Facebook Live: Power of Ketosis in Treating Cognitive Decline

In this Facebook Live, Apollo Health’s Chief Science Officer, Dr. Dale Bredesen, and Chief Health Liaison Julie Gregory were joined by Professor Stephen Cunnane from the University of Sherbrooke in Quebec. They discussed his BENEFIC trial, where he gave ketones to people with mild cognitive impairment in to achieve ketosis, which plays several roles in the healing process. Participants in this study experienced optimized brain health and metabolic flexibility.

We’ve included a complete recording of the session and a full transcript below for your convenience.

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Transcript:

Dr. Dale Bredesen (00:01): Okay. Welcome everyone. It’s such an honor and such a pleasure to have Professor Stephen Cunnane from the University of Sherbrooke in Quebec with us today, as well as Julie Gregory Welcome, Professor. Welcome, Julie. Thanks so much for joining us today.

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Dr. Stephen Cunnane (00:18): You’re welcome. It’s a pleasure to be here.

Dr. Dale Bredesen (00:20): Thanks. A book came out recently from Professor Karl Herrup from Yale, who pointed out that in his words, Alzheimer’s is “The way not to study a disease.” It’s really been a problem and another science writer, Linda Marsa, pointed out that if you look at all the different breakthroughs that have come through in oncology, endocrinology, genetics, and on and on, that really the area of dementia has been the area of greatest failure.

Dr. Dale Bredesen (00:51): I think we are all living with that, because we see various people, families, family members, things like that, that have problems. We’re all interested in how we can reduce the global burden of dementia. Professor Cunnane has spent his career on some very exciting work that relates perfectly to what we’ve talked about with ketones and with energetics.

Dr. Dale Bredesen (01:16): Stephen, if you could maybe go back a little bit and just talk about your training. I know you’re at McGill, absolutely fantastic university. What got you into the area of ketones and brain energy support?

Dr. Stephen Cunnane (01:31): I guess, what do you call serendipity. It was a lucky break. It was one of these things. I was studying the metabolism of polyunsaturated fatty acids in the infant brain. I was interested in brain development. We had stable isotope labeled polyunsaturated fatty acids. We found that there was a much larger amount of these fatty acids was turning up in molecules like cholesterol in the brain than in DHA.

Dr. Stephen Cunnane (01:58): I was completely dumbfounded as to what was going on and learn that, in fact, there was degradation of those fatty acids particularly alpha-linolenic acid. It was via ketones that it was making new lipids in the brain. I just thought this is incredible and got interested and then heard about the ketogenic diet for the control of intractable epilepsy in children.

Dr. Stephen Cunnane (02:23): I guess you could say I haven’t looked back. I was seduced by the incongruousness of high fat diets, which is still difficult for some people, cardiologists in particular to accept the beneficial effects of very high fat diets. I was caught up in this and worked on it and the opportunity to just start ketone PET imaging here in Sherbrooke, where there’s a fantastic Imaging center, brought me here from Toronto, in 2003.

Dr. Stephen Cunnane (02:56): We, again, started very tentatively to look at this Alzheimer’s was not on my radar at the time. But I realized as we made some progress in looking at the aging brain that perhaps there was something we should try to turn our attention towards. That is obviously been very rewarding as well.

Dr. Dale Bredesen (03:13): Absolutely. Well, so all of us who trained in neurology were taught that ketogenic diet was a way to approach infantile seizures, epilepsy in young children. We really not taught that, “Hey, this is something that could be good for Alzheimer’s disease.”

Dr. Dale Bredesen (03:29): What made you then go from thinking about seizures and things like that and fatty metabolism to like, “Hey, maybe this should actually be something good for the brains of Alzheimer’s patients?”

Dr. Stephen Cunnane (03:41): Well, I knew from George Cahill’s work and all the work around starvation that ketones could support probably at least 80% of the brain’s energy requirements. I thought, “Okay. We know there’s a problem with glucose. Maybe that’s because the cells are dying.”

Dr. Dale Bredesen (03:56): Yeah.

Dr. Stephen Cunnane (03:56): But there’s two fuels that are used in principle by the brain. If we don’t know anything about ketones, how do we know for sure that the cells are dying or whether they’re having a problem getting glucose?” If we do sequential PET imaging of glucose and ketones, we should be able to tell. If the images are essentially the same with the deficit in the parietal cortex, then we’ll know there’s not much … That’s probably the cells are dying.

Dr. Stephen Cunnane (04:22): In fact, that wasn’t what we saw. Then I found some older papers that showed by arteriovenous difference studies that ketone uptake by the brain was totally normal. Done at the Karolinska in 1981, and again in Japan in 1980, and 1996. That gave us encouragement that two different techniques had shown the same thing that, in fact, ketone metabolism appeared normal.

Dr. Stephen Cunnane (04:44): We gave a ketogenic substrate to Alzheimer patients to see whether when there was more MCT available, more ketones available was the capacity to use them there. It was there as well in a straight-line relationship. I thought, “There’s therapeutic potential here that needs to be explored.”

Dr. Dale Bredesen (05:02): Absolutely. Then, of course you translated this and you’ve done a study, among others, one called the BENEFIC trial, where you gave ketones to people with mild cognitive impairment, with MCI, with very exciting results. Could you talk a little bit about your trial?

Dr. Stephen Cunnane (05:19): Sure. That was funded by the Alzheimer’s Association in 2015. At that time, there were no commercially available ketone supplements. Certainly, no placebos. Two of our criteria were to have a ketogenic supplement, but to have a placebo as well, because cognitive evaluation really is borders on subjective at times, and you absolutely need the placebo control.

Dr. Stephen Cunnane (05:42): MCT was possible with a non-ketogenic vegetable oil. We developed an emotion ourselves based on skim milk, in which we mix the MCT in a kitchen blender, and it was relatively stable. It was drinkable. It wasn’t causing too many side effects. That’s how we started. We were able to produce enough of this stuff that we could do the study over six months.

Dr. Stephen Cunnane (06:07): After three years, we had … Nestle became involved partway through the trial and continue to finance it. Because originally, the original financing was to only look at metabolic changes in the brain.

Dr. Dale Bredesen (06:18): Yeah.

Dr. Stephen Cunnane (06:19): Once the results were moderately encouraging, and about 20 people per group, Nestle was interested in what we were doing, and they agreed to fund the second stage, identical to double the sample size. With about 40 people, you can look at memory deficits with some confidence that the difference will be statistically significant in MCI. That turned out to be the case in the second phase.

Dr. Stephen Cunnane (06:43): We had reasonably good proof that we could change the decline in not only memory, but executive function and language in these people. With further probing with different types of imaging, diffusion imaging and functional connectivity measurements, we’ve shown that attention and processing speed also benefit from ketones, but it doesn’t show up with the global uptake of ketones, but rather, in certain networks alone.

Dr. Dale Bredesen (07:10): Exactly. You showed in one of your papers that, of course, white matter was a critical variable here and that delivering the ketones, improving white matter structure, as you showed, could give you this improvement, for example, in processing speed. I guess one of the obvious questions, MCI, of course, can apply to people who are on their way to developing Alzheimer’s disease.

Dr. Dale Bredesen (07:33): We often point out the fact that it’s actually the third of four stages. It’s after the pre-symptomatic phase. It’s after subjective cognitive impairment. Unfortunately, it’s a little bit telling someone, “Don’t worry. You only got mildly metastatic cancer, because MCI is a relatively late stage.” Now, as I mentioned, some of them go on to have Alzheimer’s, many of them of course, about 5% to 10% convert per year.

Dr. Dale Bredesen (07:58): You talked about this as well in your paper, how quickly they convert, how many convert, and how many actually go back to normal “naturally.” What about … Were some of these people on their way to getting Lewy body disease or vascular dementia? Do you think ketones would be helpful to all of these different groups that start out with MCI as they’re progressing?

Dr. Stephen Cunnane (08:23): We didn’t evaluate biomarkers or PET imaging to assess the presence of Lewy bodies or other indication that amyloid for instance, or Tau. It was too costly to do it. We didn’t do it. We didn’t know who was destined, who would be destined to go on to Alzheimer’s, who was stable, who might even regress towards normal. We took the chance, and we screened them with the classical Petersen Mayo Clinic criteria and admitted them to the project.

Dr. Stephen Cunnane (08:56): We knew that the APOE4 carriers, for instance, might be less capable of using the ketones. At least that was what was talked about. We took a number of risks in designing this with the most inclusively, possible they were not amnestic, MCI only.

Dr. Dale Bredesen (09:13): Yeah.

Dr. Stephen Cunnane (09:14): Well, I think most MCIs have an amnestic component, which could be a minor component or a major component of their problem. It was a little bit exploratory, to be frank, in 2015, that we didn’t have much to go by to make a more informed decision anyway. We were trying to correct the metabolic defect. We didn’t know how much MCT to give it the time.

Dr. Dale Bredesen (09:37): Right.

Dr. Stephen Cunnane (09:37): We didn’t really know how big the deficit was, or how much MCT would achieve what we call to reduce the energy gap in the brain. We ended up improving, reducing the gap by about 40%, but not by 100%. There was still an energy deficit in the brain because of low glucose uptake. But there was also improvement in cognitive performance in relation to the ketone levels going into the brain, and even simply in the plasma.

Dr. Dale Bredesen (10:05): Yeah.

Dr. Stephen Cunnane (10:05): The plasma levels and the brain levels are really quite tightly correlated, which is useful because not everybody can set up ketone PET imaging for their research, but most people can afford to pay for ketone measurements in the blood and monitor the efficiency, shall we say, of the intervention they’re using.

Dr. Dale Bredesen (10:23): Right. When you look at children with seizures, of course, you’re really trying to drive to a fairly high level of ketosis, maybe 7, 8 mM BHB, something like that. It’s a pretty strict approach. With a cognitive decline, what’s your sense with all that you’ve now done looking at this? Where would you like to see people into … We always think of your mild ketosis or cognitive decline.

Dr. Dale Bredesen (10:49): As you pointed out, you didn’t completely address the deficit, but you did largely address it. The question is where optimally and theoretically would you like to see people?

Dr. Stephen Cunnane (11:01): It’s a tough question, Dale. It’s very hard to answer. We have embarrassingly low levels of ketones after MCT, if you think about it, because we gave two doses a day, 15 grams at breakfast and 15 grams at supper. You have a nice ketosis, but it’s transient.

Dr. Dale Bredesen (11:19): Yeah.

Dr. Stephen Cunnane (11:20): Within two and a half to three hours, it’s back to normal. If you average that over 24 hours, we were at about 0.4 millimolar.

Dr. Dale Bredesen (11:29): Wow.

Dr. Stephen Cunnane (11:29): Which is not a very impressive number, right?

Dr. Dale Bredesen (11:31): Right. Right.

Dr. Stephen Cunnane (11:32): But we still got improvements. We don’t know whether the additional fuel that the ketones were providing even transiently was sufficient to address the fuel issue, or whether it is addressing a different issue entirely, like inflammation in the brain, for instance, without necessarily making a huge impact on the fuel status of the brain, the energy status of the brain.

Dr. Stephen Cunnane (11:57): It’s very hard for us to say what would be a threshold that we’d like to get everyone to. I guess any improvement in the level of your ketones is going to be beneficial compared to having essentially none.

Dr. Dale Bredesen (12:09): Yeah.

Dr. Stephen Cunnane (12:09): As we get older, ketone levels seem to go down and people become mildly insulin resistant as they get older, which reduces their ability to generate ketones endogenously.

Dr. Dale Bredesen (12:21): Yes.

Dr. Stephen Cunnane (12:22): Some way to correct that, correcting the insulin resistance, I think is as a priority, whether it’s by exercise, bypassing it with an exogenous ketone, intermittent fasting, different people are going to have different approaches. Different people are going to tolerate different approaches, ketogenic diet, obviously. But it’s fairly demanding to get to 7 or 8 millimolar ketones on a ketogenic diet in adults, especially older adults.

Dr. Stephen Cunnane (12:48): I think you’ve got a lot of experience with that. You could perhaps speak to it. But not many people can do it.

Dr. Dale Bredesen (12:55): I mean, we’re typically recommending people somewhere between 1 and 2.5 in that region, and it’s only because when we’ve looked at the people who’ve done the best on the protocol, and the people who haven’t responded so well, it’s typically the people who are getting themselves into some ketosis in that range that seemed to be doing better than the ones that are down at 0.2, 0.3, that sort of thing.

Dr. Dale Bredesen (13:17): But of course, this brings up a really critical thing that comes up all the time. Endogenous ketosis, as Julie was mentioning earlier, versus exogenous ketosis, which, of course was what you did with your trials. Is your sense that there is a preference for one, or do you think that simply taking the ketosis the way to go?

Dr. Stephen Cunnane (13:40): I think it’s a choice. It’s a technical choice. It’s a logistical choice. It may be in some cases unethical choice. It’s better to take an exogenous source than to then to take no ketogenic stimulus at all. Is it possible? But endogenous generation is going to be more effective at the same ketone level, let’s say?

Dr. Dale Bredesen (14:04): Yes.

Dr. Stephen Cunnane (14:05): What we learned in one animal study we did some time ago is that of course once you mobilize fatty acids from adipose tissue, and start generating ketones, because you’re burning these fatty acids more, some of the fatty acids you’re mobilizing include fatty acids that are needed in the brain like docosahexaenoic acid, the omega-3 fatty acid.

Dr. Stephen Cunnane (14:23): It’s not a very good ketogenic substrate. It’s probably one of the worst. But the levels increase in the blood, and it will get into the brain, and it could partner with providing more ketones to help rebuild the structure, the contacts, the synapses, and to improve neurotransmission aided by an electric charge that’s helped develop by the ATP generated by ketones. I think that you won’t get that with an exogenous ketone unless you actually take an omega-3 supplement as well.

Dr. Dale Bredesen (14:55): Yeah.

Dr. Stephen Cunnane (14:56): There could be some advantages to being endogenous ketosis. But if the person is not going to be compliant or goes off after three weeks, you might as well go back to something that’s simpler, that at least solve one problem at a time.

Dr. Dale Bredesen (15:10): Yeah. I think, yeah, there are many issues here. I think one of them is just, as Julie was talking about earlier, getting into this metabolic flexibility, and I think part of it is if you’re going for endogenous ketosis, part of this is it will drive you to be more insulin sensitive with your periods of fasting and things like that.

Dr. Stephen Cunnane (15:29): That’s true.

Dr. Dale Bredesen (15:31): Yeah. I mean, overall, our goal is just fixing your neurochemistry to optimize it, and that’s your oxygenation, and that is your blood flow, and that is your ketosis. You mentioned DHA. Of course, Professor Richard Wurtman from MIT spent so many years looking at DHA, and of course, also acetylcholine, and things like that, to get optimal synaptic formation.

Dr. Dale Bredesen (15:53): Julie, I know you’ve done both these. Maybe come to you for a minute. You’ve done, of course, endogenous ketosis, exogenous ketosis, and of course, your website has thousands of people who are relaying and relating their own experience. Could you talk a little bit about what you see as the differences? Have you noticed yourself when you’ve done … I remember used to take a little MCT tablets at times, or the little capsules at times. What’s your experience?

Julie Gregory (16:20): Both gave me a cognitive boost. Both gave me energetic stability. But I prefer the endogenous ketosis for the reasons you were just speaking of, because it heals the underlying insulin resistance. I like to combine diet, with a long daily fast and daily exercise. When you put all three together, it’s not that hard.

Dr. Dale Bredesen (16:43): Yeah.

Julie Gregory (16:43): It gets me to about 1 to 2 mM a day, at least once per day. I do it mostly with that long daily fast. I feel amazing. I don’t think it’s that hard. I mean, that’s my preferred route. But when I was insulin resistant, I think using a little bit of MCT oil was amazing, because it’s very hard to mobilize fat stores when you’re insulin resistant. Your body has forgotten how to do it.

Dr. Dale Bredesen (17:12): Yes.

Julie Gregory (17:13): Yeah.

Dr. Dale Bredesen (17:13): This has been my big concern. We have had a few examples of people, especially people who were thin. We’ve talked about this before. Who have just tried to crash and get themselves into endogenous ketosis and actually get worse. This again, fits very well with the idea that this is an energetic insufficiency and other network insufficiency contributors, because they … I would wish that they would simply take the exogenous ketones, get yourself.

Dr. Dale Bredesen (17:41): As I’ve always said, when a patient comes to see us, that patient, it’s an emergency. This person is telling us they have not had sufficient support for their synaptic network, typically for years. Let’s make sure they have the oxygen and the blood flow and the ketones and all the other things that they need. Perhaps, Stephen, could you talk a little bit about … You did show statistically significant differences?

Dr. Dale Bredesen (18:11): On average, what sorts of improvements in their scores did you see overall? Did you see people who went who really got big bumps? Or was this the whole group moved a little bit? Or what did you see there?

Dr. Stephen Cunnane (18:28): Mild cognitive impairment is by definition is a mild condition. There’s not a major insult, and there’s not a lot of room to improve, in fact.

Dr. Dale Bredesen (18:36): Right. Yes.

Dr. Stephen Cunnane (18:38): That’s the challenge. You’re starting early, but it’s harder to see an effect. We didn’t get anybody making dramatic improvements. With the questionnaire we had, for most of them was that, I think, as many people on the placebo thought they’d improved afterwards as on the KMCT from their own personal impression.

Dr. Stephen Cunnane (19:00): I guess, if people are taking care of you, there’s already a sense that I’m doing better, and someone cares about me. There may be some improvements for that social interaction reason, if for no other. We didn’t see any dramatic improvements. We didn’t do MMCs, or MoCA tests at the end, because we were concerned about a learning effect that over six months, you would potentially do better artificially, but not because of the intervention per se.

Dr. Stephen Cunnane (19:30): All we know is that the cognitive performance on a number of tests, but not too many of the composites was improved. The free and cued recall, for instance, the verbal fluency, the Boston Naming, some of the attention tests, the Stroop, the trail-making, that’s still a pretty good range of test improvements with Zed scores that were improving in each case. It was related to the ketones.

Dr. Stephen Cunnane (19:54): I think if we had made a more of an improvement in ketosis, we probably would If seen … I would predict we would have seen a better improvement in some cognitive outcomes as well.

Dr. Dale Bredesen (20:05): Yeah. That’s a really interesting point. Now, do you have a preference? You mentioned the MCT oil. Of course, now, people have ketone salts, ketone esters, coconut oil, of course, which has MCT. But it’s typically a lot slightly longer chain. Do you have a preference for these various types?

Dr. Stephen Cunnane (20:29): Again, I would say, take any one of the supplements easy that you can afford, or that you have some preference for some reason. Any one of them is probably better than nothing at all.

Dr. Dale Bredesen (20:39): Yeah.

Dr. Stephen Cunnane (20:40): Coconut oil is not ketogenic. That doesn’t mean it couldn’t be beneficial, or isn’t beneficial, but I don’t … if it is beneficial, I don’t think because of ketones. Because the percentage of coconut oil that contains ketogenic MCT is really quite small. It’s on the order of 10%. It’s to dilute, which doesn’t mean the 12 and 14 carbon fatty acids aren’t beneficial, because I think they have an antimicrobial effect. Lauric acid is your classic antimicrobial. It’s the basis of soap, right?

Dr. Dale Bredesen (21:15): Yeah.

Dr. Stephen Cunnane (21:17): Maybe that’s what we’re achieving by using coconut oil, is it there’s an anti-inflammatory effect that I don’t know anything about. I can’t confirm that. It’s purely speculation. But I wouldn’t want to discourage anyone from using it, or if they’ve been trying to get into ketosis and always concerned, frustrated because they’re not, it’s because ketogenic coconut oil is not ketogenic.

Dr. Stephen Cunnane (21:40): Again, I wouldn’t want to be pigeonholed into saying that the ketone ester is better. It certainly has a higher immediate response. But there’s no long-term results have shown that that’s necessarily better.

Dr. Dale Bredesen (21:51): Yeah.

Dr. Stephen Cunnane (21:51): There’s a taste issue, there’s a cost issue, and these are, to me, it boils down to clinical and personal choices as to which one is used.

Dr. Dale Bredesen (22:01): Then that brings up measuring your ketosis. Obviously, people have done this through urine, through breathalyzers, and through blood. Do you have a preference there? Do you prefer the BHB and blood look, or are you okay with some of these breathalyzers that have been used such as biosensors got one that looks at acetone levels, for example? Do you have a preference in terms of looking at the ketosis that people have achieved?

Dr. Stephen Cunnane (22:28): Well, I think first of all, that the urinary levels are probably next to useless.

Dr. Dale Bredesen (22:33): Okay.

Dr. Stephen Cunnane (22:34): That’s my personal opinion my experience with children with epilepsy. The one of the reasons is that the urine volume will dilute or concentrate the ketones and it’s not necessarily a function of the ketone production, but rather than the urinary volume. I don’t think there’s any good reason to recommend the urinary strips. They’re simpler. They’re not invasive. But I don’t think they’re going to help too many people.

Dr. Stephen Cunnane (22:57): The finger pricks are straightforward. They’re reliable. I don’t know about the breath devices. But you mentioned our work with epilepsy starting about 30 years ago. One of the interesting things we learned by doing breath acetone measurements, by gas chromatography, a good laboratory technique not applicable in the home, but for research purposes.

Dr. Stephen Cunnane (23:20): We learned two, I think, really important things about kids on the keto diet for … They were all in good seizure control. The first thing we learned was that the breath acetone was very tightly correlated, or very well-correlated with blood acetoacetate and beta-hydroxybutyrate. It was a good measure of systemic ketosis.

Dr. Dale Bredesen (23:42): Yeah.

Dr. Stephen Cunnane (23:43): The surprise was that there was a huge variation in the breath acetone levels in children that were in good seizure control. Quite a variable level of ketosis. Now that’s seizures and its children. It’s not about cognition and aging. But to what extent do we have confidence that there’s a linear relationship? Yes. We’ve seen it with ketone PET imaging, and in MCI that there is an improvement in cognitive performance.

Dr. Stephen Cunnane (24:12): But that’s in a relatively narrow range of ketones and low. If you were to go out further to the right on the scale. Higher ketone levels in the blood, I’m not sure whether we’d plateau. I don’t know whether it would be linear or not. We haven’t done it in people who have got 7 or 8 mM ketones. I think that’s a guess at this point as to whether there’s a threshold, whether you plateau, or whether there’s a linear relationship.

Dr. Dale Bredesen (24:39): Okay. Stephen, if someone said, “Look, we’re looking at how we can get the best levels of ketones for energetics within the brain.” I can tell you either the acetone level or the VHB level, which would you prefer to know?

Dr. Stephen Cunnane (24:55): Acetone, like breath acetone versus …

Dr. Dale Bredesen (24:58): Breathalyzer, acetone or I can tell you that blood BHB.

Dr. Stephen Cunnane (25:02): But if you’re confident that both measures are accurate, I think whichever one is available, and it may be easier for some people, obviously, to provide a breath sample than a finger prick. But either one, they should be equivalent. In my experience, we published two papers, or maybe three papers on this. I have confidence that a reliable breath acetone is a reliable measure of ketosis.

Dr. Dale Bredesen (25:24): Fantastic. Yeah. I think this comes up because a lot of people don’t want to do the finger pricks. Of course, you can do breathalyzers more times during the day as well.

Dr. Stephen Cunnane (25:33): But I haven’t compared the available devices. I don’t know who’s got a reliable device and perhaps who might not.

Dr. Dale Bredesen (25:41): Yeah. Great point. Okay. Then there actually a question came in here about from, Dr. Ram Rao, who is a biochemist from Mayo, and also has done some beautiful work on, I believe, four effects on cells. He’s asking about if coconut oil is not a ketogenic. He’s saying, “Why is it that MCT is ketogenic and coconut oil, obviously, longer chains there, as you said, 12 and 14, as opposed to 8, it’s not just caprylic acid. Why are these not giving you that ketogenic effect?”

Dr. Stephen Cunnane (26:17): Well, they’re more dependent on carnitine to get into the mitochondria to be beta oxidized. If you were fasting, and took C12 or C14, you might get more ketosis than if you were just fasting. C8 and C10 can get into the mitochondria without piggybacking on carnitine. They accelerate the process of making ketones. They’re simply to dilute in natural coconut oil to have a significant impact on ketosis.

Dr. Dale Bredesen (26:49): Yeah. I mean, certainly, I would say, wouldn’t Mary Newport who suggested this and had some good results with coconut oil, I think would argue that but at least there’s … you’re seeing an increase in ketones one way or another. But it sounds as if, as you say, it’s a more indirect. You’ve got to have the carnitine, the CPT, you’ve got to have the transport to get this.

Dr. Stephen Cunnane (27:12): If the insulin resistance has come under control of insulin sensitivity is coming back towards normal, then C12 and C14 may well be contributing to ketosis and is in a situation of normal insulin sensitivity. I haven’t studied that. But that could be another reason why there’s this contradiction in a sense. How come we don’t get much ketones? Well, maybe you would if the insulin sensitivity was better on that. Again, it’s speculation.

Dr. Dale Bredesen (27:37): Yeah. Then again, maybe this … Julie, maybe you can talk about your work, as Julie had suggested years ago, “Let’s get the best of both worlds.” With people who are ably four positive, there’s often a concern for their lipid profile. There’s often a concern for their LDL particle number. When they start taking MCT oil, this can balloon up to 2,000 or above, and we’d like to see it more in that 800 to 1,200 range.

Dr. Dale Bredesen (28:05):

The question then was, “Okay. Should they just be doing something different, maybe taking some ketone salts or something like that?” Julie’s point was, “Well, what about polyunsaturated fats?” Julie, maybe you can talk about how you came up with that idea and how it’s worked for you?

Julie Gregory (28:20): Right. In our community, we experimented with shifting our macronutrient ratios to reduce carbs and increase healthy fats, and we prioritized heart healthy fats. Sure enough, we have wonderful success getting great levels of ketosis. As I said earlier, when we combined it with that long daily fasting exercise, it wasn’t very painful at all.

Julie Gregory (28:44): I think if you were relying on fats alone, it would be icky. But if you’re also fasting and doing the exercise, as we know, all three of those create endogenous ketosis. That’s how many in our community are getting in ketosis and we have great lipids, great glycemic biomarkers, too.

Dr. Stephen Cunnane (29:04): Well, that’s great to hear. I think it fits with what I know about them. The oxidation, what I mean by that is beta oxidation, so that the breakdown of fatty acids as fuels for an 18-carbon fatty acid, if it’s got one double bond, if it’s got no double bonds, let’s give it a value of 100. No. If it’s got no double bonds, let’s give it a value of 50. If it’s got one double bond, it’s about 60, or 70.

Dr. Stephen Cunnane (29:33): If it’s got two double bonds, that makes it linolenic acid, it’s got a value about 80. If it’s got three double bonds, that’s alpha-linolenic acid, omega-3 fatty acids got a value of about 100. Alpha-linolenic acid is at least twice as ketogenic as stearic acid is the 18-carbon saturated fatty acid. Going heart healthy in terms of your polyunsaturates is going to favor ketosis as well.

Julie Gregory (29:58): Right.

Dr. Dale Bredesen (29:58): Interesting. You mentioned 50 to 100 with stearic with longer chains. What if you’re comparing something like DHA to MCT.

Dr. Stephen Cunnane (30:10): Oh, DHA is essentially not. Within a 16 or 18-carbon link that that story holds. When you get to 20 and 22, it doesn’t hold at all. Arachidonic acid is not ketogenic. DHA is not ketogenic. C8 and C12, or C8 and C10 are much, much more ketogenic than DHA. But I think you’d have to practically kill someone to get any ketones out of their DHA. It’s not going to be a good source.

Dr. Dale Bredesen (30:37): What about olive oil?

Dr. Stephen Cunnane (30:38): You’ll be wasting the DHA, which you really need to help the synapses and the neurons talk to each other.

Dr. Dale Bredesen (30:43): What about EVOO, as Julie was saying earlier? What about olive oil compared to MCT?

Dr. Stephen Cunnane (30:49): Well, it’s not as good as MCT. But it’s better than saturated fatty acids. In a diet, in a ketogenic diet, for instance, or in some kind of regimen, it’s going to contribute for sure.

Dr. Dale Bredesen (31:03): Yeah. Fantastic. There are some wonderful questions here. Let’s check a couple of the questions. Irene says, “I’m recovering from toxic frontotemporal dementia.” That’s fantastic in and of itself. There is no recognized successful treatment for FTD right now. The fact that you’re recovering is fabulous. We have heard a number of anecdotes of people improving with FTD. That’s great to hear.

Dr. Dale Bredesen (31:29): It says, “I’m improving with treatment. I’m now able to cope with ketosis. But for me a limiting factor was metabolic acidosis. If I balanced this with sodium bicarb, it feels so much better and monitor pH by urine. I don’t know if there is a relationship with your research.” Stephen, have you had issues with this with people taking and caprylic acid or other things like this? Have you ever had pH issues?

Dr. Stephen Cunnane (31:56): Not even close. I’m not sure what explains her sensitivity to this type of regimen. I’m not a physician. There may be some elements that I should understand. But at the moment I can’t really explain that.

Dr. Dale Bredesen (32:14): Yeah. This is important. I mean, we do of course find that with these diseases that are really not very well understood, things like FTD and ALS and PSP and things like this. It’s often helpful to know more metabolic data and more toxicity data and some. End of ones are important in these areas that we really don’t understand very well yet.

Dr. Stephen Cunnane (32:35): If she’s losing weight that might be contributing perhaps. I guess she’s not diabetic. But perhaps that needs to be eliminated as well.

Dr. Dale Bredesen (32:46): Yeah. That’s a good point. Okay. Then there’s here from Valerie from … She says, “From flooded Australia.” She says, “I’m listening with switched on ears. MCI is mildly metastatic cancer. I’ll plagiarize that, okay. Flood brain is being coined in our region as people flood affected had to go into survival mode. It was a one in 500-year severity flood.”

Dr. Dale Bredesen (33:12): Wow. “Three to four weeks and people are struggling to cope with new flood brain fortunately counseling, chaplains, evacuation okay. I’m really concerned with my PLWD friends in the last few days that I actually get out of my … to start to reach out.” Okay. See small farms, big kids, multiple tractors. Okay. It sounds a lot of brain fog here with a lot of flooding and things like this.

Dr. Dale Bredesen (33:37): Of course, Professor Dr. Schumacher has pointed this out for years. Once you have flooding and water damaged buildings, you do start to have production of mycotoxins and brain fog and unfortunately sometimes dementia as well.

Dr. Stephen Cunnane (33:52): That’s the stress and the lack of sleep and all the aggravation associated with the property loss. It must be very stressful.

Dr. Dale Bredesen (34:02): Yeah. This is basically as we talk about how to give yourself cognitive decline. You combine all those things.

Dr. Stephen Cunnane (34:09): I can get COVID while you’re at it.

Dr. Dale Bredesen (34:12): Yeah, exactly. Yeah. Then add in some drive-thru food with some junk food and you’ve got everything. Let’s see here. The next one here is from Gail who says, “Do you know anything about high silica water, like Fiji water to help brain fog and other brain related symptoms? Certainly, there’s a lot of interest in detox, people with zeolite and of course, cholestyramine, and bentonite clay, and all sorts of things in the appropriate people who have proven toxins.”

Dr. Dale Bredesen (34:42): I think it’s becoming more and more obvious that toxicity can contribute to cognitive decline. We see this all the time in people. We see improvements as they deal with their detox. I guess that brings up the question, where does that stand with ketosis? Presumably if you’ve got better energetics, you’re going to be better at detox.

Dr. Dale Bredesen (35:05): Stephen, have you looked at all at people’s detox apparatus? For example, what happens with their glutathiones? What happens with their methylation patterns? What happens with the sulfation and various cytochrome P450 enzymes? When they have appropriate ketosis?

Dr. Stephen Cunnane (35:24): The answer is I haven’t a clue. These are relatively simple studies, but they’re laborious, and that we haven’t been able to get to that information. I do know from preclinical studies, from three or four different laboratories that the Alzheimer mice, transgenic Alzheimer’s mice in ketosis, both exogenously and with a ketogenic diet definitely have reduced phosphor-tau and amyloid levels.

Dr. Dale Bredesen (35:48): Fantastic.

Dr. Stephen Cunnane (35:50): There’s one study from Suzanne Craft published last year in which we were collaborator, in which she used the Mediterranean ketogenic diet and showed in CSF markers of neuropathology were down as well. There are early indications. There are tantalizing suggestions that that’s part of the process.

Dr. Stephen Cunnane (36:10): We might actually be engaging in disease modification. But I think it’s too early to say more than that. It, obviously, we need some more work.

Dr. Dale Bredesen (36:18): Yeah, absolutely. One of the obvious questions is related to the one that Mike is asking here. What happens if you look at this classic pattern, the parietal and temporal decrease in glucose utilization on PET scans from the FDG scans really the hallmark of Alzheimer’s disease, and then you treat them and you improve their insulin sensitivity, and you give them some degree of ketosis.

Dr. Dale Bredesen (36:43): Clearly, as you pointed out, the ketones are absorbed. What about the glucose? Do you actually see an improvement in glucose utilization?

Dr. Stephen Cunnane (36:52): No. On MCT, there’s essentially no change. There might be a 1% or 2% change, but it’s definitely within the noise. It doesn’t change. If you do exercise, it does … FDG, the tracer for glucose uptake does go up in the brain.

Dr. Dale Bredesen (37:11): Yeah.

Dr. Stephen Cunnane (37:12): If you do exercise, the transport of ketones, not only are ketones produced more doing even moderate exercise, I’m talking about Alzheimer patients. These people are not out running marathons or anything.

Dr. Dale Bredesen (37:23): Right.

Dr. Stephen Cunnane (37:23): But it’s a very sedate form of running on the treadmill or on a bike, the capacity to take up the ketones by the brain also increases. If you put an exogenous or an endogenous ketosis with exercise, you double your money as far as getting more ketones into the brain is concerned. That’s what we’re just starting a project on right now is to put the two together, both in Alzheimer’s patients and in Parkinson patients.

Dr. Stephen Cunnane (37:50): We haven’t even got the first person in the trial yet, but we decided that this is worth trying together the synergy between exercise and ketones.

Dr. Dale Bredesen (37:58): Yeah. This makes perfect sense. I mean, if you’re restoring insulin sensitivity, by whatever means, you should be restoring the ability of your brain to take it up. That makes perfect sense.

Dr. Stephen Cunnane (38:09): Yeah.Dr. Dale Bredesen (38:10): Mike is saying here, “Will following a keto diet and/or fasting at an earlier age preserve the glucose uptake than an old version?” Presumably from what you’ve just said, preserving that insulin sensitivity is really what you’re after. Mike says he’s 53. He’s in prevention mode. Fantastic, Mike.

Dr. Dale Bredesen (38:29): I know, Stephen, you said in your interview that’s online. Basically, if you start early, that’s the way to go. We’ve always said if everybody would simply get on prevention, or earliest reversal, we could make Alzheimer’s, a rare disease. It doesn’t have to be probably common disease that it is today.

Dr. Stephen Cunnane (38:49): I would encourage Mike and anybody else in their 50s to think seriously about keeping their insulin happy, basically. I just like to add an anecdote about a published report of ours that women that are 23 years old, we studied with insulin resistance due to polycystic ovary syndrome.

Julie Gregory (39:07): Yes.

Dr. Stephen Cunnane (39:08): The shocking part about this is that they were 23 years old, and they had a pattern of glucose uptake that resembled premature aging. They had lower performance on episodic memory, and trail making tests as well. I’m not saying this was mild cognitive impairment. But it’s a pattern that is setting up for. It’s increasing the risk that they will progress towards a form of cognitive deficit, and they were 23.

Dr. Dale Bredesen (39:32): Yeah.

Dr. Stephen Cunnane (39:34): I don’t think that’s the threshold. I’m sure adolescents could actually have metabolic issues in the brain if they’re insulin resistant or pre-diabetic. It’s not just women, of course, men as well are equally vulnerable. I can’t emphasize the importance enough of an active lifestyle. It’s sufficient to keep insulin under control. Of course, limiting carbohydrates is probably the most important thing you can do towards achieving that.

Dr. Dale Bredesen (40:00): Yeah. This is a really good point. Of course, when I was training, we thought of Alzheimer’s is a disease of your 60s, 70s, 80s, 90s. Now it keeps moving back. We then we realize, okay, 20 years before that, you can begin to see changes in spinal fluid and PET scans. As you pointed out, now even earlier, you can see changes in brain function and brain structure. This really is an integral over your entire life.

Dr. Stephen Cunnane (40:25): Well, when you were training, chances are there weren’t many people in their 20s with diabetes, certainly not adolescents. Whereas it now of course, there are. We’re simply insulting the brain even earlier now than we were 20 or 30 years ago by our lifestyle and some of our choices that we’re making. The brain is resilient. It’s amazingly resilient, but it does eventually hit the wall.

Dr. Dale Bredesen (40:49): That’s a good point, because as you know paper just published a couple years ago showing that we’re seeing more people now with onset in their 50s and got a diagnosis of Alzheimer’s in their 50s, onset of pathophysiology much earlier than that. I went back and asked some of my friends that I trained with way back in the ’80s. We never saw people with a diagnosis of Alzheimer’s in their 50s back then.
Dr. Dale Bredesen (41:12): Now, it’s one of the most common presentations we see people in their 50s coming in and getting diagnosed with either Alzheimer’s or MCI. There is something that is different, as you said, likely that the fact that there’s a lot more earlier diabetes and things like that. Then Alexis asks, “Is a ketogenic diet, the best diet for TBI, traumatic brain injury and neurodegenerative disease? Of course, there’s some controversy about this. But Stephen, please weigh in on this.

Dr. Stephen Cunnane (41:44): It would be speculation because I don’t know of any clinical studies on TBI that are published. I would think it would make sense. Obviously, it makes sense that you should be able to protect the brain with ketones, some people that may have succeeded in their own personal experience, whether in the military or through sports, or simply for falling down in their home.

Dr. Stephen Cunnane (42:07): But I don’t know of any convincing studies that actually demonstrate that. But it definitely needs to be studied. If you’re living with someone who’s just experienced brain trauma, I would strongly encourage you to get them on MCT or exogenous ketone or something. I did this with a friend of mine who had a skiing accident and a concussion.

Dr. Stephen Cunnane (42:27): He swore afterwards, he was a senior executive at the university, that his return to normal at work was accelerated by the fact that we were actually providing with a ketogenic with MCT. That’s an anecdote, of course. But if you’ve nothing to lose, and everything to gain by trying it.

Dr. Dale Bredesen (42:47): Yes. Energetic seem to be so critical. The irony and the paradox here with Alzheimer’s is that on the one hand, it’s really a disease of insufficiency. You aren’t getting the glucose. You’re not getting the energy. You’re not getting the blood flow. You’re not getting the oxygenation, or you’re demanding too much, as you mentioned earlier, with things like inflammation.

Dr. Dale Bredesen (43:10): Yet it’s an insufficiency that we treat, and is born. It’s born of excess. We’ve had too much sugar. We’ve been pouring this stuff in there and hurting ourselves. You have to be careful when we’re now fasting. If you’re already very frail, you got to be careful. That’s why I really like the exogenous ketones, especially early in the process to get going here. I agree with you. I think that it absolutely is the best way to go for TBI and neurodegenerative disease.

Dr. Dale Bredesen (43:42): Next one here is from Susan, who said, “Heard previously about limiting coconut fats for APOE4. We’ve talked about this many times. Julie, maybe you could weigh in on how to get the best of both worlds to get yourself into ketosis but being careful about your LDL particle number?

Julie Gregory (44:02): Right. In our community, we found that if you minimize the saturated fatty acids and lean into the heart healthy Mediterranean fats like avocados, nuts, seeds, extra virgin olive oil, we get excellent lipid by biomarkers. Just shift your priority to different fats. It seems to work very well. We still get into ketosis, and we’re protecting our hearts at the same time.

Dr. Dale Bredesen (44:29): Thank you very much.
Dr. Stephen Cunnane (44:30): But we didn’t have a rise in LDL in our six-month trial. That was a preoccupation. It was quite a number of the participants at the beginning were concerned about gaining weight, which didn’t happen. None of the classical biomarkers, even the inflammatory markers that some people allude to were not changing. The CRP, the TNF alphas, the interleukins, it’s steady.

Dr. Stephen Cunnane (44:54): Maybe that’s dose dependent. Maybe it’s the type of ketosis that you use. But in our experience so far, those red flags simply didn’t go up.

Dr. Dale Bredesen (45:04): Yeah.

Julie Gregory (45:04): That’s for even APOE4 carriers?

Dr. Stephen Cunnane (45:07): Yes. We had about 30% were APOE4 carriers, most of them heterozygotes, just a single allele. We did look at the APOE aspect. But again, we had no smoking gun primarily because we didn’t have enough people to really tease that out. But they benefited as well as the non-carriers. I’m not convinced at the moment that APOE4 is a limiting factor for ketosis.

Dr. Stephen Cunnane (45:37): That may be the case. I might be proven wrong. I’d be happy to be proven wrong by appropriate data. But so far, we haven’t seen anything coming out of our studies that suggests that that’s an issue.

Dr. Dale Bredesen (45:50): Yeah. Then you remember …

Julie Gregory (45:51): I said, “Wonderful.” I just want to mention, we do see the high LDL- particle  numbers with lots of saturated fat in APOE4 carriers. But we’re able to get around that with a heart healthy fats.

Dr. Dale Bredesen (46:07): Related issues. Stephen in your trials, any issues with liver function tests? Any issues with thyroid changes? One of the issues that’s come up is that sometimes the T3 will go down. The other one that comes up, of course, is kidney stones. Did you have any side effects in that trial with any of those?

Dr. Stephen Cunnane (46:26): No reports, although we screened for TSH, but I don’t think we looked during the intervention. I can’t say whether that changed.

Dr. Dale Bredesen (46:36): Yeah. Yeah.

Dr. Dale Bredesen (46:39): Yeah. As far as kidney stones, I think that’s more likely to be dehydration, more, at least, the endogenous ketosis presumably than the exogenous.

Dr. Stephen Cunnane (46:48): Probably.

Dr. Dale Bredesen (46:49): Then Audrey is asking, “Can I please submit a question to Dr. Cunnane? I have young onset Parkinson’s. I’m very thin as keto recommended or low carb with exogenous ketones.” Stephen, would you address that? Or Should we have her send a longer question and forwarded to you? What’s best for you?

Dr. Stephen Cunnane (47:07): Well, she can forward a question to me. I can try to answer that. As I said, I’m not a neurologist. I don’t have any firsthand experience. But I do know she needs to know about Matthew Phillips study in New Zealand, which was an eight-week intervention. They show that you can have quite a variety of ketogenic meals over eight weeks without repeating any of them, with good effects, both on the motor and the non-motor symptoms of Parkinson’s disease. That’s endogenous ketogenesis.

Dr. Dale Bredesen (47:34): Yeah.

Dr. Stephen Cunnane (47:37): One of the legendary neurologists from New York showed something in a very small trial with five or six people about 20 some years ago. It’s an emerging field. I don’t think anyone would say we have definitive results, even on Alzheimer’s, we don’t. But I think there’s every reason to believe that there should be a beneficial effect or could be at least and especially if she combines it with some degree of exercise, some type of exercise that she can imagine doing on a repeated basis, even if it’s just walking.

Dr. Dale Bredesen (48:08): Yeah. Yeah. Again, this comes back to Parkinson’s, same idea. In this case, the subsystem is motor modulation as opposed to neuroplasticity, but the same idea. We know that things that affect complex 1. You don’t have the same energetic, things that affect protein folding, and female detox abnormalities all increase your risk.

Dr. Dale Bredesen (48:33): There’s a very nice book that came out a couple of years ago, which is a prescription for ending Parkinson’s. They talk about how the exposure to toxins and how this is a dramatically increasing problem with Parkinson’s disease is just on a dramatic rise. I think another place where ketones may, in fact, be very, very important.

Dr. Stephen Cunnane (48:55): Right.

Dr. Dale Bredesen (48:58): Okay. Let’s see, insulin. Let’s see, brain fog. Okay. Great. Gloria says, “Do we drink coffee and recommend it?” Actually, I have never had a cup of coffee in my life. But there are some nice studies showing that people who drink more than … There was one study show that people that drink more than five cups a day, another one showing more than three cups a day actually had reduced risk for cognitive decline. What does coffee do to your brain energetics?

Dr. Stephen Cunnane (49:30): Well, we published a paper on using caffeine 25 milligrams versus 50. I think it might have been 50 and 100, the equivalent of two cups of coffee or four, and it will roughly double ketosis from a standing start. Not combined with MCT. It could be a tool to induce a mild form of transient ketosis.

Dr. Dale Bredesen (49:51): Yeah.

Dr. Stephen Cunnane (49:51): It’s one of the tools in the toolbox. If you don’t drink coffee, I wouldn’t necessarily go out and start. Some people make a bulletproof coffee with C8 in it or some other concoction. Again, I think you need to personalize it. Some people love to have a rule a rulebook to play by.

Dr. Dale Bredesen (50:09): Yes.

Dr. Stephen Cunnane (50:10): A lot of people say, “Well, I don’t do this, and I don’t do that, therefore, I’m not going to do it.” You have to write your own rule. Then as long as you understand the principles behind it, then you can still win the game if you … I don’t want to take the analogy too far. But if you want to benefit from it, you’ve got to figure out a way to do it in a sustainable way. Each person is going to be different.

Dr. Dale Bredesen (50:33): The armamentarium, as we’ve been arguing for a number of years now is huge. There’s a tremendous amount that you can do to change the neurochemistry to get you on the right side of this curve. Julie, you wrote a beautiful piece in your handbook about coffee and your love of coffee and how you like to have it and the things to do. Maybe you could talk a little bit about what do you do personally as far as coffee goes.

Julie Gregory (50:56): I may have a cup or two in the morning. I have a black because that’s what I’m fasting. I put a drop of that SweetLeaf Stevia in it, and certainly no cream because that would break my fast. But it makes me feel amazing. It wakes my brain up and it makes me happy. Dale, I don’t trust people like you who don’t drink coffee. You’re like not normal.

Dr. Dale Bredesen (51:22): I just never liked the taste of it. I don’t know. Okay. Here’s another one from Gail.

Dr. Stephen Cunnane (51:27): But what happy is really a pretty good objective as well. Not many people can say that at the end of the day. I’m really happy and you’ve said it more than twice just while we’ve been online together. It’s a good sign.

Julie Gregory (51:41): Yeah.

Dr. Dale Bredesen (51:42): It is a good sign. Then Gail says, “Can too much MCT oil cause insulin resistance that is exacerbated?

Dr. Stephen Cunnane (51:51): I don’t think so. I think you’ll find yourself sitting on the throne, to put it colloquially, as sooner than that. I one of the limits to MCT is GI tolerability, even well-emulsified. If it affects insulin resistance is at a dose that’s off scale in terms of its therapeutic needs.

Dr. Dale Bredesen (52:11): We often tell people start low and then work up. In your studies, did you have …

Dr. Stephen Cunnane (52:15): Absolutely. Yeah.

Dr. Dale Bredesen (52:16): Yeah.

Dr. Stephen Cunnane (52:16) We gave them a 10-day or maybe two-week titration period at the beginning, absolutely.

Dr. Dale Bredesen (52:21): Yeah. Certainly better for your gut. Well, we’ve got lots more good questions. But I know that time is getting short here. We’ll take the rest of these online and answer them there. Just a tremendous honor. Thank you so much, Professor Stephen Cunnane. Thank you, Julie. Great to talk to you guys. Thank you for the input. Let’s all hope for a reduction in the global burden of dementia and look forward to your further studies.

Dr. Stephen Cunnane (52:44): Well, keep up the good work, both of you and thank you for having me join us for this discussion. I’d be happy to fill some questions by email or whatever that you use.

Dr. Dale Bredesen (52:54): Thanks. Thanks very much, Stephen.

Julie Gregory (52:56): Thank you.

Dr. Stephen Cunnane (52:56): Bye-bye.

Dr. Dale Bredesen (52:57): Right. Bye-bye.