Introduction

Dr. Hussein Yassine is the Volke Endowed Professor of Neurology at the University of Southern California's Keck School of Medicine and Director of the USC Center for Personalized Brain Health—a groundbreaking center launched in 2023 focused on early detection and intervention for APOE4 carriers.

With over 150 peer-reviewed publications and decades of research on omega-3 fatty acid metabolism in the brain, Dr. Yassine has emerged as one of the leading voices in understanding how genetic factors, particularly the APOE4 allele, influence brain health and Alzheimer's risk.

In this candid interview with the Phoenix Community members, Dr. Yassine pulls no punches. He addresses the reproducibility crisis in science, explains why mouse models rarely translate to human therapies, and offers sobering perspectives on popular interventions from lithium to ketones.

A Note from Kevin: 
Throughout this conversation, I'll be adding my own commentary in [brackets like this] to provide additional context and perspective. While I have tremendous respect for Dr. Yassine's commitment to scientific rigor and his decades of research, I don't always agree with his conclusions (and that's perfectly fine).

The Phoenix Community operates well beyond what's considered "scientifically rigorous" in the strictest sense because we're not willing to wait decades for double-blinded randomized controlled human trials that may never come, or that might be conducted on populations vastly different from us in terms of genetics, environment, and real-world circumstances.

I believe transparency is crucial, which means sharing perspectives that challenge our approaches. In fact, I think it's dangerous to fall into dogmas or become so convinced of our own correctness that we stop questioning our positions.
The Phoenix Community isn't immune to this trap either.

So let me be clear: sharing this interview isn't me changing my stance on self-experimentation with interventions we have discussed recently like tramiprosate, lithium, or ketogenic approaches. I still deeply believe in running these calculated self-experiments.

Rather, I'm sharing this to ensure you understand that what we're doing isn't considered scientifically robust in the traditional sense.
We're operating in the biohacking frontier, which is exciting but comes with inherent risks and consequences.
I believe it is my responsibility to inform you of this reality before you decide to join/continue with us on this journey.

The Interview

Kevin Tran: [Discussing how to evaluate clinical trial results] For a lot of people, we don't necessarily have the knowledge or the time to go look into the protocol to determine if it's robust or not. We usually only read the study itself and sometimes just the abstract. If we look at other rules of thumb, quick things that we can use as proxies to know if it's robust or not, if we should look more into it or not, what would you say?

Dr. Hussein Yassine: Well, I would say that look at editorials in respected journals on how they review the work that's being done, and look at usually a letter to the editor or commentary on the work that explains what the strengths and weaknesses are. Avoid going on social media and looking at the company CEO's post.

Because often there's a conflict. The company itself most of the time would want to make sure that they have this responsibility toward their investors and stockholders. So you wouldn't typically get—I mean, again, there's exceptions. There are companies who have very high standards and that's not the case, but overall, you want a third party, a scientific third party writing a balanced commentary in a highly respected journal as opposed to a social media platform where people are voicing opinions based on how they feel or what they think is correct.

Kevin: Do you have a short list of the most reputable journals according to you?

Dr. Yassine: I don't think it's a good idea to actually name one or two or three journals. There's a lot of them. I think, you know, in general, you want to know that the person writing the review is an expert in the field, has no conflict of interest, doesn't have stocks in the company that he or she is criticizing or appraising. The review appears balanced, discusses the primary, the pre-specified protocol analysis, discusses the implications and the gaps. There are many elegant, good journals. It's not like it has to be in this journal or that journal to actually make sense.

There are several that are well-respected. But there are certain rules. Now, if you're asking me for a reference for your audience to read, I would guide them to John Ioannidis' famous study in PLOS Medicine many years ago. The title of that article is "Why Most Published Research Findings Are False." And he explains—he has a table within this paper that says if the authors are conflicted, if they don't have the proper methodology, they list all the reasons why sometimes findings are hardly replicated and identifies how to fix this problem.

Kevin: Would you say that title is correct? That “most journal publications are false”?

Dr. Yassine: I would say, I don't know if "most" is the right term, but I would say many publications cannot be reproduced or replicated because of bias.

[Phoenix Member]: Hi, I'm a professor at the University of Michigan in neuroscience, and we've gone through these papers at length, have discussed that with faculty and students. And I would agree—in many fields, more than half of the papers are not reproducible, and "false" can be interpreted in different ways. It may be in a narrow sense. What they say was correct under the circumstances that they were doing it, but the generalization was false. That could be included. But there is a lot of irreproducible stuff, especially in my field in genetics, although things have improved compared to 20 years ago when those papers were written.

Dr. Yassine: I think we are in agreement. And when we talk about false, often people think fraudulence. And that may not be the case. It's often bias. And we all have our biases. Sometimes a biased presentation can lead to false conclusions. And that's why we have this reproducibility crisis. Having better methodologies, better reporting, and more transparent systems of clinical research that include blinding and controls and so forth will help us move beyond this reproducibility crisis.

Kevin: I think it's interesting because when you think about taking bets on interventions and deciding to test them, how would you navigate these types of things? How would you identify the ones that have potentially high potential and then deciding to test it if you were an APOE4 or if you were to advise a patient?

Dr. Yassine: I do understand the background. I understand why sometimes you feel that the time is ticking and disease might be severe and debilitating and you need to do something about it. I fully acknowledge and appreciate that this is very stressful and people want something that works. But I also want to say that this is an opportunity to take advantage of people, to sell snake oils, to promote false information, and that's unfortunate.

So I think my response to you is that if the intervention is reasonable, is not toxic, makes sense to you, you feel good about it, and it's not that expensive, somebody might benefit from it. So I would go back and say, use your own clinical judgment. If you're trying a new diet or a new exercise, a new sauna, whatever that is, which may have limited side effects, you might think it works, it's worth trying. But if you're going to try a medication that has not been proven, or a complex dietary intervention that's kind of on the extreme side that has not been proven, I don't know if it's worth taking the risks. So there's always a benefit to risk ratio. And it depends on what the risks are going to be.

Kevin: My approach usually is to look for those "no regrets" moves. At worst, they don't do anything but they won't hurt you. At best, they might work, so why not try them? That usually deprioritizes a lot of medication, and it's more about high impact lifestyle interventions, that in the worst cases, they will still benefit your health and longevity anyways.

[Kevin's Note: This is exactly the philosophy behind the Phoenix Community—we focus on interventions that have high upside and minimal downside. Even if the specific Alzheimer's prevention benefit isn't proven, things like optimizing exercise, sleep, diet etc. are going to improve your healthspan / lifespan regardless.]

On Self-Experimentation and N=1 Trials

Kevin: So let's say you find a potentially interesting intervention to do. The next step would be rationally to test it, to make sure that it's actually moving the needle and that you're not doing that daily for the rest of your life for no benefits at all. So how would you design a self-experiment plan?

Dr. Yassine: I understand the premise, Kevin, but I think you might be overreaching. I don't think people can practically design an intervention to figure out if an intervention is working. Because we're prone to bias. What is it that I'm going to test to objectively tell if my disease is getting better or if my cognition is improving?

I think it is possible to be enrolled in a clinical trial. It is possible to do some annualized cognitive testing at a licensed neuropsychologist. It is possible to see a specialist and get some of the new Alzheimer's disease biomarkers, but I think it is not maybe practical or smart for somebody to do something, take a supplement, or even do an exercise and say, oh, because this changed, that means it's working.

I think this is a little bit overreaching because it doesn't work that way. We often need trials with hundreds, if not thousands, of people to figure out if something is working. If one case came to someone and they took a bunch of supplements and then the next time their cognition drastically improved, that doesn't prove much. That could be they learned the test, and sometimes when you learn the cognitive test, your second time you do it, it becomes a lot better, especially those easy screening tests like MMSE and MoCA. It's very easy for a patient to learn it if they don't have dementia. And the next time they do it, their scores go from 25 to 30. That doesn't mean that the supplement they took or the exercise they took or this combination of magic elixir is really curing Alzheimer's.

I think we have to be more skeptical. To really get objective measures of this disease process, you either go and participate in a trial that has well-defined outcomes where you might be blinded to your treatment arm, or you see a licensed provider who would be ordering certain interventions or drugs or medications and maybe blood work to figure out if it's truly working or not. As an individual, I want to help and I'm not trying to make it harder for the audience, but it's not easy simply to do blood work and figure out if this is working or not working.

[Kevin's Note: Dr. Yassine raises valid concerns about bias in self-experimentation, especially when done alone. This is why in the Phoenix Community, we emphasize structured protocols, tracking multiple biomarkers over time, and comparing notes with hundreds of other carriers doing similar experiments. While we can't eliminate bias entirely, we can reduce it through systematic approaches and peer review within our community.]

On Vitamin D and the VITAL Trial

Kevin: I mean, I guess it also depends on the intervention, right? Let's say you have vitamin D deficiency...

Dr. Yassine: So the VITAL trial did exactly that. Brought in people with borderline low vitamin D deficiency states. Thousands of people led by Joanne Manson from Harvard. And they increased their vitamin D levels from 30 to 44, found nothing, nothing whatsoever—no improved bone health, no improved osteoporosis. In fact, more kidney stones.

And there are side effects with high doses of vitamin D. You can get calcium in your blood vessels, which is not a good sign. I'm not saying we shouldn't be taking vitamin D. All what I'm saying is be careful when you make an analogy that seems on the surface makes sense, but science doesn't operate that way. And that's why you need to be either part of a trial or talk to a licensed provider because not everything is as intuitive as it seems. For some people, a vitamin D of 10 is really low, and you need to move it to 30 or 40 to avoid fractures. For others, moving to 40 might just give side effects. And that's why we have to be careful.

Kevin: I see what you're saying, but if you put yourself in the shoes of a patient, a lot of patients are taking supplements, me included. We can't wait or participate in a clinical trial for everything that we take. On the other hand, we also need to do something, right? So how would you advise us in navigating that? And we're not talking about medication, right? Let's say even diet or very basic supplementation.

Dr. Yassine: Well, my advice is very simple. If you have a really good diet that contains nutritious elements—and I would rank them with fibers and good fats as the ranking diets—and if you are exposed to the sun and you have a lot of good ingredients in the diet, you probably may not need a lot of supplements. In fact, these supplements might be actually giving you more side effects than you think.

Now, certain people, for example, have dietary restrictions. They don't eat fish or they can't eat certain meats or they can't eat certain diets and they may have deficiencies. And in those individuals, supplements make a lot of sense because they're replacing something that's deficient in the diet.

So my approach to supplements and vitamins and minerals and so forth is that they have a role, but not as "more is better." And if I really boost my vitamin D, really boost my omega-3s, I'm going to get more benefit. In fact, this is possibly not true. We know that at really high levels of omega-3s, there might be heart rhythm problems. At really high levels of vitamin D, there might be kidney stones, atherosclerosis. At high levels of vitamin Bs, other neurological things. So I know I'm not answering your question the way you may want to hear the answer, but it's a Goldilocks phenomenon. It can be too little, it can be too high. It has to be just right. And you can get it just right from a healthy lifestyle without breaking the bank.

On General Interventions for APOE4 Carriers

Kevin: So let's say vitamins, supplements, and so on might not necessarily be needed or need more proof that it works. What interventions right now would you advise an APOE4 carrier to do?

Dr. Yassine: Well, again, these recommendations are generic and do not apply to all E4 carriers. And we have to be careful that some carriers may have different—these recommendations that I'm sharing with you are just general. And if you really want to know how Kevin may differ from [Phoenix Member 1] or [Phoenix Member 2] or someone else, you need to see a licensed provider who can go over these individual risk factors and make customized recommendations.

But in general, we know that whole foods, we know that a diet that is rich in whole foods, plant-based, some animal food within it that is very rich in fibers and limited with ultra-processed foods with less sugar and so forth—we know that this is a diet that actually is good for the brain. It has been tested in several large cohorts and trials, and Mediterranean diet is one example, but not the only example. You don't need just one diet to say this is the right diet. There could be multiple versions of a good diet.

We know that common sense exercise makes sense, being active and so forth. We know that sleep makes sense and there are certain ideas about how to optimize sleep. We know that there are activities that people can get engaged in which can help cognition. We also know that there's other factors such as depression, anxiety, loneliness, traumatic brain injuries, chronic risk factors such as diabetes, hypertension, high cholesterol, and many other things. So in general, there are things that somebody who is at risk for dementia can actually try to deal with these risk factors. And finally, the younger you start, the better, because this is a lifelong process. And starting decades before dementia gives the brain the opportunity to heal and recover.

[Kevin's Note: I completely agree that everyone is different, and general advice can only go so far. That’s why it’s essential to run self-experiments—not just to identify the right interventions, but also the right dosages. The key is to follow robust protocols: isolate interventions, establish a clear Day 0 baseline, and measure both quantitative and qualitative outcomes.

This is exactly what The Phoenix Community is built to provide: clear, step-by-step guides for each intervention, so we can move beyond generic advice and discover what truly works for each of us.]

On Healthcare Provider Knowledge of APOE4

Kevin: I think I just want to jump back to what you mentioned at the beginning and it reflects what a lot of us in the community experience. We are all unique, right? We are all different, we all have different genetic background, different habits, different environment and so on. So there is no really one-size-fits-all answer except very generic answers. And the solution that you mentioned, which is going to see a licensed healthcare provider. But the problem is for a lot of us when we see them, they actually don't even know what APOE4 is. It's very, very difficult to find someone who is aware of it and on top of the research and everything because in their entire life they have maybe seen one or two maximum and might not even have helped them. So, that's why there is a need to do something from the individual perspective because the healthcare community hasn't been that helpful and that accessible.

Dr. Yassine: I want to do a little bit of a pushback, Kevin. I think the way that you're framing it is that we are dealing with a very niche, unique condition that healthcare providers are not trained to do, are ignorant or dismissive. And there's possibly some providers who are ignorant, dismissive, and they do not fully appreciate the gravity of the problem. That's definitely true.

But I would say many providers are working overtime to try to help as much as they can. And I think if you want to frame it in brain health, you don't need a subspecialist with an APOE4 background to talk about common ideas to enhance brain health. That doesn't require a very subspecialized provider.

The pushback may come if you've got really unique or specific questions on a certain supplement or a certain intervention and that provider may not be trained on. So this is where there might be a little bit of a pushback because the provider may not know if this supplement or this keto diet or this intervention is going to be recommended for an E4 carrier because, to be honest with you, nobody does. Even those who claim they know, they probably don't. And they're making this claim because they have a good heart and they want to help. But we still don't have enough research on these supplements, diets, or modes or protocols to be able to tell you they actually work better than general advice.

Kevin: Just to share a little bit my own experience—and maybe because I'm not in the U.S. and not in San Francisco and it might be different around the world—but literally, when I discovered my own status and I went to see either normal physicians or neurologists, because the physician referred me to neurologists, I was literally almost laughed out of the door, saying, "Hey, you're super young. Come back in 30 years when you have symptoms. There's no need to do anything. Just eat clean, exercise, and do that." So that's kind of my experience. I don't know if it's the experience of other people as well out there, but I've seen that mentioned quite a bit. That's why there is this entire movement of trying to take our health into our own hands, because going to see the doctors really didn't yield a lot of results there.

Dr. Yassine: All that I can say is that there's a new generation of providers who are better trained and they're more informed. E4 is a big deal, at least to me it is. I mean, we have built a center just focused on E4 carriers and trying to address this gap and need. And we're training doctors, we're training neurologists and primary care about E4. So I think this is something that we also need to understand—that we need a lot more research to be able to be confidently telling you, Kevin, this is what you're supposed to do because you have two copies of E4.

Believe it or not, it's really hard to get funding to do research, and when I go to NIH, for example, last year I went to my funder, which is the National Institute of Health, and I said I want to do a trial in those who carry two copies of E4. Unfortunately, I was pushing against a lot of competition because funding rates is like 5%. So to help out with this, we need to advocate for research. We need to advocate for E4. And we need quality research to be able to tell whether this intervention, this protocol, the supplement is really working. Otherwise, we would be selling snake oils.

[Kevin's Note: This exchange highlights the exact gap the Phoenix Community was created to fill. When the medical establishment tells you to "come back in 30 years," and research funding is scarce, we as patients need to create our own support systems. We're not replacing medical advice—we're supplementing it with peer support, shared experiences, and structured approaches to testing interventions safely.

And I totally agree with Dr Yassine that we need to have more APOE4 advocates. This is one of the core mission of the Phoenix Community.]

Audience Question: On Mouse Models

[Phoenix Member]: I appreciate you sharing your time with us. I do read a lot of actual studies. But on Facebook, on our 4/4 groups, people will see that the mouse model said this, and it was only one study, and how do you take a mouse this big, and so we need to do this much. So, do you want to comment at all on if we wanted to try something that was effective in a mouse model, how would we even figure out how to do that?

Dr. Yassine: Yeah, excellent question. Thank you for asking. Let's talk a little bit about mouse models. The reason why people use mice is because they have a lifespan of approximately two years. Now, most genetic engineering since the 90s have been really optimized for mice models. So, if you want to change the genetic composition of a mouse, the protocols are really straightforward. Mice have very high efficient breeding, which means you have colonies that actually grow quickly. And they have a brain that somehow resembles the human brain. It's a mammalian brain—not like an ape brain or a more sophisticated brain, but they do have brain features that are shared with human physiology.

Now, having said that, mice have faster metabolism than humans, right? So their metabolism is estimated to be like three times faster. If you look at their brains at the time of death—a typical mouse can live up to three years—there is no evidence of plaques or tangles. They do not develop amyloid plaques. They do not develop tau tangles. So that makes them really not great models for a disease like Alzheimer's.

So what happened about 20 years ago, several investigators started inserting Alzheimer genes into mice models. And they struggled, because when they put the amyloid genes, they developed amyloid plaque, but no tau. And when they put the tau genes, they developed some tau pathology, but no plaques. And then both models did not address the elephant in the room, which is E4. E4 is the strongest genetic risk factor for late-onset AD. If you just put E4 in a mouse model, you wouldn't get tangles, you wouldn't get plaques, maybe you would get inflammation on a high-fat diet.

So, just to tell you this background, when it comes to mice and Alzheimer's, you have to take most of the studies with a grain of salt. My lab has many models of mice, including the E4 mice models, the amyloid mice models, the tau mice models. But we don't claim that we're treating Alzheimer's. We're trying to understand mechanisms. So we're trying to understand how does APOE4 increase inflammation. How does APOE4 interact with the amyloid mutations to lead to a plaque that has an inflammatory component? How does it lead to the spread of tau? And other things.

So we never make a claim that if we treated this mouse model and cured it, then this is a drug that can be used in humans. So you have to be very careful that treatments of mice does not translate to treatment of humans. If it had, we should have had a cure for human Alzheimer's more than a decade ago. We've cured Alzheimer's in mice a gazillion times.

Kevin: So would you say that all mouse models should be disregarded and that we shouldn't act on it? Or are there some exceptions?

Dr. Yassine: Absolutely not, Kevin. So what I said is we use mouse models to understand mechanisms of disease. How does APOE4 increase inflammation? How does APOE4 spread tau or amyloid? So we're studying them for understanding the basic mechanisms. How does a drug might work? But we don't use them to actually give a drug and then cure Alzheimer's from the mouse in terms of cognition and behavior. So mice are really valuable. We don't disregard them. But we don't use them as a go/no-go to make a decision whether a drug works to cure Alzheimer's in humans. We use them to understand the mechanism of how a drug might be working on a simplified model.

On the Recent Lithium Study

Kevin: Yeah, it makes sense. What I mean by "disregard" is more from a patient perspective. I think the example [Phoenix Member] was mentioning is on lithium, right? Which is something that came very recently in Nature, which is a very reputable publication, and they made some claims and it's giving a lot of hope for everyone. Then we're deciding, okay, should we take lithium ourselves or not? So there is this gap, right? And we can't really wait for 10 years. So that is, for example, one of those specific situations. And what would you do in these situations as a patient?

Dr. Yassine: Okay, so let's talk about exactly what we just talked about again, but from the perspective of the recent Nature paper by the Tsai Lab on lithium orotate supplements. I think the way that I read this paper—and this is a really nice paper, it's an elegant paper in the sense that they actually looked at many species of lithium and identified a species that is deficient in certain mouse models. And when there's a deficiency, because they took it out from the diet, there was an association with more plaques and more severe disease pathology. And then when they added this lithium salt to the diet, they observed that the plaques were shrinking and there was less pathology and less inflammation.

And then they went on to figure out the pathway by looking at how this might be working and landed on an enzyme called GSK3-beta. And then when they manipulated that enzyme, they were able to replicate how lithium might be inhibiting the pathway and changing the readout of amyloid and tau in this mouse model.

What this tells me is that lithium in a specific form or orotate at lower doses actually might have a role in how amyloid and tau are affecting disease progression in certain conditions that are set by the experiment published. This doesn't tell me that lithium works in humans. This doesn't tell me what the dose of lithium is that needs to work. This doesn't tell me that if I give lithium to a group of people, I'm going to change their amyloid plaque accumulation, I'm going to alter their amyloid biomarkers, or I'm going to improve cognition.

It doesn't tell me any of that, unless we do a human trial where we give people randomly assigned to placebo versus lithium, do some biomarkers with amyloid and tau and ultimately find a signal that makes sense. And then once that is achieved, do another trial that looks at the effect of lithium in a few thousand people on dementia conversion, memory loss, and so forth. I cannot speak with confidence that lithium actually does what it's supposed to do in mice.

You're going to ask me the same question: I cannot wait 10 years while you're doing all these studies. I need an answer now. I can tell you, well, Kevin, you like to play cards or you like to flip dice. Flip your dice, take lithium. If you feel that as a lithium supplement, you're not overdosing, you're not getting kidney toxicity, and you're covering your bases, that's fine. But I wouldn't lose sleep if I didn't take lithium, because we may discover in 10 years that the amount of lithium deficiency required to find an effect is really hard. So you have to be living somewhere in Denmark where there's absolutely no lithium at all in the water to actually find an effect. And once you reach a minimal threshold, there's no longer an effect of additional lithium. I don't know. I don't have a crystal ball.

But again, the argument that you keep using Kevin is "I have to do something now. Otherwise, I'm doomed." And all that I'm saying is take a breath. There's a lot of good evidence that we have right now with a good diet, with exercise, and we do not need to exaggerate to get benefit.

[Kevin's Note: This is where the philosophical divide becomes clear. As someone with two copies of APOE4, I understand Dr. Yassine's caution. But I also understand that waiting 10+ years for definitive trials isn't an option for many of us. This is why the Phoenix Experiment framework focuses on interventions like lithium orotate (as an example) that have minimal downside risk—we're not talking about high-dose pharmaceutical lithium, but trace amounts that some populations naturally get in their water. It's about calculated risks, not reckless experimentation.]

Audience Question: On Omega-3s and Fish Oil

[Phoenix Member]: I've heard you speak before, Dr. Yassine, around fish oil. I know that just regular fish oil doesn't seem to help 4/4s as much and it's really eating fish that's better, and I wonder if you could talk about that just a little bit.

Dr. Yassine: Excellent. Well, thank you so much for asking. Mechanisms of how omega-3s are metabolized by the brain has been our focus for at least a decade. We've published over 50 papers on this topic. I'm not trying to belittle others. I'm not by any means trying to be an elitist. But I'm just telling you that we have been closely looking at this question for a long time.

We started looking at this question because over the past 20 years, there has been consistent epidemiology studies suggesting that higher levels of omega-3s in the blood is associated with less dementia. And this has been replicated across Europe, the U.S., China, and many other countries. So there is a signal. So we're not making this up. This is published.

So we asked, if that's the case, we should be giving people omega-3 supplements to raise the amount of omega-3s in the blood. So many studies have actually been done on that premise of giving supplements like omega-3 supplements and seeing the effect on cognition. We've summarized those studies last year in a paper that we wrote and found really overwhelmingly negative effects of taking supplements on cognition in most of the trials that we reviewed, the vast majority. We actually excluded small trials because we thought they are unreliable, so we only looked at the trials with an N of 100 and above. So a trial with a sample size of 20, sometimes they were positive, but it's really hard to make a good conclusion because that sample size is highly prone to error.

So then we asked, why is it that these trials have not panned out? Some of them are in patients with dementia. Some of them are in patients who are cognitively normal. Some are in MCI. And even my own trial, which is my own baby, spent eight years doing it, called PREVENT E4. It's going to get published hopefully in the next six months. It ended last year. We found no effect for taking the omega-3s at high doses on AD biomarkers and cognitive outcomes.

So some people have said, well, maybe you've used the wrong type of omega-3. You haven't used the one that gets into the brain. In fact, our primary outcome is the amount of omega-3s that gets into the brain, and we succeeded. So we actually found that taking high doses of omega-3s indeed had approximately 20% increase in brain omega-3 and that's pretty significant. Other people might say, well, you didn't raise the omega-3 in blood enough. The answer is, no, we did. We went from a 4.8 RBC omega-3 index, which is considered low, to 11%. That's really high.

So why didn't we see an effect? And the answer is epidemiology is very complex and observational cohorts often have confoundings. So people who are taking more omega-3s in their natural diet are likely taking cholines, phospholipids. They're likely taking vitamin D, lutein, vitamin E. It's all packed in salmon, for example. They're likely exercising. They're likely seeing their doctor. They're likely getting exposed to the sun. All of that work in concert to make the omega-3s more efficient and behave in a good way that the brain likes. If we decide to make it reductionist and just isolate the omega-3 component and ignore everything else, we're finding little effect.

And the example I tell my patients: if some patients go to McDonald's and they love fast food and they have really very low omega-3s in their blood, and they come to our trials and we give them the omega-3 and raise their omega-3 index, do we truly think we're decreasing the risk of their dementia? And the opposite: if somebody does not eat omega-3s at all, but they're constantly in the gym, they have a really healthy diet, they're metabolically very good, and we increased their omega-3 index, do we really believe that that's going to make a big difference?

So the answer is we need more personalized approaches to find out who is that person who's going to benefit from such an intervention.

[Phoenix Member]: Thank you. That answers my question. And since seeing that, we have a fisherman around here that catches fresh salmon and we try to eat it twice a week. So I hope that's covering my basis.

Dr. Yassine: Well, it will cover your basis if you walk to the fisherman, spend some effort getting the fish, walk back upstairs home, bake it with some good fiber and vegetables. Remember, this is a small single piece of a diet. It's not going to make a huge difference. Look at it as a complex pattern. That's what tracks with dementia, not these small individual components.

[Kevin's Note: This is a perfect example of why context matters. In the Phoenix Community, we don't just recommend "take omega-3s." We look at the whole picture—your diet, exercise, sleep, stress levels. Dr. Yassine's point about the "complex pattern" is exactly why our Phoenix Experiment protocols track multiple interventions and biomarkers simultaneously.]

Audience Question: On p-Tau217 Testing

[Phoenix Member]: I saw somebody in the comments section ask about the p-Tau217 test and whether they thought that was a good idea, and I thought that was a great question to ask the doctor.

Dr. Yassine: Yeah, so there's been a lot of interest in the new AD biomarkers. I wrote an article on this a few months ago. But long story short, these biomarkers are useful, but only in patients who have mild symptoms or symptoms of cognitive impairment. That's because in those populations, an abnormal biomarker may be predictive of dementia. Or if you have mild cognitive impairment or some kind of impairment and you took the biomarker and it's positive, the chance that you might be getting dementia is a little bit higher than somebody who has a negative biomarker. So this is what the evidence is showing us across many different papers.

Now, here's what we don't really know. If you are cognitively normal and you have no cognitive impairment and you have a positive biomarker, what does it mean? And I don't think anybody knows. Could you have an increased risk of dementia? Possible, but the increase might be really small. So I would not recommend measuring them in cognitively normal people because it's gonna generate anxiety.

And add to that, E4 homozygotes above the age of 50 will be guaranteed to have a positive biomarker on these blood tests, because we know part of the E4 homozygosity is that amyloid is accumulating in the brain. Now what we don't know is that some of those individuals with amyloid accumulation are going to go into the tau and dementia process and others will not. So this is why having a positive amyloid or tau biomarker in the blood, if you are a carrier of two copies of APOE4, is going to be anxiety-provoking. It's not going to tell you whether you're going to have dementia or not. It's just going to tell you, you've got amyloid in the brain. And I have E4 carriers who are 70s and 80-year-olds with amyloid in their brain with no dementia.

On Cognitive Testing and Disease Tracking

Kevin: I have one more question in terms of tracking disease progression. Is there a test that could be done without a practice effect? Something that we could use as a benchmark to measure disease progression, whether we are symptomatic or not, and to see if whatever we're doing is working or not?

Dr. Yassine: That's a really great question and I think, you know, if I did I would probably make a lot of money, but I don't. We've seen, for example, even devices that are able to analyze speech, that supposedly are able to detect it very early. We've seen people repurposing EEGs. We've seen so many actual tests that have so many different randomized questions that normally there's no practice effect, so you can measure that.

Kevin: Any of those tests that you feel is more promising than others?

Dr. Yassine: I don't know. All that I say is we need to do more research. I urge all of your members and you included to support more research in the field so we can have better answers. I think some of this might pan out in 10 years from now. We will have new devices, new tools, AI generated that can capture early disease and predict it very accurately, but we still need to do the research to figure this out.

Audience Question: On Brain Insulin and Glucose Metabolism

[Phoenix Member]: Thank you for joining us. I wanted to ask, can you tell us what is known about the role of brain insulin and glucose metabolism specifically in the brain? And as APOE4 carriers, do we essentially practice the same measures we would to have healthy blood glucose? You know, is the brain glucose metabolism system different than the blood glucose, and what is known about the role of development of Alzheimer's and that brain insulin metabolism?

Dr. Yassine: This is a really good question. I think a lot of scientists are itching their brains to figure this out because it's not easy to answer or it's not very clear. What I can say is that E4 carriers, when they have dementia or mild cognitive impairment, they clearly show glucose hypometabolism in the brain using PET scans, which means when you inject an 18F labeled glucose, there's less uptake in the brain, meaning that the brain is unable to successfully use glucose as an E4 carrier or somebody with MCI or dementia.

Now, if you dial this back and look at people without dementia or without MCI, the effect is low, meaning that it's not very clear if an APOE4 carrier is not capable of utilizing glucose. The concept is, you know, we're born with E4, right? So this is an age-related disease, and for maybe the longest time, the brain can utilize glucose. And, you know, something that's happening between the ages of 45 and 65, where the metabolism is changing, and it's becoming more taxing to utilize glucose, and maybe during that time the brain might prefer more fats. But again, this is all conceptual.

Now you mentioned insulin. We don't know much about insulin signaling in the brain and it's overhyped. I think insulin is not required for glucose uptake into the brain. The brain can actually get glucose across the blood-brain barrier through pathways like GLUT3, which is independent of insulin. And that is really important because normal physiology means that we cannot rely on insulin to get glucose inside the brain. Otherwise, it's a catastrophe because you need glucose to maintain your cognition.

Long story short, insulin signaling in the brain may be glucose independent. It might be related to something else besides glucose. It's been tied and associated with tau. In terms of lifestyle to enhance glucose sensitivity, I think it holds true for E4 carriers and non-carriers. In terms of what do you make of this information? You could see that in my advice to people, I suggest a high fiber diet, a high fat diet that's rich in good fats. And the fundamental reason for that is because we think a good microbiome with a high fiber and high fat is something that the E4 brain likes, but that does not mean ketogenic diets.

Audience Question: On HSV and Alzheimer's

[Phoenix Member]: I'd also ask for those of us who are HSV positive but never had any outbreaks, [what is the connection to Alzheimer's risk]?

Dr. Yassine: I honestly don't know, but again, this is an area that requires more research. I know there's a lot of questions on social media about this particular topic. Many people show strong evidence either way. I just would ask for caution and not to have any strong opinions on any particular topic simply because we really don't know. There are so many people with HSV infections who may or may not get dementia. Making a big claim when there's not good quality studies is premature. So I don't, I really don't know.

Audience Question: On Exogenous Ketones

[Phoenix Member]: I was wondering what your opinion was on beta-hydroxybutyrate or exogenous ketones. Is that something that you feel is a good idea for E4 carriers?

Dr. Yassine: We don't know. We wrote a review a few years ago on the fact that if the argument that E4 carriers need to take a ketone supplement because glucose is not working—and I'm happy to share it with Kevin, with all of you—it seems it's also not working for ketones. So if the brain is in this state, like MCI or dementia, where it's not able to utilize glucose, it may not also be able to utilize ketones. So I don't know where this concept is being circulated that yes, you need to switch to supplements because of the alternative energy fuel. I don't know if that concept is true. All what I'm saying is we need research. It might be true, but we still need more research.

Closing Thoughts: The Tension Between Scientific Rigor and Patient Urgency

As our interview with Dr. Yassine drew to a close, his message was clear: while the urgency felt by APOE4 carriers is understandable, the path forward requires both patience and scientific rigor. His parting advice emphasized the importance of supporting more research specifically focused on APOE4 carriers, as this remains the only way to definitively answer the many questions that persist about effective interventions.

[Kevin's Final Reflection: This conversation beautifully illustrates the fundamental tension we face as APOE4 carriers. Dr. Yassine represents the voice of scientific caution—necessary, important, and grounded in decades of research. But for those of us carrying this genetic risk, especially homozygotes like myself with a 10-33x increased risk, waiting isn't always an option.

The difference between a scientist and a patient-biohacker isn't about intelligence or understanding of science—it's about risk tolerance and time horizons.
Dr. Yassine can afford to wait 10 years for definitive trials because that's his job: to find truth through rigorous methodology.

But we can't wait 10 years. By then, the pathological cascade may have progressed too far.

This doesn't mean we should abandon scientific thinking or embrace every unproven intervention. It means we need to be smart about calculated risks. The Phoenix Community exists precisely in this gap—between the glacial pace of clinical research and the urgent need for action.

Every intervention we discuss, every experiment we run, every protocol we test—we do so with full acknowledgment that we're operating in the realm of the experimental.
We track, we measure, we compare notes, we adjust. We're not claiming certainty; we're claiming agency.

Whether you choose to wait for more robust evidence or embrace the hope and potential of emerging interventions today, that choice is ultimately yours. What matters is that you make it with eyes wide open, understanding both the risks and the potential benefits.]

If you want to go further: join the Phoenix Community

Ready to take control of your cognitive future? The Phoenix Community brings together APOE4 carriers and others concerned about brain health to share experiences, run structured experiments, and support each other through this journey.

Whether you lean toward Dr. Yassine's cautious approach or feel compelled to explore emerging interventions, you'll find a home in our community. We host regular Q&As with leading researchers, provide frameworks for safe self-experimentation through our Phoenix Experiment protocols, and offer the peer support that's often missing from the traditional medical system.

What you'll get:

• Access to expert interviews and AMAs like this one with Dr. Yassine

• Structured protocols for testing interventions safely (our XP-Packs)

• A supportive community of people who truly understand what you're facing

• Science-based resources without the hype or snake oil

• Monthly pod matching for accountability and support

Don't face APOE4 alone. Join hundreds of members who are turning anxiety into action, fear into focus, and isolation into community.

Apply to join the Phoenix community today

The Phoenix Community and Dr. Kevin Tran extends their gratitude to Dr. Hussein Yassine for his time, candor, and commitment to advancing our understanding of APOE4 and Alzheimer's prevention.
While we may sometimes differ in our approaches, we share the same goal: helping APOE4 carriers beat the odds.