Alzheimer's Antidote: Ketogenic Diet, Cholesterol Fallacies, & APoE4 Protein ft. Amy Berger

Alzheimer's Antidote: Ketogenic Diet, Cholesterol Fallacies, & APoE4 Protein ft. Amy Berger

Authored by Zhill Olonan and Geoffrey Woo • 
January 8, 2019
 • 40 min read
ketosisnutritioncognition

You’ve felt the crash after a sugar rush. You’ve felt the boost of energy from coffee. If you listen to this podcast, you’ve hopefully felt the steady focus and clarity from being in ketosis. Point is, we all know that food and what we ingest affects our brain function.

Amy Berger, the author of the Alzheimer’s Antidote, is passionate about the link between diet and brain health. Her research focuses on how a low-carb, high-fat diet can improve neurological brain conditions like Alzheimer’s, and why the wrong diet can worsen and even cause it. There’s a reason it is increasingly being called “Type 3 Diabetes”, and Amy is here to shed some light on why.

In this episode, you'll discover:

  • The potential root causes of Alzheimer's and cures for it
  • The protein APoE4 and how it may affect brain health
  • Should cholesterol truly be feared?

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Transcription

HVMN
Geoff

Hey, Amy. Thanks for coming on the program.

HVMN
Amy B.

Yeah, thanks for having me.

HVMN
Geoff

So where are you dialing in from?

HVMN
Amy B.

I'm in Virginia about an hour south of DC.

HVMN
Geoff

I was actually in Virginia Beach a couple weeks ago. I've been following you on Twitter for quite some time. I would say that you're within the keto Twitter circles of people being highly cited and disseminated. Before we get overly deep into your work around Alzheimer's, ketogenic diets, looking at cognitive impairment as insulin resistant problem, perhaps, curious to hear your own personal journey. I know you're a veteran. I know a little bit about your background, but helpful for your audience to hear your personal journey here.

HVMN
Amy B.

I came into low carb like a lot of other people do. I used to be heavier. I was not obese, but I was certainly chubby and I was chubby despite doing what I thought was all the right things, eating lots of those healthy whole grains and putting margarine on my whole wheat bread and all that and doing lots of exercise. Like you said, I was in the military. I'm not afraid of a hard workout. I'm not undisciplined. I just couldn't lose the weight no matter what I did, no matter how hard I worked. I was fortunate that I didn't have any health problems. I really was just carrying extra weight. I do have a family history of type 2 diabetes and stroke and cancer, so there's no doubt in my mind that if I hadn't found low carb, my health now would probably be a disaster. At the time when I found low carb, I really was only dealing with some excess weight.

HVMN
Geoff

So nothing wrong with your lipids or your fasted blood sugar, hemoglobin A1C?

HVMN
Amy B.

I was in my early 20s. I didn't even really have a lot of that looked at in the first place. I remember I did have one blood test for some life insurance. I got a higher premium because my cholesterol was high, but that was before low carb anyway, so who knows? No, I didn't really have any major health problems that I knew of, anyway, so of course, lo and behold, the weight came off. The weight came off without me having to count calories or deprive myself of delicious food. Over the years, my interest in low carb and keto has evolved from just starting from weight loss to all the other things low carb does. I've said in other interviews that when you get to really know the science of how this works, weight loss is the least impressive thing that this does, so I branched out into more of that. Then I've been in and out of a lot of jobs that I wasn't fulfilled by, didn't really enjoy the work, and it occurred to me I think I could be a nutritionist. I could actually help other people with low carb as full-time job, so that's what I do now. I get most of my income from writing in the low carb and keto community, but I do see private nutrition clients.

HVMN
Geoff

You've been on a low carb, ketogenic diet for how many years then?

HVMN
Amy B.

Well, I'm not perfect. There's been times where it hasn't been quite so low carb, but for the most part, I've been low carb for the longterm since 2003.

HVMN
Geoff

Wow.

HVMN
Amy B.

Before then, I started it in college around 1998 or so, but I really wasn't ready for it. I wasn't ready to do it longterm, so it was kind of on and off. I have to specify that for the most part, during that whole time, I'm not super strict ketogenic. I'm low carb, but I'm not always super keto. I do bounce in and out of ketosis very often just by default of what I'm eating and what I'm not eating, but I don't always aim to maintain a ketogenic state all the time.

HVMN
Geoff

That's pretty impressive given that the state of interest of keto really has exploded in the last, I would say, year and a half, two years. There probably wasn't that much resources for you to fully understand back in 2003. You must've been just completely in the woods with people thinking that you're crazy.

HVMN
Amy B.

It's funny. You're right in that at that time, there wasn't a whole lot. There was maybe like one or two message boards. Nobody had a blog back then. There was no blogs. YouTube didn't even exist. Podcasts didn't exist. I have to say I consider myself fortunate and lucky that there was less information when I was new because there was less misinformation and there was less nonsense. Like right now, because this is so popular, it's all well and good that there's a million YouTube channels and there's a million sources of information, but unfortunately, for every one piece of accurate, reliable stuff, you have to wade through nine pieces of garbage. If you're new to this, you don't know what the garbage is and what the reliable stuff is, so I feel like I don't envy the people that are brand new to this.

HVMN
Geoff

I think that's something that we see being polarized on the internet in social media where you have people on one side that are oh, it's a keto advocates or the carbinatti is one term that my friend, Dr. Priyanka Wali mentions, basically, people that are just like it's almost a religion for them. Then I think on the other side you have people that just are completely dogmatically against the whole notion of low carb. I think that really has not been helpful for the discussion. I think in our community, a lot of people are experimenting with ketogenic diets, intermittent fasting, and for me personally, I cycle in and out of a ketogenic diet. I think really, I think the baseline is that there's some obvious things like refined carbohydrates like sugars, clearly bad for you, but assuming that you have reasonable diet, different types of diet are useful for different types of outcomes. If you're trying to train for a marathon, trying to body build, you would have a different macro ratio and a ketogenic diet may or may not be helpful for your goals, so I think we should approach this in a more sensible way. I think a lot of what you talk about seems to focus on the data and the science that's good and try to debunk the craziness from both sides.

HVMN
Amy B.

I couldn't agree more. Obviously, I recognize the amazing therapeutic potential of a medically therapeutic ketogenic diet, but that doesn't mean that this is the only way to be healthy, the only way to support athletic activity. I do see a lot of ugliness coming even from our own community from people that I like and respect for the most part, but even if I agree with what they're saying, sometimes the way they say things, they make us all look bad when they resort to personal insults and personal attacks. That makes all of us look bad.

HVMN
Geoff

Yeah. It makes people on the low carb keto side look like religious fanatics. I don't think it's helpful to make this dogmatic when there's clearly utility in science and evidence that suggests this could be very useful for a lot of the chronic diseases that are facing Americans, especially prediabetes. A third of us to half of us are all prediabetic. Most of us are looking to go on the other side of obesity. I think one thing that I think especially that you're focused on, which is emerging interest is Alzheimer's. That's one of these subtle killers that like a third of people over 85 have Alzheimer's. That's probably higher because it's so undiagnosed. How did you start making that link from the broader impact of a ketogenic diet? Obviously, you saw your personal body composition improve. Why did you start narrowing your focus towards Alzheimer's and neurological conditions?

HVMN
Amy B.

It kind of happened not by accident but by serendipity. The first place I ever heard about a connection between insulin, glucose, and Alzheimer's was in Gary Taubes' book Good Calories, Bad Calories. I'm sure a lot of the listeners and viewers know that book very well, know who Gary Taubes is. He had a chapter in there that covered dementia, cancer, and aging and it was the first place I ever heard about this potential connection. I don't have any family history of Alzheimer's, so it wasn't that big in my mind, but it was like oh, wow, that's really interesting. Huh, look at that. It wasn't until maybe three or four years later that I was getting my master's in nutrition and I had to write a thesis and instead, we had a choice between doing a literature review or an original experiment, so I was going to do a literature review. Basically, you just scour the scientific journals for a deep dive into some particular topic. When I had to pick the topic, I said what is something that I could research that hasn't been written about a million times already, something that I would actually learn, something that I would be interested in, and something that there would be enough research on that I could even write a thesis on it. I said let me go back to that Alzheimer's thing and see if there's anything there. Even in just my initial look through PubMed, through some of the online databases, I was stunned at what I found. There were so many papers. It was everywhere. I couldn't believe that if I had already been low carb for many years by this point and I had never really heard of this and I'm into this stuff and I don't even know about it, what about the people out there that have this condition or whose loved ones have this condition that they don't even know about low carb, let alone the connection between glucose and Alzheimer's. I didn't start out from a point of I want to learn about Alzheimer's and insulin. It was like I have to pick a topic. Maybe, maybe there's a couple of papers on this. Well, yeah, there's a lot more than a couple.

HVMN
Geoff

Yeah. Let's survey what this is. Oftentimes on the program we nickname Alzheimer's as type 3 diabetes, so what is this function there and how do we compare that to the amyloid hypothesis, sort of the mainstream therapeutic approach to finding drugs that cure Alzheimer's? What is our thesis, the low carb, the glucose, insulin, Alzheimer's thesis and how do those interplay?

HVMN
Amy B.

Like you said, they regularly refer to Alzheimer's disease as type 3 diabetes. They also call it brain insulin resistance. You'll see all these things in the medical journals. Where that comes from is the primary problem in the brain of somebody with Alzheimer's is that the brain has lost the ability to effectively metabolize glucose, so I say that this is a metabolic problem, metabolic meaning energy. It has to do with the way the brain gets energy. This is a fuel shortage in the brain and because of this fuel shortage, the neurons basically starve and they atrophy. They wither. They shrivel up. You can even see this on MRIs. They can see the physical matter of the brain shrinking. The question is why and we don't know. That is the problem in the brain, but we don't know why it's happening. We could speculate as to why, but we don't know why for sure. The amyloid hypothesis is basically that there's a buildup of these like-

HVMN
Geoff

Plaques, these tau proteins, amyloid.

HVMN
Amy B.

Yeah. The tau and the amyloid are two different things, but it's these misfolded proteins that are accumulating and getting in the way of cellular communication. Amyloid is a perfectly normal process. Everybody secretes these proteins. The problem in Alzheimer's is that they're not cleared away properly. When these proteins are secreted out of the neurons, they build up outside the cell and when they build up to a certain concentration, they start to cross link and solidify into these infamous amyloid plaques. These plaques can actually get in the way of neural communication. They sort of just gunk up the works and so it makes sense oh, well, okay, this amyloid is getting in the way. Well, this must cause Alzheimer's. This is the cause. For all these years, all the research dollars, all the effort has been focused on getting rid of these plaques, except not everybody who has Alzheimer's has a lot of plaque in their brain and there's people who die from other causes with no signs or symptoms of Alzheimer's. When they have their brains autopsied, they do have a lot of amyloid, so this amyloid is either not the cause of Alzheimer's or it's not the main cause. There's been many drugs, multiple drugs now, developed to reduce the formation of these proteins and plaques and every one of them has been a failure. I say that they've been a failure in the sense that these drugs do reduce the secretion of the proteins. They do reduce the plaque formation, but those reductions have never done anything to improve the disease. You get rid of the proteins and plaques or you reduce them, the Alzheimer's still progresses. It still gets worse. They did one-

HVMN
Geoff

Right. The cognitive impairment is still there.

HVMN
Amy B.

Yeah. It does nothing to improve the issue. The phase three clinical trials on one of these drugs had to be stopped early because the people on the drug were doing so much worse than the people on the placebo that they deemed it unethical to continue. Every time we get rid of this amyloid, people with Alzheimer's get worse. I'm not saying the amyloid is meaningless. It does have an impact, but it's not what we think and it's this substance that we've completely demonized. We've deemed that this is the cause of Alzheimer's and if we could just get rid of it, then we've cured this disease. We've done the same thing with cholesterol and cardiovascular disease. We've taken this one substance that the body actually produces and we've misunderstood it. We've mischaracterized it. We statin drugs or PCSK9 inhibitors. If we could just get rid of every last molecule of cholesterol, then we've cured heart disease. Well, that hasn't worked out so well. In the same way, it's not working for Alzheimer's and the amyloid.

HVMN
Geoff

Right. Cardiovascular disease is the biggest killer in America and we have a lot of statins out there. Something doesn't seem to add up. We can touch upon statin story. I'm actually curious about that, as well, but let's focus on Alzheimer's for now. Amyloid seems to play a role, but what you're suggesting here is that is not the root cause. It might be a symptom of something that's going wrong. What is the brain insulin resistance theory here and what does that suggest for therapeutic routes?

HVMN
Amy B.

Chronically high insulin is a risk factor for Alzheimer's disease even if your blood sugar is normal, even if you don't have diabetes. Regardless of your family history, regardless of your genetics, chronically high insulin is a risk factor for Alzheimer's. The funny thing is, though, that we have high insulin, what we call hyperinsulinemia, in the periphery, meaning in the rest of the body, in the brain and the central nervous system. People with Alzheimer's seem to have less insulin. Now, the thing is, glucose transport and glucose uptake into the brain is, for the most part, not insulin dependent. You don't need insulin to get glucose across the blood-brain barrier, but there are insulin receptors scattered all throughout the brain, so we know insulin is doing something in there. It's doing something for cognition or healthy brain function. When they administer intranasal insulin, they give insulin via a nasal spray and it gets directly to the central nervous system, people with Alzheimer's have improved cognition, at least in the short term. It's a very short term effect. Why is insulin not getting into the brain or why is the brain not using insulin properly? They don't know. There's a lot of unanswered questions in this disease, but there's no doubt that the primary problem is a fuel shortage and it's specific to glucose. It's because the brain ... We can get into ketones and some other stuff. Glucose isn't the only fuel the brain can use, but in most people eating a typical Western, high carb diet, glucose is going to be the major fuel for the brain. If the brain has lost the ability to metabolize glucose and get energy from it, it's going to have a major impact on cognition.

HVMN
Geoff

I think some of the results from Steven Cunane's work, you can actually do PET scans in the brain and detect lower glucose metabolism in patients with Alzheimer's or with cognitive impairment. I think just to double down on your point here, you can actually measure the glucose uptake differences between a healthy brain and the glucose.

HVMN
Amy B.

Steven Cunane is my hero. His work and, I guess, his students, his colleagues, they are amazing. Something that we should ... Two points, one of them is like we were just talking about the statins and cardiovascular disease, Alzheimer's disease is like because we were talking about the amyloid. If amyloid was driving this condition, why would it be brand new? Why would be having this exploding epidemic now all of a sudden in human history versus a hundred years ago, 300 years ago? This is a new disease, right, or not brand new, but it's exploding in incidence in the same way type 2 diabetes is and cardiovascular disease and PCOS and hypertension, all of this other stuff that we know is driven primarily by high insulin.

HVMN
Geoff

So how about devil's advocate? How about someone would say hey, just because people are living longer now because of modern health, modern medicine. Is it because we're picking it up because people are just living longer? How would you respond to that kind of criticism?

HVMN
Amy B.

No, that's a great question and this was point number two I was going to make. It is true that we have an aging population. We have the Baby Boomers. They're in their 70s now. We do have an older population, so any disease that preferentially strikes older people is going to increase in incidence. You talked about the PET scan a minute ago, how you can actually measure what they call cerebral glucose uptake. The decline in the brain glucose metabolism that is behind Alzheimer's disease is measurable in people in their 30s and 40s, so no, this is not just an old people disease. This is not exclusively a disease of the elderly. That metabolic problem starts when people are young and at that point, you're young enough that you're able to compensate. The brain is still strong enough that it's compensating. It's only when this problem has gone on for so long that you cross the threshold where the brain can no longer compensate. That's when you start showing signs and symptoms, but by the time that happens, this disease process has been in place for decades. Nobody wakes up all of a sudden one day with Alzheimer's disease. That's not how this works. Just like diabetes, what happens? The insulin has gone up. Insulin is going up. Glucose is going up. Glucose is going up. That happens for years.

HVMN
Geoff

Yeah, and if we think about how these manifest in terms of symptoms, there's a lot of analogs, a lot of parallels. These are not just binary conditions. Even something like cancer, it's not a binary condition. These tumors grow slowly over time until it can metastasize. Then it grows really, really quickly. You see a lot of these chronic diseases seem to have similar outcomes, which suggests maybe there's similar inputs that drive these diseases. One thing that I think is just open to discussion is Alzheimer's even one singular disease? It sounds like you have multiple etiologies of where this disease comes from. What are your thoughts about that or do you really think that it is a core brain insulin resistance problem?

HVMN
Amy B.

The audience probably knows the name Dale Bredesen. Dr. Bredesen, one of his papers he identifies three subtypes of Alzheimer's that have different origins. In my opinion, Alzheimer's disease is one disease and it's the reduced glucose use in the brain. I think there are other kinds of dementia, other kinds of cognitive impairment, that I would not call Alzheimer's, so dementia is the big umbrella term that Alzheimer's is one form. You have vascular dementia. You have some of these other things, so my answer is both. Maybe it's one disease and it's not one disease.

HVMN
Geoff

No, that makes sense. I think it's how you subsegment, but I think you're right. There's different ways that the brain gets damaged that could be something like TBI or CTE over just a lot of brain collision. That's going to probably have a different etiology than a brain glucose metabolism issue with what you're defining as classic Alzheimer's and then just broader dementia. Now that if we identify brain insulin resistance as a root cause, then what would that imply in terms of therapeutic strategy because the drug companies have focused on amyloid, the amyloid thesis, and as you mentioned, those programs have failed. I think most of those big drug companies like Pfizer and Merck have pulled their neurological programs, which is scary that they've kind of waved the white flag against one of the most pervasive, insidious diseases we've seen modern humans.

HVMN
Amy B.

That's very scary, like we give up. We've tried so hard for so long that we just give up. I think that goes to show that not that this is an untreatable condition, but that they're approaching it from the wrong avenue. Just like when we give insulin to type 2 diabetics, nobody gets better. They don't get better. They get worse and worse and worse and they die. They lose legs. They lose feet. They lose eyes. That's not a treatment because you're addressing the wrong thing. If this is a metabolic problem, we have to treat it with a metabolic solution. Again, we don't know why the brain glucose metabolism is impaired, but that we know that it is impaired. We know from Dr. Cunane's work and from some other work that even though the brain is not able to properly metabolize glucose, an Alzheimer's-riddled brain still will take up and use ketones and so the answer, at least the partial answer, is if this is a fuel crisis and it's specific to glucose, is there some alternative fuel that we could give these starving neurons? Everybody listening knows yes, there is, thank goodness. We can give these starving cells ketones. Right off the bat, whatever else may be going on and whatever other interventions might help this, the number one place to start, ketogenic diet or exogenous ketones. Give those starving cells fuel any way you can.

HVMN
Geoff

I'm curious. What have you seen in terms of literature there in terms of the case studies, the clinical results? Has there been either anecdotes or studies that you've seen that show this as a more promising route?

HVMN
Amy B.

There's been everything. We hear anecdotes from people taking this into their own hands and doing it themselves. There are some clinical trials. A lot of it is animals. A lot of it is rodent studies, but there are human studies with people with Alzheimer's or with the precursor, which is called mild cognitive impairment. Most of them have been done with exogenous ketones, not with the diet, possibly because if you only give the ketones as opposed to the diet, it's one thing that you can measure versus like a diet. It does so many different things. What is the mechanism that's actually making them better or not making them better, whereas with the exogenous ketones, all you're doing is giving the ketones. There's nothing else happening. People generally do have improved cognition. Not everybody. There are some people who don't respond as well as others, but this seems to be the most promising thing so far. Dale Bredesen's program, he calls it keto light. I don't think he does the exogenous ketones. He does kind of like a lower carb, higher fat, Mediterranean-style diet, but he also includes a little bit of fasting, exercise, stress reduction, supplementation and hormone replacement based on somebody's own individual blood work. In terms of the clinical trials, yeah we do have some pretty promising stuff on ketones for this disease.

HVMN
Geoff

It seems like Bredesen's protocol is very similar to how a lot of our communities and a lot of our listeners are just doing that for lifestyle, just incorporating intermittent fasting, low carb diet. That's not elevate ketones that will cross the blood-brain barrier and, hopefully, provide alternate fuel, as you mentioned. I think just commenting on the difficulty of running a ketogenic diet study, as we were interfacing with different scientists, you can just imagine that if you're looking at population of people with mild cognitive impairment or Alzheimer's, it's very, very hard to put these people on a ketogenic diet. They just don't understand why you're feeding them so much fat, so I can imagine that like an exogenous ketone or things like MCT oil, which are ketogenic precursors, would be amenable. As you mentioned, I think Cunane has some interesting work around MCT oil recovering some of that brain energy deficit from glucose uptake deficits with something like MCT oil, so it seems that there is some sort of correlation between the amount of blood beta-hydroxybutyrate with the energy deficit you can recover in a mildly cognitively impaired brain.

HVMN
Amy B.

Even for me some days it's harder not to stick to a low carb diet. Sometimes you just want a doughnut. For somebody who's young and healthy and wants to do a low carb or ketogenic diet, it can be difficult enough, let alone when it's somebody who is impaired and especially if they're so impaired that they have somebody cooking their food for them. It's so hard to be a caregiver and then to say well, now I have to cook all this special food and do this crazy stuff. That's not a reason not to do it, but yeah, I totally agree. I understand why it's really hard to do the diet in the studies. Also, there's still a lot of fear, like oh, you can't give these old, sick people egg yolks and butter. You'll kill them. There's still a lot of fear of the high fat aspect of the diet. I think coconut oil and MCT oil and exogenous ketones can be a godsend. Like I said, get ketones into these people any way you can. I think that the ketogenic diet and combined with other lifestyle things that help reduce glucose and insulin or improve insulin sensitivity, whether that's exercise or fasting and all this stuff, to whatever extent we can potentially not just halt the disease or slow it down, but actually reverse some of the damage, that, I think, requires a fundamental big change in diet and lifestyle. Just giving the ketones, whether it's through the ester or the salts or the MCT oil, just providing the fuel isn't going to do that. That will help improve memory and cognition, which we want to do that, but in terms of actually possibly reversing some of the problem, the ketones alone aren't going to do that.

HVMN
Geoff

I agree with you. Yeah, if you're using a ketone ester and you're still drinking soda, eating doughnuts, and still spiking insulin and still putting up the insulin resistance, you might get some short-term benefit like doing intranasal insulin pump. Yeah, you want to be reversing your insulin resistance, improving your insulin sensitivity.

HVMN
Amy B.

Exactly. Yeah.

HVMN
Geoff

To be a devil's advocate here, there was a clinical trial done by Accera with their MCT oil product called Axona, which didn't pass. I believe it failed phase two or phase three, so have you looked into why MCT oil, food, medical food, failed? I think it's multiple reasons why one could see that trial failed, but just to be complete here, have you looked into that result? Any thoughts on why they didn't see any changes from MCT oil as a supplementation for these patients?

HVMN
Amy B.

I think they did find it did improve cognition in some people, not in everybody. I think specifically the people with that ApoE4 gene did not have improvement. As to why that particular thing failed, I don't know. I think some of the papers I've seen, it was successful, but not in everybody.

HVMN
Geoff

Right. The phase one was successful. That's why they rolled into phase two. I think the phase two, they're basically coming back. They're reformulating. Basically, their claim is that it didn't raise the beta-hydroxybutyrate levels high enough.

HVMN
Amy B.

If I had to guess, it could be either that, that it wasn't effective enough, or that like we were just saying, some of these people just raising ketones alone might be enough. They might have to have other stuff going on or whether like if somebody's on a statin drug and their brain is deprived of cholesterol to they're B12 deficient, they might have other things that are interfering with healthy cognition where even just raising ketones alone might not help. I'm speculating. I don't know.

HVMN
Geoff

Yeah. I think it's helpful for the discussion that it's just nuanced thought, just like we have figured this out. I think there are interesting pieces that seem to be working and there's a direction to research, but I think we're going to get more and more fine tuned exactly how a therapeutic strategy can be approached. I think going back to some of the positive stories and anecdotes, there was a 2015 case study published by Mary Newport and Richard Veech showing that a ketone ester was able to reverse Alzheimer's symptoms, so on the plus side, there is peer-reviewed data showing that this strategy around brain insulin resistance and using ketones as an alternate fuel source does work. There is still work to be done. I think folks like Steven Cunane are looking at how we can do more and more data here to actually fine tune these strategies.

HVMN
Amy B.

It's definitely not a magical cure. It's not a silver bullet. I do think it's the most promising thing we have right now, especially considering there is literally nothing else. There is no alternative. There is no effective pharmaceutical drug for this condition. There are drugs on the market, but they don't do anything. They don't stop the disease. They don't reverse it. I don't know what they do. They're palliative. They're totally useless. This might not be the perfect solution, but it's the most promising that we have, I think, for now.

HVMN
Geoff

I think that's well-justified given the body of evidence there. One thing that people interested in this space might see pop up, I'm curious to get your thoughts on this, is ApoE4, these genetic markers that seem to be, if not correlated, potentially causal to things like Alzheimer's or traumatic brain injury. Curious to your thoughts about ApoE2, 3, 4. Do we think there's a relationship with those genetic markers to ketone metabolism or brain insulin resistance?

HVMN
Amy B.

I'm not as familiar with how those genes specifically influence ketone uptake and metabolism, but ApoE4 is, right now, the strongest known genetic risk factor for Alzheimer's, so people with one, heterozygous, one copy, are increased risk. People that are homozygous, that have two copies of E4, have something like 50 to 90% chance that they're going to get Alzheimer's. I like to point out that if you have a 50% chance of getting it, well, what does that mean? You have a 50% chance of not getting it, so what is it that flips that switch? What is it that triggers that susceptibility? All I can do is pass on what I've learned from the scientific literature. It's believed that ApoE4 allele is the oldest one in the human family, like the ApoE2 and 3 appeared later in human evolution. The ApoE4 is the most apelike, the one that was really forged in our hunter gatherer times or before, so it's the one that is the absolute worst match for the modern diet that is so different from the diet that this gene may have been forged during, like either higher fat, higher animal fat, higher green vegetable consumption, but certainly not a genotype that's suited to Doritos and Pop-Tarts and Mountain Dew. It's not that this gene causes Alzheimer's. It's not an inherently harmful gene. It's only harmful when you combine it with diet and lifestyle that it's really not suited to thrive in. I would say the ApoE2 and 3 are not suited to thrive in it either because there's millions of people who have Alzheimer's that don't have E4 genes and there's millions of people who are homozygous for E4 that don't develop Alzheimer's, so having E4 by itself doesn't cause it. I think they've done the study in Nigeria. I think tribal populations in Nigeria have the world's highest incidence of the ApoE4 gene and you know what they don't have?

HVMN
Geoff

They don't have Alzheimer's.

HVMN
Amy B.

They don't have Alzheimer's. I don't mean to laugh, but if I can reassure anybody out there, ApoE4, it's not a death sentence. It doesn't cause Alzheimer's, but you have to be careful to eat and live in a way that doesn't trigger that increased susceptibility because it definitely does increase risk. I'm not saying it doesn't. It does increase risk when combined with a modern diet and lifestyle.

HVMN
Geoff

Yeah. I think that's well-articulated. One thing that has been fascinating to me is that there's actually a similar correlation towards traumatic brain injury and concussion with ApoE4 versus ApoE2 and 3. I don't know the exact specifics, but it's something like 10 times more likely to get a concussion when hit with a traumatic brain injury. That's suggests that there's some interesting relationship between etiology of TBI and CTE, which is done blind, which you might have heard of from the NFL. All these players are coming out with CTE and Alzheimer's.

HVMN
Amy B.

You're going to have to get Dave Feldman or Savon Huggins or someone on your show because I think ApoE4, it's like one gene, but it influences so many things. One of the things that it really seems to influence is something with regard to lipid processing. That's the extent of my knowledge. I don't know much about it beyond, but something with cholesterol, with fat handling, which would, obviously, impact the brain or maybe somebody with an E4 could have the same physical impact to the head as somebody E2 or E3, but they are going to have a major injury or major problem, whereas maybe the others don't and that could have to do with the repair process with the cholesterol and the fat and the brain. I don't know.

HVMN
Geoff

I want to get into one of the initial threads around statins and cardiovascular risks, but any other exciting developments in the Alzheimer's, keto, low carb world diet that is worth mentioning? I feel like we've covered a good amount in terms of the basis why traditional methods have failed in terms of amyloid hypothesis. What are the most exciting future research directions that you're most excited about?

HVMN
Amy B.

I'm just heartened by the fact this sort of alternative view is getting more attention now because as more and more of these drugs fail and people start to question that amyloid paradigm, we're starting to see more attention towards this other stuff. Even in Time magazine, CNN, mainstream media, we're starting to see more articles now about high blood sugar linked to Alzheimer's risk, high glucose and risk for dementia, so as to whether or not the public is actually paying attention to it, I don't know, but I hope it isn't going to take another 20 or 30 years before this is mainstream knowledge, but at least there are more and more researchers now saying we got it wrong with this amyloid thing.

HVMN
Geoff

Does it feel like it's accelerating? Just looking at this space and working professionally in this broad area, it does seem that the type 3 diabetes moniker is seeming to catch some sort of traction where a layperson would be oh, I kind of read that somewhere. Do you feel optimistic that it's catching on and accelerating or do you feel like since 2003, it's just like some slow linear slide?

HVMN
Amy B.

It's really slow. It's too slow. I think for you and me, we're like oh, this is everywhere, everyone knows, because we're going to the conferences where Steven Cunane talks and Dale Bredesen talks and Dom D'Agostino and all these people, like we're preaching to the choir. We're surrounded by this. This is a very loud message in a very small audience. It needs to get out. I think it is getting out. It's just really slow.

HVMN
Geoff

Okay, so work to be done then. Hopefully these conversations like these help at least arm people with the baseline tools and observations and facts where they can start doing their own homework and research and reading.

HVMN
Amy B.

Something I think we're up against specifically with Alzheimer's is it's different with obesity. It's different with diabetes where nobody questions well, of course your diet affects diabetes. Of course your diet affects cardiovascular disease. I think we're still in the early stages where someone's thinking well, what does diet have to do with Alzheimer's? Or well, if that's true, why wouldn't my doctor tell me? Why didn't the neurologist tell us that when they diagnosed dad or they diagnosed grandma? I think we're up against that sort of incredulity, that sort of like almost sense of shock that how could this be possible? How is this the problem in Alzheimer's, this glucose diabetes thing and my doctor didn't even mention that?

HVMN
Geoff

Well, it seems so obvious after you read the literature that yeah, if you're poisoning yourself chronically with things that we shouldn't necessarily be eating for 20, 30 years, it very much stands to reason that you would have these symptoms pop up. It's like the incredulity almost seems inverse now as you start learning and diving into the literature.

HVMN
Amy B.

It's like how could you not believe this book? Okay.

HVMN
Geoff

Curious what your thoughts around statins, cardiovascular risk. I think just scoping out a little bit. I think you mentioned when we're suggesting hey, older person, eat egg yolks. Eat butter. Eat fat. Usually, the typical response is wow, you're going to give that person a heart attack. What's wrong with that misconception? Can you paint a landscape of perhaps why that seem to be the standard message and why that might be wrong?

HVMN
Amy B.

It's probably pretty obvious to most of the people listening now, but maybe there's some new people. The cholesterol in the food you eat has very, very little impact on the cholesterol in your blood. It's like when you eat blueberries, you don't turn blue. When you eat broccoli, you don't turn green. When you eat cholesterol, the cholesterol doesn't just flood your arteries. That's just not how it works. Even if it did, even if eating a lot of high cholesterol foods like butter and egg yolks and cheese and red meat, even if that did raise the cholesterol in your blood, the amount of cholesterol in your blood tells you nothing about your risk for cardiovascular disease or your risk for having a heart attack.

HVMN
Geoff

Why do people say that? Again, devil's advocate, people will say like hey, you have high cholesterol. You're going to have a heart attack. Where did that come from?

HVMN
Amy B.

It's just what we were told. How long did I think that fat made me fat? That's why I ate the I Can't Believe It's Not Butter Lite and my skim milk and my coffee because, well, fat makes you fat. Of course cholesterol raises your cholesterol and of course cholesterol clogs the arteries. When you've heard something for so long, so powerfully, even if it's a lie, even if it's false, you believe it because you've just heard it for so long. At least with the cholesterol, we're starting to learn more and more that's not the case, but it's still going to take a long time before that's really, truly accepted and people no longer fear eating these fatty foods.

HVMN
Geoff

You mentioned Dave Feldman. I think his work around cholesterol and his citizen science has been really helpful for me personally just seeing the differences between LDL cholesterol, HDL cholesterol and realizing that LDL in and of itself, which is typically known as the bad cholesterol, isn't a good indicator or marker for cardiovascular risk. It's really the holistic story around HDL, triglycerides, inflammation markers like C-reactive protein, blood glucose, fasted insulin, and that whole picture of stories, really it is a lot more clinically useful for cardiovascular risk than just some arbitrary LDL cholesterol marker, which came from one observational study, the Framingham Study, which you might've heard of. I think that's where a lot of these medical standard care procedures really came from, one observational study done in a population which has LDL as a minor correlating factor, but if you actually segment out HDL, triglycerides, the inflammation markers, then it's not a signal at all, which I think is telling in terms of why we think this way and then, too, perhaps why the statin usage doesn't really seem to make that much of an impact in cardiovascular deaths in America. If you're just staggering the things that kill people, cardiovascular disease like heart attack is number one.

HVMN
Amy B.

If high cholesterol was causing heart disease or heart attacks, then nobody who had "normal" or low cholesterol, whether total or LDL, no one that had low would ever have a heart attack or ever die from heart disease, but they do every single day. I don't know exactly what the proportions are, but I've heard it's something like 50%, maybe even more of people that have cardiovascular disease or that suffer heart attacks have what we would consider normal cholesterol. Clearly, it's not what we think it is. They always use the example of Tim Russert, the news anchor. I think he was like an NBC news guy. He was on a statin. He was on a super high dose. His cholesterol was something ridiculously low and he died from a massive heart attack. Getting cholesterol low doesn't cure heart attacks and getting amyloid low doesn't cure Alzheimer's disease.

HVMN
Geoff

I think that kind of scares me is that cholesterol is the base compound that you generate testosterone from, that you generate hormones from, and if you're just crashing your cholesterol levels, are you affecting your sex hormones? I think there's a downstream cascading effect. By just jamming one variable down, what are you really impacting across the system? I think if you again look at some literature, a lot of side effects that are at least somewhat concerning.

HVMN
Amy B.

Oh, definitely. I'm not a physician. I can't advise anyone to take medication or not take medication, but there may be a small subset of people that benefit in some way from statins, but for the most part, when you look at cholesterol and what it does in the body, why would you ever want to lower it? It's like the greatest thing ever. It's the source of, like you said, testosterone, estrogen, progesterone, cortisol, all the steroid hormones. We make Vitamin D from the cholesterol in our skin. Your brain is built out of fat and cholesterol. If you don't have adequate cholesterol synthesis, you cannot have healthy cognitive function, which is why if you go to the Mayo Clinic website and the FDA's website, they list very clearly that memory loss and confusion and cognitive impairment are well-known side effects of statin drugs, so is loss of libido, depression, muscle pain and weakness. These are not little things to be toyed with.

HVMN
Geoff

My dad is on statins. It's something I've been like hey, let's look into the literature a little bit. Let's actually dive into why exactly are we doing the things that you think you're doing? Again, we're not giving medical advice. I think it's an important caveat and disclosure, but I think it's worth understanding from first principles how these things are affecting us. Just like how we think about what kind of foods we eat, we should think about what the pharmaceuticals and supplements, the nutrition that we're eating, they're all impacting our system. Kind of a fun side thread here, carnivore, carnivory, that's been a interesting, I guess, subsegment of the keto, low carb movement that has gained a lot of notoriety in recent months. Your thoughts, have you experimented with carnivory?

HVMN
Amy B.

I haven't done it myself. I would like to. I just I don't know if I can. I don't know if can actually give up my last little vestiges of plant food. I actually have a very big blog post about it coming up for one of the outlets that I write for. In general, I support it. I think it's fascinating. I think if nothing else, it raises a lot of questions. Those of us in the low carb, keto movement already knew that a lot of the conventional wisdom is BS. It's garbage nonsense, but even having already accepted that, the carnivore people force us to ask even more questions because on a good ketogenic diet, you can still eat spinach and almonds and asparagus and these low carb, higher fiber items. Now, the carnivores are saying well, no, you don't need fiber. You don't need curcumin. You don't need resveratrol. You don't need probiotics and all this stuff. In fact, that might actually harm some people. Not everybody, obviously. I don't think we can make the claim that a 100% animal-based diet is like the true human diet or the apex human peak diet, but do I think you absolutely have to eat broccoli in order to live and in order to have bowel movements? No.

Even if I did think that, there's enough anecdotes and clinical data, not just anecdotes, to say that that's not true. We don't need all this indigestible plant material and all these phytochemicals and stuff. They just raise a lot of fascinating questions. All of the nutrient requirements, the RDAs, DRIs, whatever you want to call them, were established in people eating higher carb diets, so it is entirely possible that when you eat very, very, very little exogenous glucose that your needs, your requirements for things change. Vitamin C is the example they always tout, but the same could be true of magnesium and Vitamin A and God knows what, so it's really fascinating. Do I think everybody needs to do it? No. Clearly we have millions if not billions of people around the world who live long, healthy lives eating vegetables, so I don't think everyone needs to do it, but I think it should be offered as an option, especially for people that have already done paleo or keto or the specific carbohydrate diet, all these other things, and haven't quite had full resolution of whatever weird, odd, unexplainable health problems they have because most people who go keto will have dramatic improvement in most of their issues, whatever those issues are.

Some people will still kind of have some stuff. They won't really be fully resolved or cured, whatever you want to call it. Maybe those people could've made some changes, like maybe they thought they were doing a real keto diet, but it's not. They're not actually doing, like what Stephen Phinney would call the well-formulated ketogenic diet. They might be messing around with fat bombs and who knows what, so it could be that they could have approached keto or low carb differently or maybe they really just do better on a carnivore diet. I'm not opposed to the idea.

HVMN
Geoff

Yeah, no, I think you bring up good nuances where maybe it's just like a more strict elimination diet where on keto and then when you're getting to carnivore. It's not just because eating meat is magical. It's like you just eliminated the one random phytonutrient or vegetable that seemed to be triggering some of your issues, but not necessarily meaning that all meat is the best possible apex diet, as you mentioned. Yeah, it's something that I'm actually now personally experimenting with. As I mentioned, I cycle in and out of a ketogenic diet. Now I'm playing around with a carnivore diet. It's fairly similar, right? It's like it's sauteing spinach with oil and cheese. It's like I just don't eat that, just have just more steak, basically.

HVMN
Amy B.

Are you just doing because a lot of the carnivores do all beef. Are you doing all beef? Are you doing other like pork and fish and stuff like that, too?

HVMN
Geoff

Yeah. I just had some bacon. Yeah, I think it's just very, very restricted to only eat ribeye steaks. I think after doing these kinds of experiments personally, I think you have decent discipline now with getting rid of the delicious croissant with the coffee type of a thing that I still think is very pleasurable. Maybe I work into that, just going all beef, but it doesn't seem to be any additional benefit for just like yeah, I think ... I don't know. Some variety is a delight in life.

HVMN
Amy B.

I know some of the carnivores do all beef. They just feel better. I do want to try it at some point. Again, I just don't know. I could do without most vegetables, but if I ever do it, it's going to be carnivore plus coffee. I'm never going to give up the coffee. I know some of the carnivores do make exceptions for coffee or tea. Some of them will do wine or spirits like distilled alcohol, so that might be the way I go. Certainly I have meals and I have days where I don't eat vegetables and I don't miss it. It's not 11:00 at night and I'm thinking oh, I didn't eat any mushrooms today. I think it's doable. I don't know. I don't have any major problems that I'd be looking to resolve, but I'm open to the possibility that maybe I do have some stuff, that I wouldn't realize I had those little nagging things until they went away. I'm willing to entertain that possibility.

HVMN
Geoff

The anecdotes are interesting. I think obviously, you take each anecdote with a grain of salt, but I think there's clearly some signal there. There's so many interesting results of positive benefit from carnivore. It's just personally interesting to experiment with.

HVMN
Amy B.

Yeah, but I want to say, too, I have a bad habit of being enamored with what's new and tried it, like ooh, carnivore, ooh, this, ooh, this thing. We have to remember that we tend to only see the success stories. We're hearing about all the people that are healing their autoimmune disorders and curing their digestive problems. There might be some people that have done this that did really poorly and they're just not all over Twitter talking about it. I have to remember for my own mind to be like you know what? Somewhere out there somebody's doing this and not doing well and we just don't know about it.

HVMN
Geoff

Maybe as a last topic here as we wrap up, what are some of the misconceptions or issues? You mentioned that fat bombs not necessarily be the most ideal way to enter a ketogenic diet. What have you seen as a professional nutritionist here and given your experience with your clients, what has been a well-formulated, well-adjusted ketogenic diet that you've seen people be able to sustain and what are the big mishaps or misconceptions that you see that are being disseminated out there?

HVMN
Amy B.

The first big mistake I see people making is overdoing the fat, especially when somebody's main goal is losing body fat. I say losing fat, not losing weight. The reason this diet works is because of what is not in the diet, not because of what is. The reason keto and low carb work is because there's very, very little carb. It doesn't work because there's a ton of fat. If this worked because of a lot of fat, you could eat five bagels and as long as you ate enough cream cheese and butter to keep your ratio of fat to carb really high, well, you'd lose weight, but I think you and I and everyone listening knows that it doesn't work that way. It's not like well, if you're not losing weight, eat more fat. If you don't feel well, eat more fat. Maybe that's true for some people, but I get a lot of people writing to me who are skimping on protein because they're eating a lot of fat at the expense of protein because they've heard all this nonsense about protein turning into sugar and kicking you out of ketosis, so instead of eating an adequate amount of eggs or chicken or fish or pork, they'll eat fat bombs or they'll put three tablespoons of butter in their coffee and they wonder why they're not losing weight. All the ketogenic state does is make you a fat burner. It doesn't mean that you're going to burn your body fat. You could be burning the gobs and gobs of fat you're eating. That's the biggest mistake.

Then the other one that really gets people is chasing high ketones, thinking that they have to take measures to get their ketones to a certain number, thinking that well, if my ketones were higher, I'd lose more weight or I'd lose weight faster. You probably know from the company that you run there might be some issues or even athletic performance that benefit from higher ketones, but higher ketones is not a fat loss strategy. People are going to eat more fat or skimp on protein or fast or do all these things to raise their ketones and it might actually be counterproductive. For most people, being in ketosis at all, even if you measure and it's like 0.1, 0.2-

HVMN
Geoff

It's like a binary switch.

HVMN
Amy B.

Yeah, you're either in or out. Being higher isn't going to get you more. If you are dealing with cancer or a neurological condition, that might be different, but for just overall metabolic health and especially for fat loss, you don't have to chase high ketones. You just have to keep carbs really low and the rest will take care of itself.

HVMN
Geoff

Oftentimes, as you mentioned, that the more keto adapted one is, your body's just better tuned to having a lower amount of ketones because you're using them as you're producing them. It's not like you have this overload of just overshot of ketone production, which I think brings up a good point. It's not necessarily about chasing metrics. It's about what your end use case is and not getting overly obsessed with the random metrics. I think that happens a lot with athletes, where people that are overly focused on biometrics. It's like okay, if you're in a cycling race trying to win the race, not do something at your power meter and that may be a different analogy to something like your goal is weight loss. It's not chasing ketones, what I think is important point.

HVMN
Amy B.

Some people forget that we have three major fuel sources on low carb diet. There's glucose, which you can measure. There's ketones, which you can measure. There's fat, which you can't measure and the biggest, most predominant fuel on a low carb keto diet is fatty acids. It's not ketones, so even when you see sort of low ketones, you could still be burning a high amount of fat. You don't know. We don't have a fatometer. We don't have a little handheld fat meter to tell us how much fat we're burning. People need to understand that you can absolutely be burning fat, be losing weight, have a fat-based metabolism, even if your ketones aren't high.

HVMN
Geoff

That's actually important point I think is just over glossed because everyone is burning fat period. Even if you are predominantly a carb burner, it's always a mixture and I think the nuance in the science is overly broad where it's like you're a glucose burner. You're a fat burner or you're a ketone burner. It's like it's always some sort of mix.

HVMN
Amy B.

Yeah. It's definitely not binary.

HVMN
Geoff

Are you shifting more heavily towards fat when you're eating keto versus shifting more towards carbs or eating a lot of carbs? I think there's some nuance there. Hopefully, I think we opened up enough can of worms for people to start looking to do their own homework here. How do people find you? What's exciting for you personally for the rest of the year? Where do people follow you? What are the big things you're working on?

HVMN
Amy B.

My website is tuitnutrition.com. It's T-U-I-Tnutrition.com. That's my handle on Twitter, tuitnutrition. My book is called The Alzheimer's Antidote. You can find that on Amazon. There is a Kindle version, but there's no audio version. Coming up, I'm speaking at Low Carb Houston in October. I'm speaking at an event in North Carolina in September, but I'm thinking about a second book about men's health because there is, again, chronically high insulin is a driver of prostate enlargement, erectile dysfunction, cardiovascular disease, all of these issues that men deal with that nobody's talking about insulin as the problem, so I may be doing that in the next year or so.

HVMN
Geoff

Just spend the closing thought here that for women, there's PCOS, which is correlated with insulin resistance and it sounds like you're teasing the hypothesis there's like a analog for men that's related to insulin, as well.

HVMN
Amy B.

There's scientific papers about this. They call it the male phenotypic equivalent of PCOS. People can search if they want to search like Tuit Nutrition male PCOS. I wrote a blog post about it, so it's out there.

HVMN
Geoff

Excited to see that when it comes out. I'm sure there's a lot of literature out there for half our community that are men that may be seeing some of these symptoms that will be of interest. Thank you so much, Amy, for jumping on in and having this wonderful conversation.

HVMN
Amy B.

Thanks for having me. It's so nice to talk to someone else with a balanced sort of nuanced thinking because there is a lot of black and white and too simplistic thinking in keto, so good to talk to someone else that has a better perspective on things.

HVMN
Geoff

It sure is. Thank you so much.

HVMN
Amy B.

Thanks.


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