The Peter Attia Drive - #251 - AMA #46: Optimizing brain health: Alzheimer's disease risk factors, APOE, prevention strategies, and more

Episode Date: April 17, 2023

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter In this “Ask Me Anything” (AMA) episode, Peter goes into depth on the topic of brain health, starting with how Alzheimer's disease is diagnosed, the significance of blood-based biomarkers in diagnosis, and what the various APOE gene variants mean in terms of a person's risk of developing Alzheimer's disease. Next, Peter discusses the various strategies for preventing Alzheimer's disease and neurodegeneration. He touches briefly on exercise as a potent tool, but focuses more on lesser-known factors that could impact brain health, such as nutrition supplementation, lipid management, brain games, sauna, oral health, hearing loss, and more. If you’re not a subscriber and are listening on a podcast player, you’ll only be able to hear a preview of the AMA. If you’re a subscriber, you can now listen to this full episode on your private RSS feed or our website at the AMA #46 show notes page. If you are not a subscriber, you can learn more about the subscriber benefits here. We discuss: Diagnosing Alzheimer's disease [2:45]; Biomarkers for Alzheimer’s disease, the C2N test, and other tools for diagnosis [7:30]; Genetic component of Alzheimer’s disease: genes that confer risk [12:45]; Understanding your APOE status and why it’s important to know [17:15]; The prevalence of Alzheimer’s disease and other forms of dementia, and who is at higher risk [21:15]; Can the risk of Alzheimer’s disease be decreased with behavioral changes? [24:15]; Overview of modifiable behaviors that potentially play a role in risk reduction of neurodegeneration [30:15]; Things that clearly impact brain health: smoking, alcohol, sleep, head injuries, blood pressure, and more [34:15]; How nutrition impacts brain health: common diets, metabolic health, energy balance, and more [46:15]; Comparing common diets: data showing the association between the incidence of Alzheimer’s disease and specific diets [59:45]; Supplements: EPA and DHA, vitamin D, and B vitamins [1:13:00]; Supplements: theracurmin, cocoa flavonols, and magnesium L-threonate [1:25:15]; Impact of exercise on brain health, minimum effective dose, and the most important types of exercise [1:33:00]; Challenging the mind with brain games—does it impact neurodegeneration? [1:43:00]; The data on sauna and brain health [1:49:45]; Oral health and its association with brain health [1:52:45]; How reducing lipids can improve brain health and prevent neurodegeneration [1:55:30]; The potential impact of hearing loss on brain health and neurodegeneration [2:04:30]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to a sneak peek, ask me anything, or AMA episode of the Drive Podcast. I'm your host, Peter Atia. At the end of this short episode, I'll explain how you can access the AMA episodes in full, along with a ton of other membership benefits we've created. Or you can learn more now by going to PeterittiaMD.com forward slash subscribe. So without further delay, here's today's sneak peek of the Ask Me Anything episode. Welcome to Ask Me Anything episode 46. I'm once again joined by my co-host Nick Stenson. In today's episode, we have compiled a lot of recent questions that we've received around brain health.

This has been in response to recent podcasts on brain health, Alzheimer's disease, neurodegeneration, and the recent series on limitless, where I worked closely with Chris Hemsworth during a time when he learned that he had two copies of the APOE4 gene. So needless to say over the past, call it for five months. We have been overrun by questions on all things that pertain to brain health. In today's AMA, we discuss the following, how Alzheimer's disease is diagnosed, what we need to know about it based on blood-based biomarkers,

how these predict risk of disease, what the various apoe genes mean in terms of a person's risk of developing Alzheimer's disease, and why I believe it's important for everyone to know their apoe gene, which is really code for, I believe, we can do something about it regardless of the outcome. From there, the conversation shifts over into what someone can do to prevent Alzheimer's disease and neurodegeneration. Now, we do this in kind of two formats. We spend a lot less time on the no regret move. So, there are a handful of things that are really stone-cold obvious. And there's really nothing to talk about, frankly. We can talk a

little bit about the dose. So, for example, we talk a little bit about exercise, but really only in the context of minimum effective dose. The evidence is overwhelming that exercise is beneficial, so I don't really want to delve too much into that. Instead, what I want to focus on are things that are less obvious and really scrutinize the data in nutrition, supplementation. Again, minimum effective dose of exercise, but not overall. Lipid management, brain games, sauna, oral health, hearing loss, all of these things.

I think this episode is kind of relevant to anyone who has a brain, if I'm just gonna be blunt and kind of paraphrase Richard Isaacson, because anyone with a brain regardless of their ape but we gene a type or family history is at risk. If you're a subscriber and you wanna watch the full video that's podcast, you can find it on the show notes page. Again, I think that's valuable,

because we do go through a number of figures, which of course are also available in the show notes page. Again, I think that's valuable because we do go through a number of figures which of course are also available in the show notes page. If you're not a subscriber, you can watch a sneak peek of the video on our YouTube page. So without further delay, I hope you enjoy AMA number 46. Here, welcome to another AMA. How you doing? Good. It's going to be a good one. It is going to be a good one. Before we get to it, how are you fairing out there in the cold weather and the icy climate

of Austin, Texas? I'm fearing pretty well, but I can't say the same for the trees. Is school out today or are they back in? No, it's been out for a week. Yeah, so for those listening in each chance, they're going to see any little guys running behind you today. I would go with 50-50 on that. So for those listening in each chance, they're going to see any little guys running behind you today. I would go with 50-50 on that.

For those listening, the kids have been out for the past few days. Well, Austin's been a nice storm and every now and then on some Zoom calls, you see some extra special gas behind Peter. So we'll see if any making appearance today. But what we're going to do today is something more pretty exciting about, which is really talk about something we haven't talked about in the AMA before. So we've had no shortage of podcast content on the brain, dementia, Alzheimer's, most recently with Kellyanne, Chris Hemsworth delved into it, and then you have podcast with Richard Isaacson, Lauren Rogan, Hus's San Jacine, Amanda Smith. So it's a topic that we've talked a lot about on the podcast, but recently we kind of did an analysis and we realized we haven't

really covered it on the AMA. So what we did is we went, collected all the questions that have come through, organized them, and put together what we think is a really interesting AMA for anyone who is worried about their brain, worried about Alzheimer's, neurodegeneration. Whenever I say that, I always think of what Richard Isaacson said, which is anyone who has a brain should care about this. So no matter who you are, it should be really applicable. And so...

Actually, I think what Richard said is, anyone who has a brain is at risk for this, which maybe is even a more pointed statement. Yeah, and it speaks to whether you have this in your family history, whether you don't know if you have this in your family history, or whether you know what your risks are, everything we'll cover today should be of interest for everybody. So I think with that, unless you have anything you want to add, we'll just start getting into it because I know we have a lot to get through. Let's do it. We do have a lot. I think to start off, it'd be helpful just to kind of set the stage as this applies to

how we talk about things later is it would be really helpful for people to understand even how is Alzheimer's disease diagnosed. So at the outset, I'll say that a lot of what we're going to talk about today is around Alzheimer's disease because Alzheimer's disease is both the most common neurodegenerative disease and the most common cause of dementia. It's worth pointing out that there are other causes of dementia, for example, vascular dementia, which would be quite prevalent, Louis body dementia, and there are other neurologic neurodegenerative diseases such as lube body dementia, which is not Alzheimer's, it's distinct from that and obviously Parkinson's disease. So anyway, a lot of what we're going to talk about is Alzheimer's disease and so as it pertains to the diagnosis, you know, unfortunately, it's not a neat and tidy diagnosis the way we would have for say breast cancer, right? If we're going to diagnose breast cancer, we might have some radiographic or physical findings that would, you know, rouse suspicion. And that would be confirmed

with a physical biopsy. When it comes to Alzheimer's disease, it really starts with a clinical diagnosis. So that's made by typically neurologists, and they work with the patient and people who are very close to the patient. So, you know, friends or family members, and they will assess various symptoms, symptoms such as, you know, friends or family members and they will assess various symptoms, symptoms such as, you know, difficulty remembering, events, difficulty concentrating, planning, or problem solving, confusion with location or temporal confusion.

So confused about different events over time, language problems, reduction in vocabulary, speech writing, things like that. All of those are kind of clinical. Then there may be some sort of mental status exam or neuro psychological tests. Generally, there will also be some lab tests done to rule out other causes.

And I personally, because I'm not an arousal, just haven't got a lot of experience with this, but certainly have read case studies of patients where gosh, it looks like they have all of the signs and symptoms of Alzheimer's disease, but you come to find out that they're profoundly hypothyroid or they have B12 and B6 deficiencies or things like that. So you want to kind of rule out things like that.

But the bottom line is the stiagnosis really isn't definitively made, or at least if we want to conclude it until an autopsy. Now today, there are other biomarkers that are increasing in the sensitivity for this. So we now have the ability to look at serum amyloid and towel. And those can be coupled with the things I've described above in addition to things like amyloid PET, such that a really good diagnostician can probably be almost assured

that a patient indeed has Alzheimer's disease based on the presentation. It's really interesting. And I know one of the questions we see come through is when you talk about cardiovascular disease, you have apobias kind of a biomarker that's kind of a predictor of risk and something that people can easily run and

Understand where they're at. Is there anything equivalent to that for Alzheimer's or Nordic generation? No, I would say that Alzheimer's is much more complicated in this regard and I don't think we have something that says need and tidy that said We do have biomarkers. Like I said a second ago ago, right? We have amyloid, we have tau historically. And for the purposes of research, these were typically drawn from CSF. So cerebral spinal fluid, which can be accessed via a lumbar puncture, would certainly be a way to determine the presence of amyloid and tau. Again, very impractical in the real world, right? These are not benign procedures, and they're certainly not things that we want to subject patients to rapidly.

So as we now look at other scores, like the C2N, which I can't remember if we talked about that on a previous podcast, if not, I know we have a newsletter that'll be coming out on this at some point, but the C2N developed Amaloid score uses a couple of things. It uses a patient's ApoE variant. So it sort of says is this patient three, a three, four, four, four, etc. And then it looks at the ratio of two variants of Amaloid

beta. So Amaloid beta 42 and Amaloid beta 40. And then also looks at their age. So, it takes APOE status, AB 40 to 42 ratio, as measured in the plasma, and patient age, and then it predicts the probability of AD pathology. Now, this is a test we have been using. I would say there's probably like six or seven patients in our practice that we are using this test in. And I would argue that we are still in very early days of knowing what to make of these data. So there's two reasons we kind of look at that.

One is it's one more piece of information that helps us understand risk. And it goes into kind of our overall risk assessment that includes everything we talked about before. So family history, genotype, metabolic health, apoe status, cognitive testing, and it allows us to say, okay, is risk higher, lower, and more importantly, and this is where I think it's too soon to say if it's valid, as we make interventions, as we take steps to reduce risk, we would look to see what happened to that C2N score. Did it go up or down? Now, think about it. If it goes down, it's not going down because their ApoE status changed and it's not going down because their age got younger. It can only go down because the ratio of AB 42 to AB 40 changed. So what we're basically saying is we do have a biomarker that measures the change in emaloid 42 to 40 and potentially TOW eventually,

and is that predictive of an improvement? I don't know the answer. The other thing I think I'll just say for the sake of completeness is we do have emaloid PET scans. These are not something we use clinically. We've probably done three or four of these in total and they're typically done in a research setting. I'll probably not say much more about those right now. And for the C2N, is that something, you know, you mentioned you only have it used in on a handful of patients. Is that something that it's just too new for you to kind of roll out with everybody? Or are you really only using that on very high risk based on all the other factors?

It's really the latter. So remember, every test, you have to think, every test has a sensitivity and a specificity. And when you take a sensitivity and specificity, you want to be able to say this has high positive predictive value and high negative predictive value. So if it comes back positive, I want to believe that it means something. And it comes back negative, I want to believe it means something. And in addition to the sensitivity and specificity, which are fixed for a test, the way that you as a physician or person administering the test can increase the odds in your favor is by applying this test to patients with what we

would call the highest pre-test probability. So in other words, if you applied the C2N test willy-nilly across everybody, my fear is you would probably get a lot of noise and you would, this isn't an arbitrary fear, it's just mathematics, you're going to get a lower positive predictive value. The test will mean less and you'll get lower negative predictive value as well. So the goal here is to say, look, we have tremendous uncertainty about this test. Unlike, for example, APOB, where we have really clear relationship between at least population risk and marker, and therefore I feel much more comfortable checking APOB on everybody. But when it comes to this test, the answer is no, I don't.

I think we have to reserve this for people who are at the highest risk. That makes sense. And I think for anyone who wants to dive deeper on the sensitivity specificity, positive and negative predictive value, AMA25, one you and Bob did, which really dove into, although it was cancer screening, it spent a lot of time talking about those metrics and those terms and what they mean. So anyone who wants to learn more on that, it's gonna be a great resource. The next question we see come through a lot. You kind of mentioned it already with the ApoE status.

What do we know about genetic testing and what those results can mean in someone's long-term risk of developing AD or dementia? Well, we know that there is a strong genetic component to Alzheimer's disease, and we know that there is a strong genetic component to Alzheimer's disease. And we know that there are several genes that are implicated in this. I think we can start with the three most penetrant genes or the three genes for which if you have the gene, you are most likely to indeed get Alzheimer's disease. So these three genes are as close to what we would call

the terministic as any genes are. Unfortunately, they're very uncommon. So the three genes we're going to talk about, I'm not going to say much about them other than the state what they are. One is PSEN1, PSEN2, and APP. So those three genes collectively account for 1% of patients with Alzheimer's disease. Those patients get Alzheimer's disease very early, not uncommon for these patients to be afflicted in their 50s. In fact, we now know that the incident case of Alzheimer's disease, in other words, the patient for whom the disease, I mean, it was named after the first physician who identified it, but his first patient was indeed a woman that had, I believe she had the APP mutation, but it

might have been one of the presinoid mutations. Again, I just want to put that out there as an aside, we do see that gene from time to time. Fortunately, it's incredibly rare. Let's focus on the other 99 percent of cases of AD. So 99 percent of patients who go on to develop Alzheimer's disease do not have one of the quote unquote deterministic genes. Of those patients, about two thirds have at least one copy of the APOE4 gene. Now, to put that in context, about 25% of the general population has at least one copy of the APOE4 gene. So,

25% of the population has at least a copy of one copy of E4, and by the way, most of them are just one copy. Two copies is pretty rare. That's about 2% of the population. But that 25% of the population makes up two thirds of all cases of Alzheimer's disease. So out of the gate, you realize before you jump into the minutia on this, which we'll do in a second, clearly this gene is highly associated with Alzheimer's disease. But as I've stated many times before, including stated this obviously, when we discuss this on limitless, this is not a deterministic gene. So there are plenty of patients with ApoE4, one copy or even two who never go on to develop

dementia. In fact, as I think I write about briefly in the book, there are even centenarians walking around with E4s, meaning there are people who make it to 100 with no signs of dementia who are carrying e-fours. So there are other genes at play, and some of those genes amplify, and some of those genes attenuate risk. Again, we've discussed this on some of the previous podcasts, so I won't go so deep into it other than to say other genes like clotho. So there's one variant of clothoclvs,

which attenuates risk in e-fours. So an e-3, 4 carrier that has the clothoclvs variant, their risk returns to that of a 3, 3, a 4, 4 carrier who has a cloth OKLVS, their risk returns to almost a 3-3. It's still slightly higher, but nowhere near the 4-4 risk. Conversely, the wrong mitochondrial haplotype will amplify risk. TGF beta would be another one that amplifies risk. Tom 40 would be another one that amplifies risk, although it's not clear how much Tom 40 functions. And that's 2M's, by the way, on Tom 40, T another one that amplifies risk, although it's not clear how much Tom 40 functions, and that's 2M's, by the way, on Tom 40, T-O-M-M 40. Not clear how much that factors into risk

independent of E4. Some of these genes and SNPs can be identified on regular, kind of call it commercial over-the-counter tests, such as 23 and me. But truthfully, Nick, for most of our patients, we're doing whole genome sequencing on this particular topic. The error rate is lower, and frankly, most of the genes that we care about are not genes that are showing up on the shorter SNP tests. Those were my questions, was just how easily available are some of those other tests, because we know, for someone to find their ApoE, that's just a blood-based test that is fairly readily available.

And I know we've kind of mentioned ApoE4s, but if someone gets their ApoE check, do you kind of just want to run through here are the options of what the results could be, and then in a second we'll get to kind of what that means. But I think just for people to understand who maybe aren't familiar, just what are the different combos that they could even see on that test? Two things that I want to say.

So to answer your question, there are three alleles for the Apo E4 gene. So just to be clear, Apo E is a gene. It codes for a protein uns unsurprisingly, called ApoE. But we have three different versions of that gene circulating in our gene pool. And to be clear, none of these are called mutations. These are all three wild type alleles. So one is E2, one is E3, and one is E4. E3 is the most common and E4 is the next most common and E2 is quite rare. These genes can therefore be combined in up to six ways because you're going to get one copy from your mom and one copy from your dad. So you can have a 2, 2, 3, 3, 4, 3, 3, 4, 4, 4, 4. I hope I got those all right, but it's pretty easy to do the math on that right.

2, 2, 2, 3, 3, 4, 3, 3, 3, 4, 4, 4. The general prevalence of these is, I think, 50 to 55% are 3, 3. About 25% are 3, 4. 2, 4, I think, is the next most common, not that common, probably about 5 to 10%. And 2, 2 is the rarest, 4, 4 is the second rarest, you can sort of do the math. But the majority of cases you're seeing are 3, 3, oh, and then 2, 3 is not that uncommon. So anyway, going back to your question, I think you asked a question about, do we, how easy is it to go about getting these other genetic tests to look for genes beyond

APA we for? Because APA we for is pretty easy to get checked. The short answer is it's really hard. And to my knowledge, there is still no turnkey solution for looking at the entire suite of genes that are involved in Alzheimer's disease, even kind of the 12 most relevant. So right now, we work with Richard Isaacson and his team and brute force it, meaning Richard and a team of folks literally go through the whole genome sequence, trying to identify these. There's a huge opportunity there to streamline this process,

which again, wouldn't be interesting if not for what we're about to talk about today. In other words, I don't know that this would matter a whole heck of a lot unless you believed you could do something about it, which I think comes back to kind of a broader issue around apoi for testing. When the limitless thing came out, there was a surprising amount, at least to my naive view, came out, there was a surprising amount, at least to my naive view of, I don't know what the word is, but call it just sort of backlash against like how irresponsible it was to test for ApoE in Chris. I found that to be a baseless and meritless criticism truthfully. But at the same time, I can understand where it came from, if you believed that having a copy of an apoi for a gene or two copies was deterministic and it was all a fate to complete. In other words, if you believe that having

those genes means you're going to get Alzheimer's disease and nothing can be done about it, then at least you could entertain the argument why know it now. But even if that were the case, I still think that's incorrect. I think knowing something allows you to plan accordingly, but I don't even believe that premise. I do believe there's a lot that can be done to delay onset and or reduce risk. So let's talk a little bit about what the prevalence means of these, right? So globally, the prevalence of AD is two to one in favor of women to men. So women are literally twice as likely

to get Alzheimer's disease as men. And of course, we see the reverse in Parkinson's disease. So it's sort of interesting. Where does that 2x difference come from? It's kind of a combination of individual risk for the women. So for any combination of genotype, so actually let's pull up figure one, Nick.

This will be easier to explain there. Perfect, gotta pull that. So what you're of genotype, so actually let's pull up figure one neck. This will be easier to explain there. Perfect. Gotta pull that. So what you're looking at here, this is a bit of a complicated figure until you sort of orient yourself to it. Each figure is showing you men and women. So the women are in red. The men are in green.

The first column is showing you the risk of Alzheimer's disease, the 10-year risk. So for a given age, what is the subsequent decades risk? So in the first column, that's for Alzheimer's disease. In the second column, that's for vascular dementia, which is the second most prevalent form of dementia. And the final column is just 10-year risk of all dementia. So that would include Alzheimer's plus vascular, plus Louis body, et cetera, frontal, et cetera. I think that's the first way to orient. Then if you

go by rows, you're just looking at the decade in which we look. So the top row is people in their 60s. The next row is people in their 70s. The final row is people 80 and up. So not surprisingly, as you move down the rows, the numbers get bigger, and not surprisingly the third column has to be greater than the sum of the first two columns because it includes both of them plus other things. Lastly, each box shows the six genotypes, the six combinations. So it always goes the same direction, e2232334243444, which is more or less in the order of risk, although you'll see that when it comes to Alzheimer's disease, specifically, the three two is the lowest risk. In all cause dementia, two two is the lowest risk.

That probably has to do with the impact of the E2 genotype in Lewybody and other dimensions, but we'll put that aside for a moment. So what's really obvious when looking at this is that the four four has a significantly higher risk than everything else. And then the 3-4 and the 4-2 are kind of next. We think of the 3-3 as the baseline,

since that's the most common genotype we see in the population. So in general, everything gets compared to the 3-3. You'll also notice that at any point in time, women seem about 20% more likely in a given decade to get Alzheimer's disease than men. And what that suggests is that the two to one prevalence is probably a function of that coupled with the fact that women are living longer.

That would be my interpretation of this. And Peter, you kind of hinted it out there with what you kind of loosely called some backlash around the idea of testing for someone's APEWY status and why they would want to do it. Is there anything more we can say because we do see a lot of questions come through on how robust is the idea that prevention is possible for APEWYD and what more do we know about that side of it? Again, I think this is a very important part of what we're going to talk about today. So the bulk of today's AMA is going to be around what are the measures that we can take, what are the modifiable behaviors that factor into risk reduction or prevention?

Here's the problem. Really difficult to do this directly with control trials, given the time course. You're going to see a couple of examples where we can talk about that and where we can I think pretty convincingly take a causal view, but unfortunately, much of the data here is epidemiologic. So if you look at something called the Chicago Health and Aging Project, it followed nearly 4,000 individuals who underwent regular clinical and cognitive assessment from the early 90s to about 2012, I think. These patients were 65 and older. They had no Alzheimer's disease at the outset. They were all cognitively tested, and the bottom 10% of non-AD patients in terms of cognition were excluded.

So we're trying to take out what we think were the most susceptible. They also excluded any patients who were four-fours. So if a patient is E4, you're going to see that the data are divided between E4 and non-E4. So the E4 segment is just two fours and three fours. And that was about a third of the sample. So a third of the sample had two four or three four, and a third of the sample had no E4.

So interesting population to study, there was no intervention. I want to just state that we're full of limitation here. They looked at how these patients did over the subsequent, what was it, 20 years roughly, 15 to 20 years, based on the number of healthy lifestyle factors they engaged in. So healthy lifestyle factors are all the usual stuff. I don't need to restate the obvious, right? So not smoking, getting good sleep, exercise, nutrition, et cetera, et cetera. And they broke these folks into two buckets. You either were doing zero to one or four to five.

So they wanted to kind of create a gap. So if you look at those, let's pull up the graph, Nick, if you don't mind here. I got to pull that. So what you're looking at on the x-axis is time, what you're looking at on the y-axis is cognitive score. On the left-hand side, you see the apoe cohort. That means these are the third of the patients who were e-forced. And then on the right-hand side, you see the patients who had no e-for. The solid line shows you the people who were in the zero to one healthy lifestyle factors. And the dotted line is the four to five. The line, you might be asking, well, why is this such a straight line? Well, it's because this is a linear model of cognitive decline based on this global cognition

score done from four tests over the 17 years. The shaded areas, you're 95% confidence interval. These models were adjusted for all the usual suspects, age, sex, race, ethnicity, total education, presence of other diseases such as cardiovascular disease, et cetera. What's the takeaway here? Well, let's put aside for the moment that there's confounders that can never be undone here.

So, we know, for example, that education is a huge predictor of cognitive decline, meaning high education is less than low education, but it's also a marker for socioeconomic status. And socioeconomic status has its other reasons that it might factor into this. So if you put all that aside for a moment, two things at least to me stand out when I look at this graph. The first is at the beginning of the study, both groups, all four groups, if you think about it, the e-forz and the non-E4s and the healthy

lifestyle versus the non-healthy lifestyle, you see how they all had about the same cognitive score. Yeah, it's pretty interesting. What happens is two things. The E4s, even with healthy behaviors, still fall faster than the non-E4s with healthy behaviors. So it really speaks to the risk of E4 later in life. But the other thing, of course, that stands out is healthy behaviors offset much of that

risk. So in other words, the rate of decline of the E4s doing the healthy things seems to be slightly less, maybe it's not statistically significant, in fact, it's not. So you would just say, seems to be identical to the non-e-forz who are not engaging in the healthy behaviors. In other words, this suggests that you have some control

over this. This is malleable. Again, I want to restate that, right? If you look at the left-hand graph in the dotted line, including that confidence interval, it's basically identical to the solid line on the right. So another way to look at this is healthy behaviors have a greater impact on E4s than non-E4s. The space between the lines on the left

is greater than the space between the lines on the right. That's what that means. The lift that you can get with healthy behaviors seems to be even greater as an E4 than as an E3. It is really interesting to see that graph that way, and it really leads to what you hinted at just a second ago, which is we're now going to spend the rest of this AMA with the true focus of what are these things that you can do to prevent Alzheimer's dementia to really try and work to keep your brain as healthy as possible. And we'll cover a ton of questions that we get, but I think what would be really helpful is even though we're going to spend more time than less on some of these different preventions,

just because we don't have the time and the day to cover them all in detail. Do you just want to give people that kind of quick list of hey, here are all the factors that you should think about before we kind of start picking them apart. Thank you for listening to today's sneak peak AMA episode of the drive. If you're interested in hearing

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