about the work of Matthew Philips, we can certainly talk about the work of Dr. Dale Bredesen. If we get away from this model of a pill, or perhaps two pills, and recognize that in each individual we can identify areas that maybe contributing to this brain decline, and remedy those, if people are willing, then absolutely. I mean, Dr. Bredesen wrote a book about that recently, the people that he’s reversed, I wrote the foreword to it, as a matter of fact. That he’s reversing dementia. And I wrote the foreword saying that this is landmark. I mean, it really it’s incredible. If I were on the Nobel Prize Committee, his name would be right there on the table because he’s done it, he has done it with a totally different paradigm that doesn’t put hopes in a multi-billion dollar blockbuster drug that’s gonna give shareholders a great return on their investment, but rather leveraging as many as 36 different endpoints or influxes that can have an impact on changing what may be a skew in the brain.
It’s a tough concept to get people to get their arms around. But your point is certainly well taken, that it is happening. Maybe the ketogenic diet is not for everyone, and I don’t think that it is. I think in individuals whose brain metabolism might be normal, or can we fingerprint people based upon their glucose scan versus their keto scan and determine who then would best benefit from a ketogenic diet. But we need to also a look at the other inputs, are there infections going on? Is there chronic lyme disease? What’s the blood sugar? What’s insulin sensitivity looking like? What is the uric acid level? All of these things are extremely valuable in and of themselves, they might be playing the lion share of role here as it relates to that particular person’s individual issue.
I think of the person who says, “Doctor, my feet are hurting. “I walked five miles today, “and look at the blisters I have.” And my response is, “Were you’re wearing shoes?” And he says, “No.” And so I give him some shoes, and the next time he comes back, he has blisters again. And I said, “Well, why didn’t you wear the shoes?” He said, “Well, I have a size 10 foot, “and you gave me a size six shoe.” And he, of course, it didn’t fit him, and in my response, I say, “Well, most people, that’s the size most people wear. “so that’s really your problem.” So the that’s what we’re trying to do though, with Alzheimer, we’re trying to put everybody into one size shoe. And as Dr. Bredesen made very clear, people have different requirements, different needs in terms of first identifying what’s going on in their particular situation, and then providing that suite of remedies.
Heather Sandison, N.D.
So one of the very appropriate criticisms of Dr. Dale Bredesen approach, what I do every day in my office is that there’s not enough research. You are very research-driven, and one of the things I appreciate so much about you is that when the data changes, you change your mind, right? Which is what any rational person should do.
David Perlmutter, MD, FACN, ABIHM
And I get criticized for it, but that’s okay.
Heather Sandison, N.D.
Well, I’m here to tell you how much I appreciate it. And so when the data changes, hopefully there will be a groundswell of support for this from neurology offices, from primary care offices, where they will say, “Hey, there is something you can do.” It’s not just Aricept and amiodarone, there is a lifestyle that you can choose to follow, and you may get benefits from it. And not just with dementia, but hey, your hemoglobin A1C is gonna get better, that gout may go away. You’re gonna see resolution often of blood pressure. And so what do you think would be the research? What is the paper that you would need to see or read? What is the study? What would be the design of the study that would make you fully convinced that this is reversible?
David Perlmutter, MD, FACN, ABIHM
I’m gonna have to tell you that I’m embargoed from answering that question right now. I will say that it’s been written, and I’m gonna have to leave it at that. There a number of things that I do that I’m gonna have to, I would just say be confident. I can’t really take it further than that right now, but unfortunately the research has already happened, books have been written. And it’s so frustrating that it doesn’t seem to move the needle because the mainstream doctors are told, “This is the pill, and if it doesn’t work, “hang on, we got a new one coming down the pipeline.” Pfizer abandoned medication research for Alzheimer’s because they just weren’t finding anything, they were losing millions and millions of dollars. So what Dr. Bredesen has come up with is a totally different paradigm. I think coming up against mainstream medicine and specifically mainstream neurology is very, very compelling and very challenging. And I would hope that this would rise to the top and people would pay attention to it, but hope is not a strategy.
And I don’t know what the right strategy is. I mean, I’ve talked about this topic with Dr. Bredesen on any number of occasions, and we’ve said, “Yeah, publish the research, “we gotta write a book.” And now he’s on his fourth book, I guess, and it’s happening that he’s doing these things, but, ah, it’s very frustrating. ‘Cause he’s getting the results that nobody else is getting, and yet it’s so challenging to get people to pay attention to that. And here’s a guy whose heart and soul in this, he dedicates every ounce of his energy to this whole idea of a multifaceted approach in terms of identifying causality, and then rectifying whatever is askew. And you couldn’t ask for a more dedicated individual in your corner, and yet I think he’s making progress, I think more and more people through the work of other doctors who are using his protocol like yourself, who are following the protocol. I think that’s certainly helping a lot. Percentage wise it’s not a huge number as they’re based to Alzheimer’s patients who by and large are gonna take the Aricept, and the amiodarone or nothing, hopefully. But we gotta stay with it.
Heather Sandison, N.D.
I wanna stop you there. You said, “Aricept, amiodarone, or nothing, hopefully.” Tell us a little bit about why you would prefer a patient take neither?
David Perlmutter, MD, FACN, ABIHM
Well, research shows that neither is the best choice that these drugs don’t work, they’re associated with side effects. And publishing in JAMA network several years ago, Richard Kennedy indicated in looking at a fairly large number of individuals that those individuals taking at least the cholinesterase inhibitors Aricept actually demonstrated a more rapid decline, cognitively, than those who did not. Here’s a drug being given to Alzheimer’s patients to slow down their cognitive decline, and low and behold, they decline more rapidly. And yet it’s still okay to write prescriptions for this drug. I would say, don’t get me started, but I’m started that’s for sure.
Heather Sandison, N.D.
Well, I wanna just offer. I have seen patients who have started on those drugs and then when they come off of them, when they try to come off of them, they get precipitously worse. And it’s been hard to recover.
David Perlmutter, MD, FACN, ABIHM
No question, about it. I mean, what happens when you’re working at the NDA receptor, or you’re inhibiting cholinesterase and therefore building up acetylcholine, what happens when you stop that? I mean, there’s rebound effects and it’s been well described. And don’t think that the manufacturers don’t know that because people say, “Hey, we’ll stop the medication, “see what happens.” Bingo, people get worse. So I don’t see the sense in use them, that’s my opinion, I can back it up. But I wanna look at the glass being half full and focus on these ideas that we really are getting our arms around these fundamental mechanisms that are leading to brain functionality decline. And now that they’re being addressed, whether they infection, toxic, metabolic, degenerative in terms of being related to other degenerative conditions. What they may be, and identifying them, and then remedying those underlying problems, and seeing the results that Dr. Bredesen is describing that is to me, the glass half full, the glass is really almost pouring out the top.
Heather Sandison, N.D.
It’s such common sense, right? This paradigm, that instead of naming a disease based on what the symptoms look like, you start to ask the question, why? Why did this happen? And you even mentioned inflammation as one of the potential causes. And I wanna just push back a little bit on that because I think of inflammation as downstream, that’s-
David Perlmutter, MD, FACN, ABIHM
Oh, I agree with you.
Heather Sandison, N.D.
There’s something else-
David Perlmutter, MD, FACN, ABIHM
It’s mechanistically very important, but I think it’s clearly downstream from many of the upstream mechanism including metabolic dysfunction, possibly even infection. I mean, the notion of infection being related to Alzheimer’s has been around for a long time. I think Dr. Ruth Itzhak’s work at Cambridge was published 25 years ago, identifying one particular organism, herpes simplex virus type 1 being colocalized to beta-amyloid and inducing an inflammatory response. But I think biggest player clearly in our modern world in terms of inflammation has to do with our glucose insulin dysregulation model. And that is so catawampus these days, and it’s downstream issues that further augment inflammation like obesity, and disruptions of the microbiome leading to gut permeability and upregulation of LPS transgresion across the bowel lining and therefore, even higher levels of inflammation.
But I agree, it’s a downstream issue. And I think to approach it appropriately, we have to look at those upstream issues like uric acid, like blood sugar, like fasting insulin levels, not necessarily glucose levels. More tangentially looking at A1C, at Body Mass Index, all of these things that clearly, pun intended, feed into inflammation, which ultimately the brain is inflamed, it’s on fire, that’s the meaning of the term. And then the downstream effects of that being things like upregulation of free radical production, compromised mitochondrial function, and ultimately this energetic issue.
Heather Sandison, N.D.
I wanna talk a little bit about “Grain Brain.” You published this originally in 2013, it’s been what? At some point it’ll be a decade, next year.
David Perlmutter, MD, FACN, ABIHM
That’s right.
Heather Sandison, N.D.
Like we’ve already talked about as the data changes, you change your mind, so you’ve made updates to this. And I’m curious, I mean, in 2013 you were one of the first people saying that even if you didn’t have celiac, you may wanna consider getting away from gluten because of this downstream effect of inflammation, leaky gut. And there, I’m sure you got a lot of criticism and pushback, I can only imagine.
David Perlmutter, MD, FACN, ABIHM
Which is a good thing.
Heather Sandison, N.D.
Right, of course.
David Perlmutter, MD, FACN, ABIHM
If you’re putting things out and there’s no pushback whatsoever, then you’re at status quo. If everybody says, “Yeah, I got it, old news.” Then you’re not helping to move the ball down the field.
Heather Sandison, N.D.
Well, you certainly did. And you continue to, I know that the updates and the latest edition include things like the microbiome that you started to talk about. So I wanna understand with your just assessment of the literature where things are right now, what is the best diet for our brains?
David Perlmutter, MD, FACN, ABIHM
Hmm, and I would tell you, it depends on who is your patient. So it’s often said that it’s more important to know the patient who has the disease rather than the disease the patient has. So I think we are now in the time of personalized medicine and I think it’s not appropriate to be very specific about a dietary recommendation per se for any individual, but I think we should have dietary goals. What are those goals? Our goals should be to make sure this is a diet that’s going to be really effective, and helping keep blood sugar normalized, that’s going to keep down inflammation, that’s going to provide the suite of micronutrients that we know are important, and will certainly nurture the gut bacteria as well. Now, might that be different based upon your unique polymorphisms in terms of how you produce B vitamins, or how you are able to detoxify a certain toxins to which you are exposed and therefore, you as an individual might need upregulation of certain pathways.
Might you then wanna concentrate more in cruciferous vegetables or et cetera? That’s where the personalization comes into play, but I think the fundamentals are those goals. We want insulin sensitivity to be improved and then maintained. We want to nurture the widest array of gut bacteria. We wanna reduce gut permeability. We want to be sure that we are not creating a situation where we’re actually enhancing in the brain fructose production through the polyol pathway. We don’t wanna increase fructose production anywhere in the body. So our goals of reducing inflammation, reducing a free radical mediated stress, et cetera, are the endpoints and how we get there can be through multiple roads leading to Rome. In other words, again, what works best for you? And that’s where the notion of wearable devices, continues glucose monitoring, et cetera, comes into play, because then I’ll know what Heather may need in terms of her specific diet that might well be different from what I might need.
Heather Sandison, N.D.
Right, right, and what were some of the things that have surprised you over the past 10 years, as you’ve kind of dug deep into this? What are some of those tenets that you sort of let go of and are now using?
David Perlmutter, MD, FACN, ABIHM
Well, I’ve never admitted this before, but I will right now. And that is, I was more taken by the role of our gut bacteria in terms of overall health and certainly brain health. That was more of a revelation to me than the notion that gluten can have a neurological, in some people can cause neurological manifestations. That was simply reading research, primarily a researcher at Oxford, Marios Hadjivassiliou who started publishing this stuff, and I thought it was really interesting. I started getting results in my practice by reducing gluten in patient’s diets, and their headaches would improve, et cetera. But the microbiome relationship, no one was talking about. And to me, it kind of stood to reason, if glucose homeostasis and inflammation were sort of cardinal players in brain degeneration, then making the leap to the role of disturbances of the gut bacteria in those two parameters. At that point, people starting to realize that changes in the gut bacteria could predispose to type 2 diabetes. And even that things like fecal microbial transplants could help with type 2 diabetes. Whoa, if it’ll help with type 2 diabetes, then there may well be something going on in the gut that relates to the brain, so that was the bigger leap for me.
Heather Sandison, N.D.
Oh wow.
David Perlmutter, MD, FACN, ABIHM
Over the years, I think that some of the things that have changed for me before “Grain Brain,” well before “Grain Brain” was the adoption of recommendation for more levels, higher levels of fat in the diet. 25 years ago, I was sort of parroting the standard discussion of low fat diet being a good diet. And it realized, we all realized where that actually came from and what a disservice that was for those of us practicing clinical medicine or nutritional counseling, you name it. So that was a big shift for me, that was prior to “Grain Brain” that’s for sure. So the diet moving forward with time has become much more plant-based, and there’s still room for meat in my diet, but much more plant-based because I’ve realized that a dietary fiber is so underrepresented in our modern world, and is yet fundamentally so important to nurture our gut bacteria so they can help resolve inflammation. They can help with production of appropriate neurotransmitters, appropriate B vitamins. We can help produce serotonin by down regulating pathways that take tryptophan away from serotonin, the cholinergic pathway. So many different things that are gut bacteria do they actually are involved in changing gene expression for crying out loud, so-
Heather Sandison, N.D.
Yeah, I was just gonna ask you exactly that question, in a nutshell or in the most succinct way possible, what is the gut brain connection? And you already mentioned a neurotransmitter balance, and genetic transcription, can you sort of synthesize for us, I think we hear that term, it’s very trendy, gut brain connection, gut brain connection, but what does that mean?
David Perlmutter, MD, FACN, ABIHM
Well, I would say frankly, that we shouldn’t be even having this discussion, that they should never have been segregated. When did that all begin? With Descartes, and the idea that while we have the bellows, which are the lungs. And we have the pump, that’s the heart. And there are these independent parts that ultimately come together to form the body. That’s never how the human body was looked upon prior to Decartes. It’s always been looked upon as sort of a unified whole, and dare I say, a holistic perspective. So the notion that, I’m trying to defend that there’s a relationship between the gut and the brain, which now I’m not being, that’s something I’ve done countless times. So there are multiple levels by which they’re connected, but ultimately they’re all part of the same that everything is responding to the same influences, that the gut represents a powerful, this is a great place to start, a powerful way of informing the brain as to the external environment.
That’s really one of the most important things that the gut does, it informs the brain as to what what’s going on in the outside world, in terms of the environment, in terms of food availability, in terms of even water availability, in terms of threats, for example. But there are physical connections, of course, there are immunological connections that are profound. There are chemical connections that we’re just beginning to understand in terms of things produced in the gut that directly moment to moment influence brain functionality. There are relationships and mechanisms we talked about earlier, like inflammation and glucose homeostasis that are profoundly influential in terms of brain health and a functionality.
And there are top down issues as well related to the gut from the brain, again, physical as well as chemical, hormonal. So the relationships are multifaceted and are are seen at multiple levels. So to me, why should it be a surprise that it’s now as you say, trendy to conceive that the gut is somehow involved, and influences the brain. It’s only been the past couple 100 years that they were segregated, and it’s now time to really recognize that our entire bodies are functioning with just continuity between all seemingly disparate parts.
Heather Sandison, N.D.
And this is where that Bredesen paradigm shift around dementia starts to make a lot more sense, right? In that idea that we’re putting the body back together, and myself as a naturopath, that’s the way I’ve been trained, so I sort of take it for granted. We have to put the body back together, the person back together, that person-
David Perlmutter, MD, FACN, ABIHM
Reintegrate.
Heather Sandison, N.D.
Reintegration, yeah, exactly. And that even though many people end up with the same diagnosis, we like this from an ICD-10 perspective, from an insurance perspective that fits the model. But when we can set that aside and say, okay, how did you arrive at this imbalance? What are the things we need to offer to the cells, to the body, to the system to help optimize function? Well, then we can change the conversation from talking to Dale Bredesen to talking to somebody like David Sinclair, where we’re saying, “Okay, how do we live to be 150?” And really have these fabulously wonderful lives where we get to show up at our great-grandchildren’s college graduations, and be part of really just enjoying our elder years and contributing in our elderly years?” That wisdom and experience is so valuable, not only for one family, but for society as a whole. And so when we have people with sharp, clear minds who are able to show up at work or at church, or at family gatherings, that there’s so much we’re throwing away when that’s not happening, and yet it’s all possible today.
David Perlmutter, MD, FACN, ABIHM
It is, and it really is. And if you wanna blame somebody, you can blame me for not being as totally effective as I could be, and blame Dale Bredesen because we can’t get the word out, and we’re trying some people that.
Heather Sandison, N.D.
Stuck that with you.
David Perlmutter, MD, FACN, ABIHM
But that’s the issues that we are up against incredibly powerful forces that would have us believe that Alzheimer’s is simply a loss of acetylcholine in the brain, acetylcholine hypothesis, the cholinergic hypothesis, and that if we can put the acetylcholine back, then everything’s gonna be just Jim dandy or-
Heather Sandison, N.D.
Or take amyloid plaque out.
David Perlmutter, MD, FACN, ABIHM
Or amyloid or Alzheimer’s is simply the accumulation of beta-amyloid in the brain. If we can keep it from happening or take it away, problem solved. And that’s the narrative that makes its way certainly to the general population, but much more importantly, is what doctors are being told in their journals, at their meetings. And then through the advertisements for the drugs that target those specific activities. It’s hard to go up against that because truthfully doctors want to practice medicine within a 15 minute window, that you’ve got, you name the problem, and then you have a pill. And as it relates to neurology, oftentimes it’s diagnosed in adios, ’cause there is no pill. But in another specialty is, “Oh, you have high blood pressure, “here’s your blood pressure pill, see you later. “You have diabetes, here’s the drug, take the drug. “And as long as you take that drug “and keep filling that prescription “year after year, after year, until you die, “we will accomplish our task, “which is getting your blood sugar under control.” No, that is not the task, that’s not the challenge.
The challenge is to treat the diabetes, to treat the fire and not just the smoke. And we know Dr. Sarah Hallberg has shown us that you could put diabetics on a ketogenic diet, and they can come off their drugs and not ever need them again. That’s treating the fire, not just the smoke. It’s a tough road, but we’re still in the batters box and we’re gonna keep swinging as long as there’s something to hit. And once in a while we hit, and in my life, for example, you said a lot of people have read “Grain Brain.” How many will act upon what we wrote about? Not everyone, that’s for sure. But a percentage of people have read it, and a smaller percentage of them will act upon it. But you know what? If one family can be spared of the agony of Alzheimer’s that I went through with my father, then it’s worth it. At the end of the day, at the end of my life, it’s worth it.
Heather Sandison, N.D.
Well, I agree with you completely, Alzheimer’s is optional. There are things that we can do today to prevent it for the vast majority of people. And if we can spare one family from the torture that is dementia, then it’s worth showing up. Thank you so much for showing up here today, for lending your time and expertise to this, and for inspiring all of our listeners who are joining us.
David Perlmutter, MD, FACN, ABIHM
Thank you for having me. And I sure appreciate the opportunity. And my hope is that, there’s something here that people can hang their hat on just as a way of just opening a little part of your mind, that there may be another way out there. And that frankly, we are each involved in choosing our brain’s destiny. It’s not something we can outsource.
Heather Sandison, N.D.
I’m certainly inspired by the sheer volume of phone calls that we get both at my clinic and at Moroma the residential care facility, and how many, usually it’s a daughter, That they come in enthusiastic
David Perlmutter, MD, FACN, ABIHM
Interesting.
Heather Sandison, N.D.
And ready to get started. And really I’m inspired, not just the caregivers, but the patients who are the pioneers in this space who are showing us what’s possible, it’s incredible.
David Perlmutter, MD, FACN, ABIHM
That’s right.
Heather Sandison, N.D.
Thank you.
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