In episode 131, Jesse talks to Dr. Richard Wurtman, Cecil H.Green Distinguished Professor emeritus at the Massachusetts Institute of Technology, about a new dietary protocol that could prevent, or at least seriously reduce the progression of, Alzheimer’s Disease.
Dr. Wurtman, both a scientist and a medical doctor, wanted to develop a food-based treatment for pre-Alzheimer’s. He found that individual foods can control the product of key brain chemicals. Losing synapses is a major hallmark of Alzheimer’s, so the next question was: can consuming certain foods or compounds create more synapses in the brain?
A Medical Food to Treat Alzheimer’s
The result: Souvenaid, a medical food for people with Alzheimer’s or at risk of developing Alzheimer’s. Medical foods are foods specially formulated for the treatment of a disease.
Along with phospholipids, antioxidants, and B vitamins, Souvenaid contains choline, DHA (an omega-3 fatty acid), and uridine. While the first two compounds can be easily obtained via diet, most of the uridine in foods is in the form of RNA, which is not bioavailable. The only time people are regularly exposed to bioavailable RNA is in breast milk or infant formula.
A two-year study found that drinking 125 mL of Souvenaid per day protects pre-Alzheimer’s individuals against memory loss.
Souvenaid seems to work by enhancing the formation of synapses and reducing brain shrinkage, particularly in the hippocampus, the part of the brain that stores short-term memories for long-term retrieval.
The benefits are strongest when the LipiDiDiet is started in the earliest stages of the disease.
Something You Can’t DIY
Word to the wise: The specific Souvenaid formula is what has been studied. Taking the individual ingredients by themselves is not necessarily going to be useful.
For example, Souvenaid doesn’t just contain Choline. It also has large amounts of the three vitamins (B6, B12, and folic acid) necessary for the liver to produce choline, amplifying the effects of the choline in the formula.
Need further proof? The European Food Safety Commission ruled that it’s no longer allowed for DHA manufacturers to claim that DHA benefits cognition, because the data don’t support that claim. However, it’s clear that in combination with the rest of the ingredients in Souvenaid, DHA does have a protective effect on memory.
- The Effect of Souvenaid on Functional Brain Network Organisation in Patients with Mild Alzheimer’s Disease: A Randomised Controlled Study
- A Nutrient Combination that Can Affect Synapse Formation
- Two-year, EU-funded Study Reveals a Medical Food in the Form of a Daily Nutritional Drink Can Help to Conserve Memory, the Ability to Think and Perform Everyday Tasks, as well as Reduce Brain Shrinkage in People with Very Early Alzheimer’s Disease (AD)
- The LipiDiDiet website
PS: Don’t forget (see what we did there?) to join our weekly newsletter below!
Episode Transcript hideshow
Dr. Wurtman: There are at least three different regulatory categories that relate to what we’re talking about. One regulatory category is, of course, dietary supplements, nutritional supplements. These are only for normal people. You may not make any claims for them in terms of treating any kind of a disease. You can say, “Well, it keeps the brain younger, it keeps you feeling more fit,” that kind of stuff, but it’s against the law and the FTC gets after you if you make any kind of medical claims. The second is what I’m talking about, and that’s a medical food. And a good example of a medical food, you probably know this—ever hear of the disease called phenylketonuria, PKU?
Jesse: No, actually.
Dr. Wurtman: Okay, well it’s a disease. You probably don’t have any infants, but if you had an infant, you’d hear about it, because every infant, their urine is tested. If something turns green, it means their liver cannot metabolize an amino acid called phenylalanine, and if you don’t get rid of it, then they’re going to have cerebral palsy… And the way it’s treated is you make a diet that contains not pure protein, but the protein is broken down to its 22 amino acids and one of them is thrown away, so they get no phenylalanine. Now, if you ate that, you wouldn’t grow, you would do very badly. But if they ate the regular protein, they would get this disease. So, this is a good example of a medical food, a food that is generated just for a specific population.
What I’m going to be talking about is a medical food that is generated for people that have dementia or are likely to get dementia, people that are good candidates or bad candidates for Alzheimer’s disease. And the third category, of course, is a drug. The whole idea behind a drug is you can make medical claims. That’s the defining characteristic. It doesn’t matter whether if it’s a natural compound or an unnatural compound, it all depends on the claim. It’s that simple. If you want to claim that “I have done studies, and I have shown that giving so and so to people suffering from so and so helps to make them better or keeps them from getting worse,” then it’s a drug. And it doesn’t matter if you’re starting out with sugar. If you suddenly found that taking certain quantities of sugar stops diarrhea—I just made that up, don’t believe that for a minute—and you wanted to claim that on a label, you’re dealing with a drug. There’s nothing about the biochemical pathway, per se, that defines whether something is a drug or a food or what have you. It’s just the label you want to put on it.
Jesse: So zeroing in now on your work on prospective treatments for Alzheimer’s and pre-Alzheimer’s, can you tell us about those studies and how those got started?
Dr. Wurtman: Many years ago, I was interested in what controls the production of certain neurotransmitters in the brain, particularly one called serotonin, which I’m sure you’ve heard of, it’s involved in appetite and mood and all sorts of other things. And it comes from an amino acid called tryptophan, and the enzymes enact in the tryptophan and generate the serotonin. And I noted that one of the enzymes involved is kind of like a weak magnet, it doesn’t really add much attraction for tryptophan, so you have to have very high concentrations of tryptophan locally in order to activate the enzyme and make more serotonin. And I did some studies that showed that, yeah, if you increase serotonin concentration, if you gave rats tryptophan, you would get more serotonin. And then I asked, well, what might increase tryptophan in the brain and tryptophan uptake into the brain dependent on blood levels? But also other amino acids compete with tryptophan, and so if you gave rats carbohydrates to eat, which causes insulin to be secreted, that lowers the levels of the competition, and as a consequence, more tryptophan gets into the brain and you get more serotonin. And that kind of opened, I think, the field basically of showing that individual foods could quite normally control the production of key brain chemicals, like some of the neurotransmitters, because they’re made by enzymes that are weak magnets.
Okay, so ever since that time, I’ve been looking around for other biochemical processes in the brain, the rates of which might be controlled by the availability of the substrate, the precursor, the thing that they act on to make their product. And I found that for a bunch of other neurotransmitters. Then I got interested in the category of chemical called phosphatides, and phosphatides are lipid compounds but they’re made in the brain, they’re made in all cells, and they’re a major constituent of membranes. And there are three key constituents, and so my laboratory found that if you give each of these three constituents, you can increase the rate of producing the final product: phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, etc. That was extraordinary because now we have big increases in the main constituent of membranes.
Well, what about the other constituents of membranes? Well, the other constituents are certain proteins. For example, the proteins in synapses that make the transmitters, and that receive the transmitters, and so forth. And then it turned out we were very lucky, because one of the precursors, one of the things you had to give, uridine, which affects the rate of producing this lipid component, this fatty component, is also something that activates receptors, we call them, in the brain. Now by doing so, it turns on the production of these key proteins. So when you’re giving this cocktail that we’ll talk about, not only do you get more of the lipid component of the membranes, but also you get more of a particular protein component, so you’re making really more active membrane.
Then I began thinking, well, what about membranes in the brain that are likely to turn over pretty quickly, like synaptic membranes? Is there any possibility that by giving these compounds, you can get more synapses? And you couldn’t study this directly in people—you know, they’re quite alive. Eventually, people did figure out a way of studying it in people, and it’s done by using a complicated electroencephalographic technique. But anyhow, at the time what we had to do was basically look for the intermediate anatomic thing, the thing that’s intermediate in making a synapse, called a dendritic spine, and you have to have dendritic spines to make most of the synapses in the brain, and if you have a dendritic spine, the odds are 95% that it’ll wind up becoming a synapse…
Jesse: A quick interruption just so people can sort of visualize this: the dendritic spine, should we think of that as essentially like a prong of an antler?
Dr. Wurtman: That’s a good idea. Yeah, exactly. You have the dendrite coming out from the receiving cell, and then it produces this structure, this dendritic spine, it has a lot of different proteins inside it, etc. And when stimulated by the transmitter released by what will be the presynaptic cell, you make more of these dendritic spines. And then if there’s enough stimulation, if enough calcium comes in, then you’ll start making more dendritic spines and you’ll start making more synapses. So hey, now we’ve got something here. So by getting compounds, most of which are in foods, it will actually increase the production of dendritic spines, which almost certainly will increase the production of synapses, and there’s no argument against that.
Then my graduate students did some studies on rats to demonstrate that if you measured the rate at which rats learn things—for instance, you use something called a Morris water maze. You have a big tub, and if the tub was filled with water high enough so that the rat can’t stand up in it, but in the middle of the tub you put a platform, so if the rat is smart, it’ll swim over to the platform, stand on the platform, and then it won’t be bothered by the water. Well, you do that on successive days and the rat gets smarter and smarter, it’s highly motivated to escape the water. And we found that if we give these animals, for a couple of weeks, these precursor compounds, these things that are needed to make the phosphatides and to turn on production of the proteins, they actually do learn faster.
Well at that point, of course, I got to wondering about people. Now, I have a dual career. Half of me is a basic scientist with a laboratory and graduate students and post-docs and so forth, working on rats and mice and cells and culture. The other half of me is I’m a medical doctor with some training in neurology, and so I have kind of a dual career. And once we’re fortunate enough to find an animal, to find in the laboratory that, hey, if you give more of A, you get more of B, then I can ask the question, is there some clinical circumstance in which you’d like to have more of B? Is there some disease that is not adequately treated because you don’t have enough B, and so might patients with that disease be helped if we gave these precursors and made more B? Well, the immediate one I thought about was Alzheimer’s disease because I’ve been interested in that for a long time anyhow, and I’ve been interested in the possibility that these patients that have Alzheimer’s, they have too few synapses. That’s why they have memory disturbances early on, not because they have too few neurons. They do lose neurons much later on and their brains shrink, which is not a good thing. But early on, for the first N years, their problem is an inadequate number of synapses.
So now if we have a strategy that increases synapse formation in experimental animals, might it also work in people, and might it also work in people with diseases like Alzheimer’s that have a deficiency in synapses, and as a consequence, might not remember better? Now we’ve got some indirect measurements using scanning, etc. that suggested that this was possible. So in order to go ahead and have tests done on this, now you’re talking big money. This is not something that universities can do. Up until this time, all of my research had been within MIT and Harvard Medical School and had all been funded, thank you, by the National Institutes of Health, no corporate connections, etc., all kind of basic science stuff. But in order to go ahead and get this tested, first, my university said, “We’ve got to go ahead and patent it.” So MIT did go ahead and patent the stuff I have been telling you about. And then there was the question of, with the patents, finding a company that would be interested, a licensee, a company that would license the patents and then be interested in setting up and sponsoring clinical trials to see whether or not it actually worked in people. I was very lucky, found a company that was interested in doing that, it’s a company that I’m sure you must be a client of. Do you eat yogurt?
Jesse: On occasion.
Dr. Wurtman: Well the company is Dannon, Dannon yogurt. But Dannon is known as Danone.
Jesse: Yeah, they’re one of the world’s major food brands.
Dr. Wurtman: Indeed they are, but in addition to that, they have a very big multi-billion dollar component called medical foods, or foods for special medical purposes, so they already had an interest in producing this category of compound, they had some experience with it. So I began collaborating with them and they funded two large-scale clinical trials on people that had early Alzheimer’s disease, and it worked fine. It stopped the progression of loss of cognition, loss of memory particularly, in these people. But these were short-term studies, like three-month or six-month studies, and they were not terribly large, but at least they suggested, hey, there might very, very well be something there.
Well, what happened with the recent study is this. The European Union—which is a government agency, it’s not a company, right—decided for its own purposes that there’s an increasing toll of Alzheimer’s disease and other kinds of dementia as well, and it’s terrible for the people that have it and for their families, but also it’s terrible for society because so many of these people wind up in nursing homes for years and years and years, and if they can do something to increase the amount of knowledge about the disease and maybe come up with something that, at the very least, slows the disease, that would benefit everybody. So they had a competition and the company, Danone, has a branch called Nutricia, Nutricia is the branch that does medical foods, they submitted and applied for—I had nothing to do with this, but I was delighted to hear about it—a proposal that a study be done. The study is called the LipiDiDiet—I don’t know who named it…
Jesse: From Dr. Seuss.
Dr. Wurtman: Dr. Seuss, okay, that’s what it sounds like. And what happened was just this past week, the first presentation was made at one of the regular international Alzheimer’s disease meetings called the Springfield meeting, because originally they took place in Springfield, Illinois, but now they’re all over—this one was in Athens this past time. And they demonstrated data from two years, that if they took people who they knew had a very good or very bad chance of developing Alzheimer’s, and gave them this stuff for two years, it protected against most of the memory loss, and most striking—I’m shocked by this—it protected them against the shrinkage of the brain. Not totally, but about 38%/40%. I’d like to try and figure out how it works, but that is kind of a big deal. And the study will go on for another three or four more years because the stuff had no toxicity, it never has, and the compliance is excellent. People in both the placebo and non-placebo parts of the study all want to stay in the study, so they’ll probably wind up having data on it for six years, which is really kind of a wonderful thing.
Jesse: That’s fantastic. How many people were involved in the study, or still are involved in the study?
Dr. Wurtman: 300, or 317, something like that. I have a policy: I never get involved in clinical trials for things I invent. Because I figure, look, if it works for me but doesn’t work for other people, what good is it? The way this clinical trial is being done, the way they’re all done, is a group of scientists get together and generate a common protocol, and then they decide how many subjects they’ll need in order to have a statistical chance of demonstrating an effect if it’s there, it’s called “powering” the study. Then they try to engage other laboratories to participate.
So in this case, there were either 17 or 19, I forget which other studies, all in Europe or Israel, all over, because it’s European Union, they funded it, and all the data are pooled and the investigators and the subjects have no idea if they are placebo-treated or have received the active stuff. And I can affirm the having no idea, because look, I’m the inventor, right? I had no idea at all until a week ago, in Athens. So, that’s how they’re done. You want people basically that have trouble remembering events but not that have sufficient deterioration so that their memory scores are low enough so that they’re categorized as demented. They’re not demented. But these same people, they have to have something we call biomarkers, and that’s kind of new. Changes based on imaging or based on chemical measurements that tend to correlate with incipient or prodromal or developing Alzheimer’s disease. So in order to be admitted to the program, somebody could not have the disease, but they had to have some kind of mild memory problem, plus biomarkers. And it took them a long time to find the people for this, that’s why they had 17, 18, or 19 groups.
Jesse: What was the average age in this cohort?
Dr. Wurtman: I think it started out somewhat younger than one would have expected. It started out at I think people in their 60s, but I’m not sure.
Jesse: For the food protocol, what percent of a person’s diet is actually made up by the protocol calorically? Is this just a mouthful of something once a day or is this a major part of the way a person eats?
Dr. Wurtman: Well the product is called Souvenaid and it comes in a snazzy plastic bottle, 125ml I think, lactose-free, doesn’t taste too bad, either. 125ml, I’d rather it was 0 calories, but you can’t do that, and one takes one of these every day. As the inventor, I’m fortunate, because I’m the only person in America I think that has had access to this—the only person besides my wife. It’s been like five or six years now, and are we smarter than we were? I don’t know, but at least we’re not dumber. Maybe we are and I just don’t realize it.
Jesse: Let’s talk about some of the things that are in it. I guess it’s really just three ingredients, right?
Dr. Wurtman: Well, there are more. The main three ingredients, which is really all you absolutely need, plus some others and I’ll tell you why. Of the three main ingredients, two of them you can get from the diet. You can get choline by eating your fill of egg yolks and certain meats; your DHA, docosahexaenoic acid, I’m sure you know all about that, you can get that also from eating various foods. But the third one, the most interesting one, you can’t. And regardless of what you may read on the internet about tomatoes being… No, there is nothing that normal adult people ever eat that raises blood uridine levels or UMP levels. What’s the reason for that? The reason for that, and this was shown at Yale 25 years ago, most of the uridine in foods is in the form of RNA. And you know RNA, obviously.
Jesse: Ribonucleic acid.
Dr. Wurtman: Exactly. That is not bioavailable. It’s all broken down. It does not liberate free uridine into circulation. So you can eat your fill of foods that are rich in RNA, and in fact, most of the foods you eat contain RNA, right? But they will not raise your blood uridine level. Now the great exception to that happens in infancy. You’re going to like this story, I think. Because in infancy, babies drink mother’s milk, or they drink infant formula, and mother’s milk contains uridine in a different chemical form besides RNA. It contains uridine as the thing we put into Souvenaid: UMP, uridine monophosphate. That is bioavailable. So at the time when people are making synapses at the fastest rate, they get much larger amounts of uridine per kilogram of body weight than you or I do because they can get it from the constituents of mother’s milk. It’s also present in all the infant formulas, I gather, that are sold in America. They were put in 20-25 years ago; they call uridine a constituently essential nutrient. The reason they put it in had nothing to do with the rain. The reason they put it in was that somebody had discovered that the maturation of immune cells in the intestines requires the presence of uridine. So by happy coincidence, infants get it either way: they either get it from mother’s milk or from drinking the infant formulas. Now, you have uridine in your blood. Where does it come from? The answer is it’s made in the liver, kind of like a hormone. The liver makes and it secretes UMP, and in there you will always have it in your blood as far as we can tell. It’s just there’s nothing you can do to raise it unless you essentially get Souvenaid, right? Or drink mother’s milk, which is not likely to happen very often.
Jesse: Now, it is possible to get supplemental uridine in capsule format. Is that bioavailable in the way that the infant formula and mother’s milk is?
Dr. Wurtman: No, uridine by itself isn’t, no. The other thing is this: the big danger is a protocol was developed, and that protocol was tested and was found to be useful, and will continue to be. But anytime you mess around with a protocol, then you’re way up by yourself in left field. There is no evidence, for instance, at this point that giving these three compounds alone would be useful because that’s not the way the study was done. If you look at the label on a bottle of Souvenaid, you’ll find that there are other things in it. For example, one of the things you need is dietary choline. I’ve been working on choline for a very long time and early on we kind of discovered we couldn’t give people high doses of choline. Why not? Because when you get above maybe half a gram of choline per day, much of it is broken down in the intestine by bacteria that generates something called trimethylamine, and that is what makes a rotten fish smell like a rotten fish.
Jesse: Oh no.
Dr. Wurtman: So there was a big problem with compliance and you couldn’t really do a study on it. You know, the liver normally makes choline, you don’t get it just from your diet, you also get it from the liver. And if we put into the drink extra large amounts of the three vitamins that are needed to make choline—B12, B6, and folic acid—then the liver would make more choline, and that would raise blood choline levels and would amplify the effects of the choline that you’re putting in the Souvenaid. And the other ingredients also have amplifying effects, so I would not encourage people to believe that taking anything they can concoct in their basement is going to have this effect, and really, it could be dangerous to do that.
Jesse: One question about the protocol. Basically, it’s a small amount of Souvenaid that people are taking on a day-to-day basis. How does this work with the rest of their diet? Were there any foods that they were told not to eat, any potential conflicts with what somebody’s normal diet might be?
Dr. Wurtman: No, not to my knowledge. You know, you wouldn’t think it, because look, the Souvenaid contains DHA, choline, and uridine, but those three compounds are also present in your diet all the time anyhow, it’s just the uridine in your diet isn’t bioavailable because it’s mostly RNA, but it’s in the diet.
Jesse: I just wondered if they were tracking that because let’s say somebody eats a ton of eggs anyway and they’re already having elevated choline levels from their baseline diet, if they’re taking that into account when they look at the results.
Dr. Wurtman: Well, I’m not sure it would make much of a difference. I think what you want is what we would call saturating levels of the substrates. But I’m not sure that the dose-response curve goes on infinitely. Down the line, what’s probably going to happen—I hope—I have no evidence for this, but what I hope will happen is that when this stuff becomes generally available, particularly here in America where we’re kind of experimentally-inclined, people will try it on Mondays and Tuesdays, standing on their head and looking at the moon, try it all kinds of ways, and data will accumulate about is there a relationship between the different high levels and the clinical response. That’ll happen, but it’s not a known yet.
Jesse: A couple things I noticed reading the documents that you sent over. One was that EPA might be a perfectly good stand-in for DHA. I was just sort of wondering about that because I’ve talked with people about fish oil plenty before and those are always thrown around simultaneously, DHA and EPA. From a biochemical perspective, what’s the difference between those two, and is there ever a time when somebody should look for one but not the other?
Dr. Wurtman: The way the study was done, as you’ll see—I think if you go on the Internet and look up Souvenaid, I think it gives the composition, but it contains a certain amount of DHA and a certain amount of EPA. Now, I don’t know how they calculated what percent of each to add, but anyhow, it has a certain ratio within it, so what you can say is well that’s the ratio that was tested and that’s the ratio that works. Now in terms of your question, would it work as well with more EPA or less EPA? I don’t know. Somebody has to do the study and see. I’m not trying to avoid the question. It’s almost like an article of faith with me, I’ve seen it all my life. You just have to have good data before you can make a claim because otherwise… For instance, it used to be the case, I’m sure you’ve spoken about this, it was believed that all polyunsaturated fatty acids were good, you had to have plenty of fatty acids. And then it was realized omega-6 and omega-3 aren’t the same thing, right? So we keep adding knowledge and changing what we’re recommending.
And again, I don’t know the extent to which EPA can substitute for DHA. DHA itself is kind of controversial in this field. There are maybe 100 papers I’ve seen trying to see whether just giving DHA by itself will have an effect on cognition or memory, and it’s like 50/50, many say yes and many say no. I think the reason for that probably is that people start out, as you’re implying, with different levels of DHA in their blood based on their diet. And if their DHA levels are low, then there might be a partial deficiency in the brain, which could be corrected by providing supplemental DHA, and as a result, there might be a small improvement in memory. That’s just my theory. It’s by no means the same as giving DHA or EPA or any of the above to what you’re seeing with the Souvenaid. I don’t think any single nutrient is going to have much of an effect, because what happens is, as we’ve been discussing, you have a biosynthetic pathway that critically involves three different compounds. So, fine, you give one nutrient, so you jack up that one, but then you’re immediately limited by the other two.
Jesse: One of the other interesting quotes in there said those patients who have lost the least cognitive function have the most to gain. Could you unpack that statement a little?
Dr. Wurtman: Yeah, I think it means it tends to work best early in the disease. Again, this was a study in people that did not have Alzheimer’s but had prodromal Alzheimer’s, which by definition is quite early in the disease. What it means maybe is you have, let’s say, a dendrite and there are like a half a dozen dendritic spines coming off it. Now you’re down to two or three, and then you’re down to one. Maybe the responsiveness is not as great, I’m just speculating on that. But I think there is enough information now that suggests that the earlier people can be caught, the better it is. And now, thank goodness, we do have biomarkers which really can help discern which people really are at risk of developing in the next year, or two, or three.