Does Creatine Help the APOE4 Brain? What the Clinical Trials Show

[0:00]If you carry APOE4 like I do, or if you simply decided that you'd like to have your brain as sharp as possible for as long as possible, you have probably never thought of your brain as an engine that can run low on fuel, but it can. And the cheapest fuel in the building is a $15 powder sitting in every gym on Earth.

[0:24]The evidence for it is better than you would expect and thinner than the internet claims. Let's separate these two. Here's the thing about your brain. Whatever your gene says, it runs on fuel. And long before anything feels wrong, that fuel supply can start slipping. Now, if you carry APOE4 like I do, this part changes.

[0:42]The fuel drop is consistently seen in young carriers who feel completely fine. That used to scare me. I found out I carry two copies of APOE4 in December 2024, and suddenly this brain energy gap stopped being aligned in the textbook. It became my problem. But whatever your genes say, a few gap has a flip side.

[1:03]Fuel is something that you can change. So here's what you are working out with today at the end of this video. The actual human trials on creatine and the brain, the strong ones and the one that found nothing because you deserve to know about both, not just the sensational headlines.

[1:19]Why this matters even more if you carry APOE4 And what exactly the trial used down to the grams and the number one Well, number on your next block test. That's going to look scary and is not. Be careful on that one, because that's one of the most important questions that I always receive in the Phoenix community.

[1:40]As always I removed all the hype because I'm sure you and I the same here We hate the whole hype about a new miraculous supplement that comes out every week. I'll give you the actual numbers and the holes in the numbers, and then you decide what it's worth for you.

[1:55]So a quick background note on why I'm the one telling you this. I'm a doctor of pharmacy, and I was reading Clinical trials for living long before I ever built anything. I also realized I carry two copies of APOE4 myself, so it became not only academic, it became a survival mission for me.

[2:13]And that's why I built Phoenix. Part of Phoenix is building Phoenix AI, which is an AI that is trained on all the clinical trials and all the research on APOE4 specifically, and enriched with all the experiments that carriers in the Phoenix community are running. In fact, we are running n equal one experiments on what works for each one of us.

[2:37]To get the idea of certainty on all the interventions that we are doing, and the result of that is pulled back into Phoenix AI, which then looks at careers similar to us and what works for them to give us ideas on things that we should test next. And part of that is, of course, looking at all the research that is available out there.

[2:57]That's why I'm so knee deep into everything, and that's why I do these videos, to share back what I learned from an APOE4 perspective. So the brain fuel problem we're about to dig into is my baseline too. And the way I read supplements or interventions is very simple.

[3:14]I look for no regrets move or as low regret as possible. So you want a huge upside and a disproportionately low downside if something goes wrong or if something doesn't work. So in this case, you are looking at low price to do it, the low risk of harm and basically all the data we can find before we actually touch something.

[3:35]So creatine at around 15 bucks per month and with a very good safety profile in the trials were about to look at, clears that path. So let's start with the result that made me focus on it. Creatine help people thinking together on a night when it should have fallen apart.

[3:51]And it did it in about four hours, not four weeks for hours. Here's the study. In 2024 searchers in Germany run a double blind, randomized crossover trial, the same 15 people I know It's not a lot of people got both creatine and a placebo just on different nights and a small one 15 healthy young adults average age was 23.

[4:14]So hold on to that because they are probably not you. When I look at the data on our channel, we're mainly looking at 50 to 70 year old adults. So for these specific healthy young adults, they kept the researchers kept them up most of the night, about 21 hours of partial sleep deprivation, the kind that reliably tanks how you think, how efficient your thinking is.

[4:39]And then on one night they gave a single high dose of creatine, and on the other night the placebo, which is an identical looking dose of corn starch So nobody in the room knew which night was which on the creatine night, people's memory scores and the processing speed held up measurably better than on the placebo night.

[4:57]The peak was around four hours after the dose lasting up to nine hours, and the line that matters most. The author said this revises the old assumptions that creatine only works over a longer period of time. Now, let's be honest right, while looking at 15 people, they were very young.

[5:14]They were sleep deprived, which is definitely not the same as aging. And it was only one acute result. And that is not the final word on anything, but it also reframes the whole thing. The gym supplements, because creatine has been used in the gym for a longest time, just walked into the brain health conversation.

[5:32]So a sharper all-nighter is still a long, long way from the disease will actually care about. So the obvious question. Does any of these touch a brain that's already in trouble? And that's the actual next trial that I'm going to discuss with you, Researchers gave creatine to people who already had Alzheimer's disease, and eight weeks later, the creatine inside their brains have gone up 11%.

[5:55]This is the CABA pilot, run out of Kansas published in 2025. 20 people with Alzheimer's given high dose creatine twice a day for eight weeks. They scanned the actual creatine inside the brain before and after, and it rose by about 11% on average and went up in 85% of the participants.

[6:13]So the supplement was feasible and well tolerated even in people with dementia. And on several cognitive tests, the scores improved. For context, 65% of these participants were APOE4 carriers, which is very interesting to note because usually trials don't differentiate us and 90% of these participants tested positive for amyloid, which, as you know, is the sticky protein that accumulates between the brain cells in Alzheimer's disease flagged here by a blood biomarker.

[6:41]And they also tested P-tau217. Now the giant asterisk and I’m not skipping it. This was a single arm pilot. So there were no control group. And it was only 20 people, which is not a lot of people. And only eight weeks, which is not very long. The authors themselves wrote that they urged caution when interpreting these results.

[6:59]So you probably want to do that too. But within those limits, it shows something real creatine can reach the brain that needs it most. That alone earns a real trial, not just a victory lap One uncontrolled pilot and one all-nighter study If that were the whole file, I'd tell you to wait.

[7:16]It isn't. If you zoom out to everything pulled together, a clearer picture shows up. If you are over 50 and wondering whether creatine actually does anything from memory, here's the pooled answer from 16 trials. A 2024 meta analysis combined 16 randomized trial of about 492 people Creatine improved memory and that improvement was statistically significant, which only means the result is unlikely to be a fluke of what happened to land in which group.

[7:43]It tells you nothing about how big the effect is. Two different questions and they get kind of mashed together constantly. The researchers graded their own confidence in the memory finding as moderate, not as high. Creatine also sped people up on attention time, on processing speed time, and they graded their confidence in those as relatively low.

[8:03]Then the second meta analysis, this one purely on memory and only in healthy people, found the part that should make you lean in. The memory effect was far bigger in older adults. A quick transition, an effect size, just measures how big a gap opened between two groups. Near zero means no real difference.

[8:21]Near one is a very big effect size. So in the 66 to 76 group, the effect size was 0.88. That's really large in young people. It was basically zero 0.03. Now hold on, look underneath that number because I almost missed that. The older adult result rests on two studies, 57 people between them.

[8:43]And its confidence interval runs from 0.22 all the way to 1.55. So confidence interval is just the range. The true answer is probably hiding inside. Narrow means we know the size wide confidence interval means we don't, and that one is wide enough to cover anything from a barely that effect to an enormous one.

[9:02]The author actually said it themselves. Across the trial they pulled, there was a moderate risk of bias, meaning design weakness that could still tilt the result and significant heterogeneity meaning the studies disagreed with each other more than chance explains. That's there were not mine. Caution is warranted. The bigger meta analysis is blunter still Most of the trials were run in healthy adults, and there is limited evidence available for specific populations, such as the elderly.

[9:30]So I want you to see how shaky that is. I just told you before that the effect is biggest in the elderly, and the literature turns around and tells me that the elderly are exactly who it has studied least. Well, both of these can be true, and I'm not burying the second one, you know, to protect the first, because you deserve to know.

[9:49]So the honest answer is this on memory, the effect points upward with age. How far upward Nobody can tell you yet. And be precise about what didn't move at all. Overall, global cognition and executive function never reach significance. Unfortunately, there is one additional wrinkle in all of this.

[10:08]In that first meta analysis, the attention benefit showed up in adults under 60 and not in the over 60s. So age runs one way for memory and the other way for attention. So that is a lot of noise. There's no one clean rule. It's basically not creatine makes you smarter.

[10:26]It's not a smart pill like you see in the movies. It's a memory tool. And on memory, the people it has helped most are the oldest people anyone has tested, which for once I believe is good for us, for this audience. So that's the what real gains but very narrow.

[10:41]Best documented for memory and biggest in people who are older further along are running low to begin with. Which raises the question that actually matters for you and I. Why would running low to begin with describe an APOE4 brain in the first place? That's what we'll cover in chapter two, and I believe it's one of the most interesting part of this video.

[11:00]So why does it matter? Your brain can run low on fuel decades before anything feels wrong. And if you carry APOE4 like I do, the clock starts earlier. Still, your brain runs mostly on glucose and cerebral glucose Hyper metabolism, the brain pulling in and burning less glucose is consistently observed in young cognitive normal APOE4carriers.

[11:22]So as you know, APOE4 is the strongest genetic risk factor for Alzheimer's disease and one of its earliest fingerprints is not a memory problem. It's an energy problem. So what's going wrong? The leading explanation is that APOE4 pushes the brain toward a wasteful shortcut, it burns glucose down to lactate instead of all the way down and gets a fraction of the energy for it.

[11:45]And to be careful here, because the shortcut was measured in mice carrying the human APOE4 gene and in APOE4 brain cells in a dish. It's animal and cell work. Nobody has watched it happen. Inside the living human brain. But the same researchers did measure in actual people 94 cognitively normal volunteers.

[12:05]The young woman carrying APOE4 burn measurably less energy at rest and carried more lactate in their blood decades before any symptoms. So that's a real human finding. It's also a subgroup the authors went looking for after they collected the data. And they say themselves it needs confirming. So that's a very strong hint.

[12:22]It's not a settled fact yet. I want to make quick clarifications here so you don't mix two things up. This is about glucose being used inside the brain. That is very different from the glucose in your blood. Your fasting glucose target is a blood number. The fuel gap shows up first.

[12:39]And the thing that shows up first is also where you get the earliest shot at doing something. So if the earliest problem is an energy shortfall, the obvious move is to ask what tops the brain's energy back up. And it turns out the brain already runs a built in battery for exactly this.

[12:54]Creatine is how you make that battery bigger. Think of creatine as a rechargeable battery for your brain cells. And that's not a metaphor. I'm kind of stretching here is the actual chemistry and how it works. Your cells run on a fuel molecule called ATP, and when a brain cell fires hard, it burns ATP down to ADP faster than it can build fresh ATP from scratch.

[13:17]That's where phosphocreatine comes in. phosphocreatine creatine instantly hands the phosphate back to ADP and rebuilds ATP on the spot. The enzyme used is creatine kinase more creatine stalled means a bigger, faster result. So is there human evidence creatine actually moves that machinery? There's some. And in the same Alzheimer's pilot, a companion paper found ATP and ADP both roles after eight weeks.

[13:43]And I have to be exact about where they measured that because I believe it matters. They measured it in white blood cells, not in the brain. So it tells you creatine lifted cellular energy somewhere in the body. It does not tell you it lifted energy inside a neuron.

[13:59]So the same caveat as before small uncontrolled pilot And these authors asked for cautious interpretation too. But the direction is exactly what the battery model predicts. A bigger battery doesn't grow you and your brain. It keeps the one you've got from browning out under load. Now, if you are tracking the trials closely, something might be bugging you.

[14:18]The doses in these two studies were just different. They were very, very widely different. So which one is actually right? One study used a single dose, the other use 20g a day for two months. So how can both of them be right? The answer is the blood brain barrier.

[14:34]That's the filter deciding what gets out of your bloodstream and into your brain. Creatine crosses it through one specific transporter. And that transporter already runs close to full. So creatine trickles in very slowly. That's why chronic dosing makes sense. You are passionately filling the tank. And that explains the Alzheimer's pilot 20g a day for weeks.

[14:56]Building up the brain stores. And the single big dose is a different idea. And I want to flag it as an idea. The researchers propose that when the brain is under heavy energy demand, like, let's say, an all nighter, and you flood the bloodstream with creatine at the same moment, uptake briefly can jump up.

[15:13]That's their proposed explanation for their own result. It's not a separately proven fact. So I don't want you to think about either or. Daily dosing fills the tank. A big single dose is an emergency top up under stress. We are talking about the same fuel and two completely different jobs.

[15:28]Okay, now you know that creatine can reach your brain. You know why your brain might want it and you know the two ways to dose it. So let's get practical. What did the trials actually do and what do you actually need to watch out for. So looking at what to do if you want to copy what the creatine trials actually did, here are the exact numbers.

[15:45]The Alzheimer's pilot used 20g a day, split into two ten gram doses for eight weeks. So if you want to look at it, usually for the gym, we are looking at only five grams, five grams a day. That's the general thing. And if you don't have a measuring tool that comes inside it, five grams is basically a level type of teaspoon looking like that a little bit more I guess.

[16:10]Be careful because I realize that teaspoons have different volume across countries. So if I were you before you actually go, years of taking it a certain way, I won't want you to just measure user weight like a food weight to be able to know how much it is right?

[16:26]If you want to take 20g, you can look at a tablespoon and it's a lot. And then you need it to make it like very, very big ones around. This would be around 20g I believe. Like slightly more. The creatine that I am using is and that we're using the studies are creatine monohydrate.

[16:44]Basically all the creatine out there is the same. Don't believe the ones that say that is higher quality and so on. You want to look at creatine monohydrate. It is only one form. It's pure creatine monohydrate. In the supplements you want to see that it's only creatine monohydrate.

[17:00]If you want to look at the ones I use, I use optimal nutrition, but you could use any of those. It's exactly the same. Just look at 100% creatine monohydrate. And this was the form used in all the 16 trials in the meta analysis. And it's usually the cheapest one as well.

[17:15]Now there is something else that you need to know if you start your protocol with creatine, because it's the one thing that keeps popping up in the community. And I received, I believe, at least one question by email every two days about it, saying that, hey, I can’t take creatine, it hits on my kidney because of it, because your next blood test might show something that might freak you out, but it should not.

[17:39]Here's why. The creatine in your muscle and brain naturally breaks down into a waste product called creatinine supplement creatine, and you're feeding that pathway. So the creatinine on your blood panel takes up and it looks like a kidney flag, meaning your kidney has an issue. It usually is not one.

[17:57]In the CABA trial that we mentioned earlier, creatinine rose from 0.94 to 1.25, and the rest of the metabolic panel stayed stable. So the marker your doctor reads as kidney function is literally a creatine byproduct. So more creatine going in means more creatinine coming out. It's not a malfunction.

[18:15]That's the chemistry working exactly as designed. So there's two one limit on that. The trial screened out people who already had elevated kidney labs before it started. So it can't tell you what creatine does to a kidney that's already struggling. And the creatinine number doesn't announce its own cause.

[18:31]What makes that trial we are showing isn't the creatinine reading by itself. Is that everything else on the panel stay put. So don't dismiss the result like that, but don't panic at it either. Tell whoever ordered the test that you are taking creatine and let them read the whole panel.

[18:45]As always, talk to your doctor for this. A higher creatinine here is usually the supplement doing his job. It is not your kidneys failing, it was just used as a marker as a proxy for kidney function. So I want you to know that before you panic on the phone with your doctor and before you write off creatine as a supplement, I also want to tell you about something else that appeared in Phoenix.

[19:10]As you know, creatine is kind of the perfect example of a supplement where the data is good and the price is tiny. So the next step can be hard to implement. Inside Phoenix, you can pull up creatine in the supplements library and see the actual evidence. Great and more useful than that.

[19:25]What others APOE4 carriers similar to you have reported, and a few things that we have found inside our own APOE4 carrier members confirm everything that we've seen here on the people who are taking creatine, and on the days that are taking it through the check ins, we see that they have less brain fog and higher energy.

[19:48]The effect size is significant. But we have also found another early signal that was not apparent in any of the trial is that creatine tend to have tanked the sleep architecture at high dose. We were talking about 20g per day. This is quite a high dose, and for a few carriers inside our community they have detected that their sleep architecture, the REM sleep and the Deep sleep was reduced on the days they took creatine and it took a few weeks of stopping before it came back to normal.

[20:23]So these are the type of experiments that we run inside the Phoenix community, because who knows what might be happening and who cares about what happens on other people. You want to know if creatine works for you specifically as an individual, because maybe you have other type of genes, maybe you have other type of environment that makes you more or less susceptible to the benefit or to the downside of taking creatine and Phoenix, our app is built for you to detect this type of insights.

[20:52]So inside Phoenix you basically log it into my stack, you upload your blood work, you do your daily check ins, we connect to your wearable, and then we get insights on how that supplements is working on you. Does it increase your concentration? Does it reduce your brain fog?

[21:07]Does it increase your cognition or does it reduces your sleep. And then you will know. And the beauty of all of that is Phoenix is the biggest research cohort on APOE4 in the world. And we are just getting started because whenever you are running an experiment like that, validating whether creatine works on you or not, that data is pulled back into Phoenix AI.

[21:30]And remember, Phoenix AI has all the information about the clinical trials out there, all the information about all the research out there, and all the information about other APOE4 carriers running experiments inside Phoenix, which means that whenever you run an experiment, you pull back your information into that Phoenix AI that gives us insight across APOE4 carriers.

[21:50]Remember that when we talked about clinical trials, usually they forget about APOE4 carriers or they take decades and decades to come or they are no sponsored well, we decided that we will generate the data ourselves. So if you want to join us and build additional data points not only for you to know what supplements, what interventions work for you, but also help the research overall on APOE4 carriers.

[22:15]Join us in the Phoenix community and start tracking your interventions. The link to join is in the description below. Because I want to emphasize that last point. You should stop guessing alone. You want to do that with an army of people that are like minded, that are similarly motivated about their brain health, who are also APOE4 carriers.

[22:36]All right. Now, to get back to getting the most out of creatine because the data is pretty clear that creatine works better when it's not working alone. We're talking about the muscle brain axis here. A 2026 review calls creatine plus structured exercise a safe and promising strategy to counteract age related declines in both body and brain.

[22:56]And the cognitive gains show up most in people with lower baseline creatine Think about why basically lifting going to the gym builds muscle, and muscle is the body's biggest creatine reservoir Exercise itself drives brain energy metabolism, so you are feeding the same battery from two ends at once.

[23:14]For me personally, resistance training is the one lever I would never stop. Powder. No powder. I work out 1.5 hours every day. Six days out of seven I lift weights. I take the creatine. I feed the same battery from both end and that stack beats either one alone.

[23:32]All right, now that I've handed you the upside for a while now, if I stop there, you would walk away with only half a picture. And the missing half is also the half that should keep me and you honest about the result. Because I also want to talk about the caveats and everything.

[23:47]Let me argue against, well, this entire theory for a second. One clean trial gave creatine to older women for six months and actually found well, nothing. It's a 2013 study published in PLos One a 24 week, double blind, placebo controlled trial in healthy older women. creatine with or without strength training did not improve cognition on any measures.

[24:08]And here's the part I least want to tell you, because it undercuts the best number in this video. And everyone likes in it’s story But well, I'll always want to show you like both sides of the story, right That null trial isn't standing outside the meta analysis arguing with it.

[24:23]It's actually inside it. It's one of the two studies that make up the 0.88 in order are those that we covered earlier two studies, and one of them found nothing at all. That is exactly why the range around the number was so wide, and exactly why I keep telling you to hold it loosely since the beginning, so the evidence is actually genuinely mixed.

[24:41]The pooled memory resulted in positive. The longest cleanest trial ever run in older adults says nothing happened. Both are true at the same time. That's what real science looks like before it is settled. So hold both of them. Promising a low risk is not the same as proven, and that mixed picture is exactly why I want to zoom out one more level to how much weight any supplement claim should carry right now.

[25:03]For a carrier who feels fine. Six months ago, I'd have been more confident telling you a supplement moves Alzheimer's risk then a giant trial humbled the entire field. The EVOKE program ran two phase-three trials of oral semaglutide taken as a daily pill in nearly 4000 people with early Alzheimer's Two years to the main readout A drug the whole field had real reason to believe in, and it did not slow the disease.

[25:27]The gap against placebo was near enough. Zero both trial were stopped. I'll cover that EVOKE trial in another video. But here's the part that should stick with you. The drug didn't move the brain chemistry in the spinal fluid four markers of Alzheimer's damage dropped, and the people carrying those brains got not one bit better.

[25:45]So I want you to remember, based on that, right before going back to creatine moving a number on the lab report is not the same as helping a person. You are using a lot of proxies to measure your brain and your cognition, even your cholesterol levels, your omega 3 levels on the blood test.

[26:02]All of those are proxies that we are trying to optimize for. And the most dangerous thing I believe in is that if you're trying to maximize a proxy, but in real life, you don't get the benefit. Let's say you have perfect blood biomarkers, but you still get Alzheimer's Then what? Then you feel like you optimize for the wrong thing.

[26:21]That's why in the Phoenix we are optimizing also for functional health. We want to know how you actually feel, how your cognition is, how you perform on the brain test and the cognition test, because that is what matters. It's not a number on the blood work In the end, what matters for us as patient is not whether our cholesterol numbers is excellent, our ApoB is great, and so on.

[26:46]It's whether our cognition is intact or improving. Its whether we are sharp or not, and it's whether we are functional now and ten decades and years later on that is what matters. And again, what matters is not whether it's a placebo effect or not. Whatever you do, if it works for you functionally, that's what should stick.

[27:07]And that is what Phoenix is optimized for. So anyways, when I zoom it back, I want to hold creatine to the same bar you know in terms of evidence. When you have very, very small trials, there is a high probability that when an actual very big trial comes out, it'll give you the other answers and disprove whatever was proven there.

[27:27]But the reframe is that it does not kill the case for you specifically. You just need to test it by measuring what is the downside that you are taking and what is the potential upside for creatine I believe the upside is great. You get better cognition, you get better functional health, and the downside is a little bit annoying to pay $15 a month and then taking that supplement once or twice a day, that's it.

[27:52]So I would definitely want to test that as an experiment for yourself and then measure it. I would love you to join Phoenix if you're not part of Phoenix and log this information, because that will then serve the general community as well and get back that information. If you're not part of Phoenix, you can also comment in the description or in the comment below, and we'll gather that data as well and get some insight that way.

[28:16]Either way, I really believe in n equal one citizen science on what works for you and what doesn't. Remember, you are not the passenger watching your genes drive your life. You are actually the one driving what fuel goes into the tank of your car Okay, I don't know how good that analogy was, but anyways, cheers.

[28:35]I'll see you in the next video. Bye.