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

Hey everyone, welcome to a Sneak Peek, Ask Me Anything or AMA episode of the Drive podcast. I'm your host Peter Attia. 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 Peteratti md.com 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 four or five months we have been overrun by questions on all things that pertain to brain health. In today's AMA we discuss the 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 spent 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 in 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, saunas, 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 going to be blunt and kind of paraphrase Richard Isaacson, because anyone with a brain, regardless of their APOE genotype or family history is at risk. If you're a subscriber and you want to watch the full video of this 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 on 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.

Peter, welcome to another ama. How you doing?

Good. This is going to be a good one.

It is going to be a good one. Before we get to it, how are you faring out there in the cold weather and the icy climate of Austin, Texas?

I'm faring 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, any chance they're going to see any little guys running behind you today?

I would go with 5050 on that.

For those listening, the kids have been out for the past few days while Austin's been in Ice Storm. And every now and then on some Zoom calls, you see some extra special guests behind Peter. So we'll see if any make an appearance today. But what we're gonna do today is something we're pretty excited about, which is really talk about something we haven't talked about on an AMA before. So we've had no shortage of podcast content on the brain. Dementia, Alzheimer's, you know, most recently with Kellyanne. Chris Hemsworth delved into it. And then you have podcasts with Richard Isaacson, Lauren Rogan.

Who?

Hussain Yassin, 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 an 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 kind of 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 just 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. But it's worth pointing out that there are other causes of dementia. For example, vascular dementia, which would be quite prevalent, Lewy Body dementia. And there are other neurologic neurodegenerative diseases, such as Lewy 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, 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 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, 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 neuropsychological tests generally. There will also be some lab tests done to rule out other causes. And I personally, because I'm not a neurologist, 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 this diagnosis 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 tau, 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 APOB as 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 neurodegeneration?

No, I would say that Alzheimer's is much more complicated in this regard, and I don't think we have something that's as neat and tidy. That said, we do have biomarkers, like I said a second 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. But the C2N developed amyloid score uses a couple of things. It uses a patient's APOE variant, so it sort of says, is this patient A3, A3, 444-et-Cetera. And then it looks at the ratio of two variants of amyloid beta, so amyloid beta 42 and amyloid beta 40, and then also looks at their age. So it takes APOE status, AB40 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 or 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 stat has 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 amyloid 42 to 40 and potentially tau 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 amyloid 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 used it 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, with 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 pretest 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 negative predictive value. Ama25 1 you& Bob did, which really dove into, although it was cancer screening, 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 going to 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 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 deterministic as any genes are. And fortunately 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 to 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 presenilin 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% of cases of AD. So 99% of patients who go on to develop Alzheimer's disease do not have one of the 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 2/3 of all cases of Alzheimer's disease. So out of the gate, you realize before you jump into the minutiae 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 discussed this on Limitless, this is not a deterministic gene. So there are plenty of patients with APOE 4:1 copy or even 2 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 E4s. 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 Clotho K, L, V S which attenuates risk in E4s. So an E3.4 carrier that has the Clotho KLVs 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. Tom40 would be another one that amplifies risk, although it's not clear how much Tom 40 functions. And that's two M's by the way, on Tom 40 T O M, M40, 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 23andMe. 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.

That was one of 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 Apoe 4s, 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 APOE4 gene. So just to be clear, APOE is a gene. It codes for a protein 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 two two, two, three, three, four. Three three, three four, four, four. 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. The general prevalence of these is I think 50 to 55% are 3, 3, about 25% are 3 4. 24 I think is the next most common, not that common, probably about 5 to 10%. And 22 is the rarest. 44 is, 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 23 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 ApoE4? Because ApoE4 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 APOE 4 testing. When the limitless thing 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 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 APOE4 gene or two copies was deterministic and it was all a fait accompli. 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 2 to 1 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 genotypes. So actually, let's pull up figure one. Nick, this will be easier to explain.

There, Perfect, got it pulled up.

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 dementias. So that would include Alzheimer's plus vascular plus Lewy 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. E22, 32, 33, 42, 43 and 44, which is more or less in the order of risk. Although you'll see that when it comes to Alzheimer's disease, specifically the 3:2 is the lowest risk in all cause dementia. 2:2 is the lowest risk. That probably has to do with the impact of the E2 genotype in Lewy Body and other dementias. But we'll put that aside for a moment. So what's really obvious when looking at this is that the 44 has a significantly higher risk than everything else. And then the 34 and the 42 are kind of. Next, we think of the 33 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 2 to 1 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 at it there with what you kind of loosely called some backlash around the idea of testing for someone's APOE 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 ad, 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 controlled 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 4:4s. 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 2, 4 or 3 4, 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 0 to 1 or 4 to 5. So they wanted to kind of create a gap. So if you looked at those. Let's pull up the graph, Nick, if you don't mind. Here.

Got it pulled up.

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 E4s. And then on the right hand side, you see the patients who had no E4. 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, your 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 E4s 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 E4ers 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 kind of 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'd 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.

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