Dr. D'Agostino: And you learn these things as you go. There's a learning curve to the ketogenic diet. I went right into the classical ketogenic diet. I bought the book, you know, "The Ketogenic Diet for Pediatric Epilepsy" and now it's "The Ketogenic Diet for Epilepsy and Other Neurological Disorders," same author, Dr. Eric Kossoff, Dr. Mackenzie Cervenka from Johns Hopkins, and the team there. They advocate for a variety of different types of ketogenic diets and then adjusting it to the patient and their circumstances too is going to be important in the world of epilepsy. So, it remains the only widely accepted application of the ketogenic diet at this time is really epilepsy and metabolic disorders like glucose transporter type 1 deficiency syndrome, PDH deficiency, and things like that. And interestingly, there are inborn errors of metabolism that are contraindicated with a ketogenic diet like, you know, carnitine transferase activity, CPT1, you know, whether it be primary or secondary too. So it could be deadly. A ketogenic diet could potentially kill you if you have carnitine, you know, transferase deficiency. So that's a whole another topic we could discuss.

Dr. Patrick: You bring up an interesting point with the contraindications because I'm interested in a few of those aspects, so for one, perhaps other genetic variants that maybe aren't as rare. So, for example, you know, APOE4 allele, which, you know, a quarter of the population has one of those alleles. Like how is it known how people with that polymorphism respond to ketogenic diets? And also you mentioned, you know, briefly about people that sort of race into the ketogenic diet without any sort of slowly carbohydrate restriction and how it can elevate some biomarkers like triglycerides, for example. I'd love to talk about like what biomarkers do you think are good to monitor and to see if someone is favorably or unfavorably responding to a ketogenic diet, and at what point would you...? Like how many times would you do it before you sort of give up and sort of modify the diet or change maybe types of fat? You mentioned the types of fat or, you know, things like that.

Dr. D'Agostino: Yeah. I think it's important. A lot of people jump into the ketogenic diet. And, you know, just from a standard diet... It's important to test the water. If you're not using it for epilepsy or another disorder, you want to titrate the carbohydrates down and track and monitor along the way. You maybe do like cut your carbs in half or by two-thirds or whatever, and then at the four or six-week mark, get blood work again and look at your glucose response, check for hypoglycemia, things like that.

So APOE4, you know, that's about one quarter, right, of the population. I get this question a lot, and I don't think it's ideal. Even the books on ketogenic diets say that it's an unnatural diet and it's not healthy and it's not sustainable. So these are from the people who researched the ketogenic diet who published the most on the ketogenic diet who are in the trenches using this diet as a medical therapy for like known conditions that are responsive to the ketogenic diet. So with that said, you know, dietary teams that manage patients for up to 10 years, 20, and even I had some correspondence with the team that are measuring people and cardiovascular parameters too, their heart health for 30 years. So, in patients, for example, with inborn errors of metabolism that need to be on, like, a classical type ketogenic diet for like three decades, and they're still doing...all their blood work looks great. So I think that's a good example that the diet is not going to kill you. It would have done that a long time ago in these patients that are on like a four to one or three to one ketogenic diet.

But I think it's important to... In the context of APOE4, extremely high fat is probably not ideal. So you want to take probably a more moderate approach and just restrict carbohydrates. I think it's really important to get lots of fiber, lots of phytonutrients. We know the data on fiber is just really, really good. There's no arguing. And people argue against fiber, but I think the data for fiber is really good, not just for the microbiome, for the phytonutrients, the micronutrients. As, you know, there's been a lack of appreciation for micronutrients and ketogenic diets, and that has caused problems like selenium deficiency, which led to cardiomyopathy, and there's case reports where people have literally...I think one or two where people have literally died from cardiomyopathy because of selenium deficiency associated with the ketogenic diet. So you want to make sure you supplement appropriately, but you don't have to supplement if you formulate the ketogenic diet appropriately with the right types of foods, but it's not always possible.

But for APOE...and getting back to your APOE. So a diet that's moderate in fat, moderate in protein, and I think of carbohydrates as fiber, so plant-based fiber, moderate protein, and then fats. The types of fats are important. So, monounsaturated fatty acids as opposed to a long chain like saturated fats. Medium-chain triglycerides are probably helpful. There is a study that was done using a product that is caprylic triglyceride, which is MCT. At the time it was called AC-1202 by Accera. It was a product that was designed for Alzheimer's disease as an alternative energy substrate that would be given. And the results of the study showed that improvements in mild cognitive impairment were associated with ketones. So there was a correlation with that. But they did not see the correlation people with APOE4, which was kind of interesting. Although I think a larger study probably would have shown like a difference.

But I think the take-home message is that a diet that's very...like super-restrictive and high in fat is probably not ideal for APOE4 patients, and adding ketones in the form of exogenous ketones could probably be ideal. There was a case report on a patient that I am familiar with that...I'm familiar with the wife of the patient that had passed away, but he was maintained on a ketogenic diet and then later on ketone esters and exogenous ketones and was...did quite well in this diet for a long time. And it wasn't a restrictive ketogenic diet, but he did much better with ketone supplementation as it means to improve his cognition and different behavioral parameters too. So I think that would probably be the better way to go.

I'm very cautious in speculating and giving medical advice. I'm not a medical doctor. I am a professor and I'm professing that I think that a more moderate style Mediterranean-like low-carb/ketogenic diet with supplementation in the form of things like omega-3 fatty acids, MCT oils. The fatty acids comprising the diet should be more along the lines of monounsaturated fats and not so much heavy saturated fats, which in the context of APOE4 is probably not a good thing to chronically maintain a state of ketosis with superhigh saturated fat.

Dr. Patrick: Yeah. So maybe more avocados, more of the nuts, and olive oil, salmon, which is a good type of polyunsaturated fatty acid. I mean, that's the kind of diet that I was doing and will try again. And we'll talk a little bit more about why I'm so interested in ketogenic diets. I don't have epilepsy, and I'm certainly not someone that eats a standard American diet either. There are so many interesting effects being in a state of ketosis and having the ketone bodies elevated, and that to me are very interesting and, you know, I think possibly beneficial for healthspan, for cognition, and so...