APOE4 Carriers: This Common Shot May Cut Dementia Risk

[0:00]A hundred and four million people. 21 studies, and one ordinary vaccine you can already get at a pharmacy across all of them The people who took the shingles shot were diagnosed with dementia about a quarter less often with Alzheimer's It's closer to half. That is exactly the kind of number that should make you suspicious because it made me suspicious.

[0:29]Healthier people get vaccinated and healthier people get less of everything. So I went looking for the one study that couldn't be explained away. I found it in Wales and it turns on a single birthday. What does it mean? Listen to the following. What the accident actually measured. The one line gave researchers something they almost never get a test where who was offered the shot and who wasn't was decided by something as random as which side of a birthday you landed on.

[0:59]The precise figure is a 3.5 percentage point drop in new diagnoses among the people who actually received the shot, and that is where the 20% come from. The confidence interval runs from 6.5 to 33.4, and it never touches zero. So as you know, a confidence interval is the range of answers The data can't rule out when it stays clear of zero.

[1:21]No effect isn't one of them. So what is interesting is that the shot most people get to avoid a painful rash Did that by accident. Now let's slow down a little bit, because a number like that can do two opposite things to you. If you carry the APOE4 gene, the variant that raises your baseline Alzheimer's risk like I do, or if you've just decided you'd like to keep your brain health as long as possible, your first feeling is probably hope.

[1:48]Then usually suspicion behind it, because now a days you'll hear so many different miraculous interventions, supplements and everything. All right, that's good, because I want you to hold onto both hope and suspicion. Here's the reframe. Dementia gets sold to us as kind of fate, especially for us APOE4 carriers You read the genotype, you feel the floor drop and the story in your head becomes it's coming and there's nothing I can do.

[2:15]And to be frank, doctors out there, neurologists or your GP usually are also the kind of people who tell you. Hey, come back when you have symptoms, when you have Alzheimer's symptoms, which as you and I know, that will be way, way too late to act. So it's in your power to do the research and to do what you can to, if not prevent it, at least delay it as long as possible.

[2:37]Let me start by a quick introduction. For those of you who don't know me, I'm a doctor of pharmacy and I carry APOE4/4 homozygous. I'm also the founder of the Phoenix community, which is the biggest APOE4 community of patients running experiments together. Our entire goal is to run trials on our own in real life situation, not in sterile clinical environment.

[3:05]Because what matters to us patients is actually whether something works or not. We actually don't care that much if it's placebo, we don't care that much if it is not replicable. If something works on us and we prevent Alzheimer's on us, that is good enough. And the key part of having a community is to see all the other experiments all the members are running and get, if not insights, at least ideas on what works for other people who are similar to us.

[3:33]So then we can try it on ourselves. And that is what Phoenix is about. And part of that is training our AI Phoenix AI on all the different papers and all the different clinical trials that exist out there on dementia, Alzheimer's, and APOE4 So basically, I read all of these papers for one thing.

[3:52]What is the actual signal and is it real or are we being sold something by someone. So in this specific case about the shingle vaccine I want you to work out with first why this is not your average People who did a healthy thing were healthier study because that happens so many times across different studies, a lot of confounding factors that people who are doing specific type of interventions actually care more about the health.

[4:19]So they also have a lot of other interventions that will lead to that population having less risk overall I'm also looking at every place the finding got checked, including one that ran across 100 million people. That is a bed load of people. Then the leading theory is for why a rash shot the shingle vaccines touch your brain at all.

[4:40]And finally, I'll be honest about the gaps as always, including the big one. Nobody has tested whether this works the same if you carry APOE4 or not. So that gap matters, especially because APOE4 changes a lot of mechanism inside our body, not only lipid transport but a lot of other mechanisms as well.

[4:59]And this gap matters. So let me start with why this one study is built different. As I mentioned earlier, most health news you read is correlation. You know, people who took a supplements or ate a food or got a vaccine were healthier later. But the problem is those people are different in a thousand ways.

[5:16]you can't see because healthier people overall get more vaccine. Wealthier people take more care of the health overall So you never know if it was the shot or just the type of person who shows up for the shot. So the Welsh study got around that with a trick called That is basically a very simple idea behind the fancy name.

[5:38]Think about two different people, one born the last week of August 1933, one born the first week of September. They are basically the same age, the same generation, same everything. But one was eligible for the vaccine and one was banned from it purely because of the calendar. So the researchers checked, and across that line, the two groups looked the same on everything they could measure.

[5:59]They had the same rate of flu shots, the same rate of other routine preventive care, the same past diagnosis. The only thing that jumped was the shingles vaccine itself, from basically 0.01% uptake in the people just one week too old to 47.2% in the people just one week younger.

[6:17]That vertical cliff is the whole game, The authors said it plainly This gives evidence that is, in their words less vulnerable to confounding and bias than the usual associational studies, when the only thing that differs between two groups is the only one thing you're testing, you are not guessing anymore.

[6:34]You're close to finding causality. Now, one study in one country run by one team. there is some reasons to be skeptical, and I believe it's the right instinct. And I think it's a good habit to assume something is a fluke until someone else tries to break it. Right.

[6:53]So that's exactly what happened next. People went and checked on other continents in millions of people with completely different methods. So let me show you how that turned out, because this is where it stopped being a curiosity and starting being a pattern, a pattern that we should care about.

[7:08]Let's talk about Australia. So the same accidental experiment opposite side of the planet with the same answer. So the same accidental experiment opposite side of the planet with the same answer. Australia had its own birthday cut off with basically a different date November 2nd, 1936 A different health system, a different population.

[7:23]Researchers ran the exact same regression discontinuity trick on Australian primary care records, and they found the same thing being eligible for the shingles vaccine lower new dementia diagnosis by 1.8% points over 7.4 years. That is, with a 95% confidence interval 0.4 to 3.3. P equals 0.01 A p-value is the chance of seeing a gap that big, or bigger, if the vaccine did nothing at all here about 1 in 100, which is very low.

[7:55]So the authors use careful language saying these is evidence more likely to be causal than ordinary associational studies. And here's the part that kills the obvious objection if these were just healthy people get vaccines, the vaccine would look like it helps everything, and it did not. The Australian team checked it against 15 most common conditions in their record and against other preventive screenings.

[8:19]The vaccine moves dementia. It didn't move anything else. One study is the headline two studies on different continents using the same trick, pointing to the same way is not the headline anymore. It is a pattern. I love patterns and you should too, So Two natural experiments. But those are still a particular method.

[8:35]What happens when you zoom all the way out and just count enormous number of regular people? That is the next layer, and the scale is genuinely hard to wrap your head around. In Korea, 2.5 million Koreans plus a 100 million people Meta analysis check. So to give you a bit of context on this one, separate teams wanted to know if the shingles vaccine and dementia link holds up in giant everyday population.

[9:00]Not just clever, but the experiments that were run in Australia and Wales. Korea basically run a nationwide cohort with 2.5 million adults. People who got the live shingles vaccines had a lower rate of Alzheimer's, with an adjusted hazard ratio of 0.75. A hazard ratio is just the speedometer for diagnosis.

[9:19]It compares how fast something is showing up in one group versus another. Here, 0.75 means Alzheimer's was showing up about a quarter slower in the vaccinated group we are looking at a 95% confidence interval 0.71 to 0.78. Then a meta analysis pulled the whole field 21 studies with 104 million people.

[9:41]Shingles vaccination was tied to about 24% lower risk of any dementia, and about 47% lower risk of Alzheimer's specifically Out of every adult vaccine they looked at, herpes zoster had the biggest Alzheimer's reduction of the bunch, and that is 47%. Now, the honest footnote because I promised it these big number studies are associational.

[10:04]That 47% is really impressive, but it sits on top of huge variation between studies, and you can't fully rule out that healthier people got vaccinated in that specific case. So that's exactly why those birthday experiments that we mentioned earlier in Australia and Wales matters so much because the method lean on each other, but step back.

[10:22]It isn't one lab's pet result The whole field is leaning in the same direction. Now here's a practical wrinkle. The shot in those birthday experiments was the old live vaccine. And in a lot of countries that one's basically been retired. It's been replaced by newer one that carries no life, various at all the recombinant shot branded Shingrix So the obvious question that should probably be in your mind is, does the newer shot do anything for your brain?

[10:48]Or did we just get excited about the vaccine that's already on its way out? So they tested it and the answer flips the script a little bit. The newer shingles shot might be the better move for your brain actually. And they actually compared the two head to head.

[11:03]Let me give you the backstory. Around October 2017, the US largely switched off from the old live shingles into a newer recombinant one Shingrix that switch created another natural experiment. People who happen to be get vaccinated just before the switch got the old shot, and people just after basically got the new one.

[11:23]So again, run that type of experiment. And the newer recombinant shot came out looking at least as good and arguably better. It was tied to a 17% increase in time lived free of a dementia diagnosis, which worked out to 164 straight days without a diagnosis in the people who eventually got one.

[11:41]And it didn't just beat the old shot, it beat two other vaccines. Older adults commonly get flu and Tdap on dementia risk. That comparison matters because if any old immune nudge helped equally, you'd expect flu and Tdap to look the same, but they did not. Something about the shingles shot specifically stands out.

[12:02]It's the same job, different shot, and the modern one looks stronger for your brain. So it's pretty cool because one needs to replicate. Second, it scales. And third, the modern shot looks even better than the old one that people run studies on. There was one additional question knowing at one that matters whether you are completely healthy right now or already watching this disease up close, does this only help people who are still totally healthy, or does it do anything once the disease has already started?

[12:29]And here is the answer. And it actually kind of surprised me. It seemed to help even after the clock has already started, which is quite rare, knowing how Alzheimer's work and Dementia works. So the same team went back to the Welsh records and looked at the whole arc of the disease, not just brand new cases.

[12:46]Two things came out. First, being eligible for the vaccine was tied to fewer diagnosis of mild cognitive impairment, which is called MCI, which is the fuzzy in-between stage between dementia that 1.5 percentage points over nine years, and that is at a 95% confidence interval, 0.5 to 2.9 and P equals 0.006.

[13:08]So it's not only delaying full dementia, it's pushing back the earlier stage too Pretty cool right. Second. And this is the one that is very interesting among people who already had a dementia diagnosis. Being eligible for the vaccine was tied to fewer deaths from dementia, down 8.5 percentage points over nine years.

[13:26]Again, 95% confidence interval 0.6 to 18.5 and P equals 0.036, the authors read, was that the vaccine may prevent or delay impairment and slow the cost in people already living with dementia. Now, one fair caveat the deaths estimate has wide confidence intervals because it's a smaller group, so I would hold that a little bit more loosely, but the shape of it front of the disease, middle of it, even near the end.

[13:55]That's not what the coincidence usually look like. So at this point, the is it real question is mostly answered because you've seen the results across different countries, different methods, different vaccines, across 100 million people, and it works across the whole disease lifespan. And the evidence we see is about as strong as you can get without a true randomized trial, which basically would be almost impossible to run given the whole duration and the vaccinated non-vaccinated type of information we deal with here, which kind of falls the new question, the one I was thinking about before filming this video. Why?

[14:30]Why on earth would a shot for a skin rash do anything to our brain? And the answers starts with a virus you almost already have inside of you. Right now we're talking about VZV reactivation and neuroinflammation Right now we're talking about VZV reactivation and neuroinflammation The virus that gave you chickenpox never actually left your body.

[14:51]If you had chickenpox as a kid. And actually most of us did that virus, it's called varicella-zoster didn't get cleared. It went quiet and hid inside your nerve cells. It is still there Decades and decades later, as you age, your immune surveillance weakens and that virus can wake back up sometimes that's full shingles the rash and the nerve pain.

[15:16]But sometimes it reactivates quietly under the radar without a rash And here's the leading idea for the brain connection. One mechanism review proposes that this quiet, repeated reactivation acts as a I quote renewable peripheral immune stressor. The Translation is that a low grade fire that keeps relighting, keeping your immune system, including the immune cells in your brain, in a constant, primed, irritated state.

[15:44]The vaccines job in this theory is very simple, right? It keeps the virus suppressed so it stops relighting that fire. The same review puts it as the vaccine possibly reducing cumulative inflammatory tone. So to be extremely precise here, this is a hypothesis. I believe it's biologically plausible and it's been published, but it is not completely proven.

[16:06]Nobody has shown the chain end to end in humans Still, the logic is very clean, quiet, the smoldering virus and you may quiet the fire. It keeps lighting in your brain. That's the theory. But there is a second theory, and it's a completely different idea about what the shot is actually doing.

[16:26]The two theories matters because they point to different ways this might help and to different people it might help most. Here's the fork in the road. We have two competing mechanisms and one trackable dial So these two competing theories for how a shingles shot protects the brain is unfortunately impossible to tell them apart based on the data that we have.

[16:45]So a quick setup of the scene. Scientists agree the shot seems to lower dimensional risk. They do not agree on why, and it splits into two camps. Camp one is the antiviral idea The shot works by specifically keeping the hidden chickenpox virus in check. That's what we mentioned just a few minutes earlier.

[17:01]camp two is a little bit wilder. It is called trained immunity. The idea that the vaccine gives your innate immune system a broad reset, a nonspecific tune up that lowers inflammation across the board, not just against one virus. That's why some researchers contrast the specific antiviral effect against this trained immunity effect, and that both could be happening at once.

[17:23]Now, here's where this stops being a science debate and starts being useful to you. Both theories point at the same dial. We are all looking at inflammation, and inflammation is something you can actually measure. The cleanest and the cheapest proxy for inflammation is what we call hs-CRP High sensitivity CRP, a simple blood marker of systemic inflammation High sensitivity CRP, a simple blood marker of systemic inflammation For context, plenty of people walking around at two, three or even higher.

[17:50]Whatever your genes say, I'd want that number comfortably under 0.5. Definitely under one. If your hs-CRP is higher than one. I would put that as one of the high priority opportunity to work on something, for especially for someone who is thinking seriously about brain health. I track mine religiously.

[18:10]I do quarterly blood tests and it's one of the few windows we have into exact fire these vaccine theories that talking about. We don't know the mechanism yet, but the dial it points to inflammation is one you can measure today. And the two theories are anyways pointing towards that.

[18:27]So we've got very strong near causal evidence and two plausible reasons it might work. But again plausible is not proven. And I want to spend a little bit of time to talk about the gaps in this story, because I believe that matters, especially if you carry APOE4 like I do let me give you the three caveats, starting with the one that's personal for you and I.

[18:49]First, APOE4 gap if you carry APOE4 or you just here for the straight, talk about your own brain. Here's the line I have to be straight with you about every single number I've given you so far. The 20%, the Australian replication, the welsh study, the 100-million-person meta-analysis came from the general older population.

[19:08]Not one of those studies broke the vaccine effect specifically for APOE4 carriers, not one. So when you see a number claiming these slashes your risk as a carrier by some specific amount, well, it is for the general population and not for us carriers. The only study in this whole stack that even looked at APOE4 did something different.

[19:24]It looked at the shingles disease, not the vaccine. And on whether your risk differs by carrier status. And it said that had, quote, not been studied where they could pick the signals was inconsistent between men and women. But here's the empowerment side because a gap is not a no.

[19:39]Nothing in the biology says carriers are somehow excluded from benefit this broad and this consistent. And if the mechanism really is inflammation, well, I believe that it should matter for us at least as much as for anybody else, if not more. But that is just reasoning. It's not a measured result, and I'm not going to dress it up as a certainty.

[19:58]And I want to spend a little bit of time thinking about that, that gap, the fact that nobody has measured carriers is exactly why I build Phoenix. Here's the thing. We can sit around for years waiting for some institutions to study people like us, or we can be the data.

[20:13]If you looked at trials, you'll be so shocked. And I am that 70% of all Alzheimer's cases are from APOE4 carriers, but Just a small, small, small Amount of studies have APOE4 carriers as a population or even as a subpopulation, which means nobody is studying us APOE4 carriers specifically.

[20:37]So this is why I did two things. Number one is inside the Phoenix community We have this clinical trial engine that surfers real registered studies and helps you find the ones you're actually eligible for that are targeting APOE4 carriers, because I want you to be aware of those.

[20:54]And you might want to participate, because the more data we generate in this clinical setting, the better it is for all carriers out there. Number two, and I believe that is the most powerful one. My vision is that the actual studies that will serve us is not run in a clinical setting, because what matters to us as patient is not the same as what matters to actually scientists.

[21:19]We don't have the time to run studies that last ten years plus and require millions and millions of funding on a specific intervention that might or might not get funding from Big Pharma because it can't be sold We want to look at any interventions, even the ones that can't be commercialized and don't get funding.

[21:39]And we want to run these experiments now because no one has time to waste. So inside Phoenix, we have this entire Phoenix research arms where we are running our own citizen science. And one experiment, we have the tools to help you define which interventions work for you or not.

[21:59]So you have the certainty that whatever supplements, whatever interventions you are doing, actually work for you as an individual. And what is very important is your data is not only useful to you, it's useful for the rest of the community. Now look at all the different hundreds of members who are running these experiments on themselves.

[22:18]Whenever we find a signal, let's say on a lifestyle intervention, on a diet, on a supplement and so on, that gives us an additional signal that this thing is actually helping one individual carrying the APOE4 gene And when it's not only one person, but we can see this across hundreds of APOE4 carriers, we can then have these insights and these signals that will benefit you in return.

[22:42]It gives you ideas on what to check and what to experiment on yourself. And as soon as you experiment on yourself and validates whether this works or not, it pulls back that information into the collective community, where in the end we'll be able to say for APOE4 carriers, these are the interventions that work the best work, the best as reduce in cholesterol at improving your sleep at reducing dementia risk and removing your brain fog and so on.

[23:07]we are running all of these research in real time, in actual real people's lives. Because instead of looking at what happens in a hospital or clinical setting where everything is controlled, we are actually measuring real life situation. How do those interventions work out in your everyday life when you don't have 100% adherence When everyday lives can happen, not every day is the same.

[23:32]And where you have your entire environment that creates this confounding factors. With enough APOE4 carriers and enough members running these experiments, we then generate the biggest and largest study about APOE4 and what can be done to beat the odds. So if that interests you, join the Phoenix community, because we need as many APOE4 carriers as possible.

[23:53]This will help you as an individual find which interventions is great and working for you, and this will help the entire APOE4 community to find actual answers on what is specifically working for us APOE4 carriers All right, now back to the shingles vaccine. Let's talk about caveat number two, because you've probably heard that one, that it probably only works for women.

[24:17]And it's half the story because several of these stories broke the results out by sex. And the pattern showed up. That got a lot of press. In Wales, for example, the protective effect was much stronger in women than men. The follow up study found the same lean in the Shingrix data, so the new vaccine, women got more benefit than men 22% more time lived diagnosis-free versus 13% for men Except for the Australian replication, the same rigorous method specifically tested for sex difference and found none, in their words, no evidence of a significant treatment effect.

[24:49]heterogeneity by sex. So the status between men and women is that it's stronger than women in some data sets. It's no difference In another, it's real, but it's unsettled. So nobody actually knows why. Because inflammation and maybe could be around menopause. It could be about hormonal difference. It's very, very difficult to know.

[25:10]So if you're a man, don't write yourself off on the basis of a pattern that you don't even replicate everywhere. Caveat number three. And I think it's the most important for how you actually live, because it changes the shot from the magic bullet into what it really is.

[25:25]The protection might fade. Remember that giant Korean study I told you about with the 2.5 million people If you read the fine print on that one, the protective effect attenuated over time. It was the strongest in the years right after vaccination and drifted back towards baseline as the years stacked up and it got weaker in smokers and drinkers, which tells us something important.

[25:46]The shot is not operating in a vacuum. It's one input into a system. You're also feeding or wrecking every single day that actually fits everything else we've covered in this video. If the benefit runs for lower inflammation, then of course the lifestyle stuff that drives inflammation up like smoking and heavy drinking, bad metabolic health can eat into the gain the vaccine gives.

[26:08]So a shot. The vaccine is a head start. It's not like a force field protecting you. What you do for the next decade still decides the race So put it all together. Strong near causal evidence, a plausible mechanism, and three real caveats. There is no APOE4 carrier specific data.

[26:25]There is an unsettled sex pattern and benefit that fades without upkeep, which lands us on the only question that actually matters. Knowing all of that, the good and the finished, what do you actually do? So first of all, because there's positive expected value, you should act before certainty.

[26:42]Again, we don't have time to wait until it is clinically certain that something benefits us or not. Sometimes you have to take a leap of faith, especially when the side effects and the downside is minimal. You don't have to wait for the 2029 trial to do something with this, because, number one, the shingles vaccine is already recommended for older adults.

[27:03]Full stop it just to prevent shingles. So that recommendation exists with or without any brain benefit. So for a lot of people, this isn't just some exotic intervention. It's a box that's already on the list and that you are already probably doing. On top of that, the cost effectiveness model that was run on Chinese adults with marketing impairment MCI estimated that vaccinating them at 50 could avert around 12% of dementia cases in that group, and that it pencils out as cost effective and the proof everyone is waiting for, well, it's finally being built.

[27:35]The first big randomized trial with a pre-specified dementia body is called DAN-ZOSTER And it's recruiting right now around 162,000 people. The recombinant shot dementia tracked at three years. That's kind of the gold standard this whole field has been missing. The catch is that the results are not expected until about 2029.

[27:53]So here's how I, and I probably think you should think about is in medicine, you almost never get total certainty. You get evidence strong enough to move on. And I believe this clears the bar because it's an already approved, already recommended vaccine with a known safety record. It's backed by the strongest causal great evidence we've ever had that the shot moves dementia risk for the right person talk through with their doctor.

[28:15]That's more than enough to act now without waiting for 2029. In case you're wondering where to get it and what's available on you, I found you towards the Phoenix community because depending on where you're coming from, you might get different answers. And to close this video and to go back to where we started a line through a single birthday in Wales, nobody meant to run an experiment, and it turned out into the strongest signal we have that the cheap, ordinary vaccine can push back the disease most of us are quietly terrified of.

[28:42]Or maybe not that quietly. So here's the one thing to do. First, if you are near the recommended age band in your country, put the shingles vaccine on the agenda for your next appointment. It's not a brain drug per say Nobody has earned that claim yet, but put it on the list of the thing because it already should be there.

[29:01]And let the upside you might be getting from it be, you know, a free upside like a free lunch. And if you carry APOE4 like I do, even though the carrier specific number still does not exist, even though this is something that we are starting to do in the Phoenix community, it's not the reason to feel powerless.

[29:18]It is a reason to get counted. And the trial matching tool are in the description below. It's available for free as well. And if you join the Phoenix community, join the experiments that we are running and let's get these answers once and follow does the shingle Vaccine help APOE4 carriers Reduce or prevent or delay dementia and Alzheimer's.

[29:39]These are the things that we can earn ourselves and not wait until there is a study that comes out. Remember, you did not choose your genes, but you absolutely choose what you do with it the next decade. That's it for today. I'll see you in the next one. Bye.