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It's /. 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. Next Ensign. 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 podcast on
brain health, Alzheimer's disease, neurodegeneration and
the recent series.
Limitless. Where I work 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 bring help. In today's am a, 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
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 talked a little bit about
Their size, 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 our 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
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 as 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.
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. Am a number 46.
You're welcome to another am a, how you doing? Good. It's gonna be a good one. It is gonna 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 feeling pretty well, but I can't say the same for the trees.
The school out today, or are they back in
know? It's been out for a week.
And so for those listening any 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.
Out for the past few days while Austin's, been an ice storm and every now, and then on some Zoom calls. You see, some extra special guest behind Peter. So we'll see if any make an appearance today, but what we're going to do today is something we're pretty excited about which is really talk about something. We haven't talked about on the 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.
Into it and then you have podcast with Richard, Isaacson Lauren Rogan, Hussein, you seen 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 in 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, am a for anyone who kind of is worried about their brain worried about Alzheimer's, neurodegeneration
raishin, 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, it speaks to whether you have this in their family history, whether you don't know, if you have this in your family history or whether you know what, your risks are, everything will cover today, should be of interest.
Or 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. As 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
Degenerative 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, is distinct from that and obviously Parkinson's disease. So anyway a lot of what we'll talk about is also a 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 four
Breast cancer, right? If we're going to diagnose breast cancer, we might have some radiographic or physical findings that would arouse 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 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 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 a
presentation. It's really interesting. And I know one of the questions we see come through is, you know, when you talk about cardiovascular disease,
You have a p.o. be as kind of a buyer marker 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 are
neurodegeneration know, 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 cerebrospinal 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 C 2N, which can't remember if we talked about in a previous podcast, if not, I know we have a newsletter
It'll be coming out on this at some point, 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 3, a 3 4 4 4 etcetera. 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 a pony status, a be 42, 42 ratio, as
Road 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 they're a Bowie.
Status changed and it's not going down because their age got younger, it can only go down because the ratio of a be 42 to a be 40 changed. So, what we're basically saying is we do have a biomarker that measures the change in Emma, Lloyd 4240, and potentially Tao 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.
Actually 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, use 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 you really only using that on very high risk based on all the other factors,
it's really the latter. So you remember that every test, you have to think every test
has a sensitivity and 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 - 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
Is test two 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, a poby
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, and May 25 one. You and 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 a deer dementia.
When 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 PSE n1p sn2 and a peep
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 Appa
Mutation, but it might have been one of the priests until and 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 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 percent 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 percent of population makes up two thirds of all cases of Alzheimer's disease. So out of the gate you realize before you jump into the
Usha on this, which will 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 to who never go on to develop Dementia. In fact as I think I write about briefly in the book, there are even
Canarians walking around with ephors meaning, they're people who make it to 100 with no signs of dementia who are carrying ephors. 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 podcast so I won't go so deep into it other than to say other genes like cloth. Oh, so there's one variant of cloth. Okay LVS which attenuates
Risk in ephors. So Annie 34 carrier that has the cloth okay? LVS variant their risk returns to that of a 33, a 44 carrier who has a cloth okay. LVS their risk returns to almost a 33. It's still slightly higher but nowhere near the 44 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 two M's. By the way, on Tom for tto mm40, not clear how much that factors into risk independent of e, for some of these genes and Snips 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. Snip 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 a Bowie Force, but if someone gets their apoe check do you kind of just want to run through here?
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, a pokey for Gene. So just to be clear apoe is a gene that codes for a protein unsurprisingly called apoe, but we have 3 different versions.
Ends 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 e. 2 1 is e 3 and 1 is e for. 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 22
2, 3, 3 4 3, 3 4 4, 4. 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 4, 4 4. The general prevalence of these is I think 50 to 55 percent are 3-3 about 25% are 3424. I think, is the next most common not that common probably about 5 to 10%.
And 22 is the rarest four fours is the second rarest, you can sort of do the math, but the majority of cases you're seeing are 330, 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 they put we force pretty easy to get checked. The short answer is it's really hard and to my knowledge. There is still no
And key 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 apoe4 testing when the Limitless thing came out there was a surprising amount at least to my naive view of what the word is, but call it just sort of backlash against like how irresponsible it was to test for apoe and Chris I found that to be a baseless and meritless criticism truthfully. But at the same time I
Understand where it came from. If you believe 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 jeans 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 to
It 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
So for any combination of genotype so actually let's pull up Figure 1 - will be easier to explain their
perfect. Gotta pull that.
So what you're looking at here, this is a bit of a complicated figure but 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, Etc, frontal Etc. I think that's the first way to orient. Then if you go by Rose, 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,
The 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 E2 to 32 33, 42, 43, and 44.
Or, which is more or less in the order of risk. Although you'll see that when it comes to Alzheimer's disease, specifically, the 32 is the lowest risk in all cause dementia. 22 is the lowest risk that probably has to do with the impact of the E2 genotype in Louis body and other dementias. But we'll put that aside for a moment. So what's really obvious when looking at this
That the 44 has a significantly higher risk than everything else. And then the three four and the four to our 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 33, 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
221 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 there with what you kind of loosely, called some backlash around the idea of testing for someone's a buoy 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 a d and what,
Or 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
And 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 twenty twelve. I think these patients were 65 and older. They had no Alzheimer's disease at the
Outset. They were all cognitively tested in 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 nany for. So the E4 segment is just two fours in three fours, and that was about a third of
The sample. So a third of the sample had 24 34 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
Dinner. 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 etc, etc. 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 a pulled up. So what you're looking at on the x-axis is time, which is
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 ephors. 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 425
The line you're going 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 area is 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, Etc. What's the takeaway here? Well, let's put aside for the moment.
Meant 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 higher 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 to things at least, to me stand out, when I look at this graph, the first is at the beginning of the study both
Both groups, all four groups, if you think about it, the ephors in the non ephors 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 ephors, even with healthy behaviors still fall faster than the non ephors with healthy behaviors. So it really speaks to the risk of e for 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 ephors, 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 ephors 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
Call to the solid line on the right. So another way to look at this is healthy. Behaviors, have a greater impact on e4 is than on ephors. 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 is an E4. Then 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 will cover a ton of questions that we get. But I think it would be really helpful is even though we're going to spend more time than less on some of these different prevention's just because we don't have the time in 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 peek. Am a episode of the drive? If you're interested in hearing the complete version of this, am a you'll want to become a member. We created the membership program to bring you more in-depth, exclusive content without relying on paid ads. Membership benefits are many and Beyond the complete episodes of the AMA. Each month, they include the following. Ridiculously
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