Hey everyone, welcome to the dry podcast. I'm your host, Peter Atia. This podcast, my website and my weekly newsletter, all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop.
And we've assembled a great team of analysts to make this happen. If you enjoyed this podcast, we created a membership program that brings you far more in-depth content. If you wanna take your knowledge of the space to the next level. At the end of this episode, I'll explain what those benefits are.
Or if you wanna learn more now, head over to pyratiamd.com forward slash subscribe. Now, without further delay, here's today's episode. I guess this week is Dr. Tommy Wood.
Tommy is an assistant professor of pediatrics and neuroscience at the University of Washington. Tommy's research interests include determining how multiple types of brain injuries can impact brain health across lifespan, as well as developing easily accessible methods with which to track health performance and longevity in both professional athletes and the general population. Additionally, Tommy has acted as a performance consultant for professional athletes in a dozen different sports and most recently worked with a number of formula one drivers through his work with Hinsa Performance, which is how Tommy and I met about five years ago. He also serves as an associate editor of the Wiley Journal, Lifestyle Medicine, is a founding trustee and director of the British Society for Lifestyle Medicine and works with a number of digital health companies for charities that focus on how lifestyle and the environment can affect long-term health and chronic disease.
In this episode, Tommy and I focus our conversation on the brain, although we do also pepper in a few conversations around F1, given Tommy's mutual interest with MIGHT. First, we speak about age and age-related cognitive decline. We talk about what cognition and cognitive decline is, including a discussion in depth around memory, reaction time, executive function, memory retrieval, and more. We speak about the root causes of age-related decline and look at cognitive demand, including how we should think about distractions and multitasking.
From there, we look at what skills are needed to avoid such a sharp age-related decline and the benefits of different types of brain stimulation. We then talk about different theories on the different types of pathology in dementia and neurodegeneration. Includedness, we speak about the lifestyle factors that can help prevent dementia and the importance of muscle. We also look at various supplements that can help with the prevention and survivability of dementia.
We end this discussion at talking about head injuries. We speak about what a concussion, metromatic brain injury are and what the various symptoms are. And ultimately, what are the things that someone can do to minimize the severity of these? So without further delay, please enjoy my conversation with Dr.
Tommy Wood. Hi. Hi. Hi.
Hey, Tommy, good to see you again. It's been, gosh, about six months since I last saw you at CODA, which of course we'll talk something about why you and I would run into each other at CODA, given our mutual interest in Formula One. But there might be some people listening to this who aren't familiar with you or your work, though it's certainly been referenced and you've been on a number of podcasts. So why don't you give us a little bit of your background and we'll kind of go from there.
Sure. I do have a varied experience and background, which I think is useful for the bunch of things that I do, but also sometimes slightly confusing, because people will know me from Wina Arena, but not know the work that I do elsewhere. I'm an assistant professor of pediatrics and neurosciences at University of Washington in Seattle. The majority of my work there is in basic animal, preclinical research in brain injury.
We look at ways to treat the injured. New born and pediatric brain, and we also do some work in traumatic brain injury. But before I got to that point, I trained as a medical doctor in the UK. I worked as a doctor in Central London for a couple of years for a day in my PhD in physiology and neuroscience.
So though I'm not a registered medical doctor currently, I'm active medical licensed. I do medical training and that sort of helps inform a lot of the work that I do. Alongside, that sort of formal training pathway. I spent a lot of time working with athletes.
I was an athlete myself. As a student, I spent some time coaching athletes, particularly rovers, and that was my main sport. And then later on during my PhD and I was doing my postdoctoral work, I worked with a company that worked with athletes, trying to improve performance or their overall health. And then longevity and sport, that was probably the main thing that we really saw a lot of people wanting to focus on.
So I have this kind of track-along side where I've worked with athletes in various ways. And then through that, got to working with Formula One drivers in particular through a company called Pinsernave had our good mutual friend Luke Bennett on the podcast before. So that's kind of where I do some some additional work is in athletic performance and health. And in addition to that, also have some interest in long-term, cognitive functions.
So we look at how the brain responds to injury. We look at how to repair that or mitigate injury processes. But what I'm really interested in is how all these things tie together. So how to aspects around lifestyle and the environment affect how your brain functions throughout your entire lifespan.
And so I work with some dementia charities in the UK, related to that. And I'm also a founding director of the British Society of Lifesal medicine. So particularly in how we can use lifestyle to improve population health. Thanks, Simon.
That makes a ton of sense, hopefully for people now to understand the very nature of your, both your skill set and your interest. So let's just start by diving into cognitive decline. And at the further you tell me how you want to do this, would you like to do this starting with a cognitive decline vis-a-vis dementia? Or do you prefer to talk about it through this sort of more ubiquitous age-related cognitive decline?
So we can start with age-related cognitive decline because that's pretty well described. So if you look across large population sets, you'll see that with increasing age, you see a pretty linear decrease in standardized cognitive function. And that's across all the different types of ways that you can measure cognitive function aspects of executive function, working memory. Except for one type of cognitive function, which is historical memory.
And that's probably because of the way that those memories are encoded. They're sort of moved from the main memory storing machinery to spread throughout the cortex. And they're sort of protected from some of the changes that happen as we get older. But in general, you just see the steady decrease in cognitive function as people get older.
If you then translate that to what might call some kind of pathological cognitive decline, which would then lead into frank dementia, which is a long-term loss of significant cognitive capacity or cognitive dysfunction, then you might see an accelerated trajectory. So there's some period of what we call mild cognitive impairment, which you can diagnose with some standardized cognitive tests. And then eventually that will continue into frank dementia, which there are many subtypes. But the one that probably people are most familiar with and are most concerned about for themselves is Alzheimer's disease or Alzheimer's dementia.
And there are probably multiple things that drive both of those parts. But in some individuals, this accelerator decline then ends up having the diagnosis of dementia. Tundra, let's go back to the beginning of that and just make sure that we've given people a real sense of what cognition actually is. One of the most common things I hear from my patients is some sort of complaint around memory.
Just yesterday I was talking to a patient. And he noted the fact that he had been recently remarried. He was very happy about that. But said, you know, one of the unintended consequences of getting remarried is he just inherited like 100 new people in his life.
Because all the folks who were his wife's side of the family and her friends and stuff are now kind of a part of his life. And he said, I can't remember their names. It's the ability with which I can meet a person, remember their name is decidedly different from when I was 20 years younger. So he's in his late 50s, contrasting this with being in his late 30s.
So obviously that's one component of cognition. By the way is hands down, the one I hear people most complain about. I don't hear many people complain about decreased executive function, decreased processing speed. I would suspect it's because maybe most people aren't pushing those to their limits.
And or we don't have as readily available tools to internally discern decreases in that. But can you just expand more broadly on overall this, both the depths of cognition and what it entails, but also this phenomenon that I'm sure the moment someone hears what you do for a living, they're probably right up to you at a party giving you the same complaints. Absolutely. And it's very difficult, actually.
So you can define these domains of cognitive function. You essentially already defined them as executive function, which is usually around complex decision making. But you might, for the average person, it might be, you know, that time when you think about saying something, then you realize it's a bad idea to say it. That's executive function.
That's your pre-frontal cortex is jumping in and saying, that's a really bad idea, even if it sort of flashes through your mind. But then you have various aspects of short term, and long term memory, processing speed, reaction time is probably important as well. However, when you talk to individuals about cognitive function, they have their own things that they want to be good at. So it's very personal from an individual.
Yes, because we can use a standardized battery of tests, and that's what's done, technically. But there's usually some aspect of function that they notice is declining over time or that they want to be better at. And then they can sort of put focus attention into improving that. And I believe that you can improve that pretty much any stage of life.
So that's part of it. And you mentioned memory, and of course, this is something that people will mention the most, and will notice it themselves. But there's actually two different parts to memory, and it's different probably in most people, even in the setting of sort of standard age-related cognitive decline and in those who have some kind of pathological cognitive decline. The first part of memory is encoding that memory in the first place.
The information comes in, and your brain signals through a stock coding and other. You're a transmitter to actually say, this is something that we want to recognize and store. And that's the process that seems to be particularly lost in those with pathological cognitive decline. That's why things like no-nest or eight inhibitors were and are still used in an outside disease because that helps the bolster some of those encoding processes but through a slow coding signal.
And this takes place predominantly in the hippocampus? Yes. That's where a lot of the process starts. But over time, you get the consolidation and these memories may get moved around.
Like particularly, like we talked about historical memory, they get shifted throughout the neocortex, which is basically the rest of the outside of the brain. The other aspect is retrieval. There's information in there and it's getting it out. And retrieval speed is something that seems to slow down with age.
But part of it, often we think of this as pathological, part of it may be that over time, just accumulate more information. And the more information that's in your hard drive, the harder it is or the longer it takes to bring out a certain piece of information. Yeah, this is sort of the argument that Arthur Brooks used that as we're aging, as you add memories, you're creating volumes in a library. And the more volumes in the library, the longer it takes the librarian to go and get the specific reference they're looking for.
How can we figure out the relative contribution of library size versus library and speed when it comes to accessing these memories? Because I guess this is another maybe way to think about that. But the example that resonates for me personally is I either meet somebody and can't remember their name but five minutes later I can. Or I have an idea, I want to say something about it and at the last minute I can't remember, but then 10 minutes later I can remember.
So it's not that it's not there, but boy it took me a long time to get it. So I think in reality it's probably very difficult to pass all of these out. And so I don't think we could pretend that we know exactly the relative contributions. However, some of this is certainly affected by other factors.
And that's something that you can take into discussion with the individual patients or individuals who are concerned about memory. So it seems like sleep impairment or some kind of sleep deprivation or suboptimal sleep impairs retrieval. So then that could maybe open up discussion about sleep. Subjective stress seems to also play a role here.
So I think some of it is accepting that your library is larger and some of it is thinking about other factors that may be impairing or allowing for that process to be suboptimal such that retrieval is harder. Another part that comes into play here, which is also important and it falls into that same line of thinking, is that as your library gets bigger, your librarian becomes more selective in terms of the things that they want to actually put on a bookshelf. So imagine as you've met hundreds of people in your life, thousands of people, you add a hundred new people, it's very easy to say, do you know what, the first time I meet this person, I may never see them again. So maybe it's not actually worth encoding that memory and you become more selective in what actually gets stored.
So that may be part of it as well. And these are not necessarily pathological processes. These may be your brain doing its normal job of how do I figure out what's worth storing and then how do I retrieve what I've decided to store? This may be a question that goes beyond your level of expertise, so I apologize if I'm asking you something outside of the scope.
But I guess what is a memory physically and why is there a finite amount of storage? So if I have an understanding of why a hard drive is finite and if I only have two terabytes on a hard drive and I keep adding video to that, eventually at some point there is no more storage capacity, I don't think I have enough of an understanding of what a memory is and why it would therefore have a physical constraint. So there have been, and I will absolutely agree with you, this is beyond my area of specific expertise. I know that this is a topic that is hotly debated where some people have said that comparing human memory to a hard drive is essentially, it's a complete fallacy, it's nothing like that.
We use it because it's something that we can understand, it helps us sort of apply a very complex process to our own thinking and understanding of how our brains might work. But in reality, that is not how memories work and there shouldn't be a limit on capacity in the same way that there is with a physical hard drive. However, you might still understand that there are probably still a finite number of things that your brain will choose to encode and store for the same reasons that you only want to have the information that's probably maximally useful for your survival for one of a better way to think about it. And then that puts some constraints on how the system sets up what it decides to store in the retreat.
My eight-year-old son last night was asking me these questions. It's amazing when kids ask questions, you can't understand, you can't come up with an answer to it. He was asking me where the memories were in his brain and how they get there. And I'm like, these are really good.
Like when I was eight, I wasn't thinking of great questions like this. So anyway, it's disappointing that I can't answer my child's questions. OK, so we've established that as time goes on, presumably two things are working against an aging individual. One of them, not pathological, one pathological.
So the non-pathological is you just have a greater reservoir of memories and your brain might be selectively choosing how to prioritize new encounters and new memories with some understanding that the denominator keeps growing and I have to be selective. But there's also, as you said, where I think as you're implying, there probably are some pathological changes. And whether we use the terminology or not is probably controversial. But there are some age-related changes that are occurring that are also, for lack of a better thinking in our analogy, slowing down our librarian, reducing our librarian's vision, some way that makes it actually more complicated for us to do these things.
What do we think is at the root of that age-related decline that is specific to be it retrieval, computational cycles, processing, and executive function, all of these things that we would all prize as important pieces of cognition? So the way that I think about it is that we know with aging, we tend to see a decrease in size or atrophy of the frontal and then the temporal, particularly the medial, temporal parts of the brain. And medial temporal lobe is where your hippocampus sits, as well as some parts of the cortex around it that support the parochorn hypocharys in the inter-renal region. And there are multiple schools of why those areas of the brain may be particularly vulnerable, some maybe because of their specific function in memory, or because they're deeply involved in the initiation and the continuation and structure of sleep, which is obviously very important for memory consolidation and also various processes of recovery and repair.
There's also, if you think about the whole number of things your brain is exposed to, those areas of the brain seem particularly susceptible to negative outside influences and then also susceptible to beneficial supportive processes like actually putting greater demand on those areas of the brain such that they respond and increase in their function. So when I think about the various buckets of things that are required for a healthy brain for one of the first phrase, they are around supply, vascular supply, supply of metabolic, energetic substrate, they're important things around structure and function. So this could be structure related to neuronal membranes, so the importance of, say, a DHA, a megaphasic acid, which are concentrated in synapses, they're important for communication between neurons. And then might congeal function as an important part of that.
And then you might think of actually placing a demand on those structures. So in most aspects of biology, the function of an organ is proportional to the demands based on it. So you increase capacity. But then that also requires some period of recovery.
And that's where sleep and other things come into play. Plus, you might want to avoid negative outside factors. So we think about dementia. We know that there's some risk associated with things like smoking, potentially air pollution, chronic inflammatory, or infectious conditions like peridons or diseases seem to be associated with it.
So you want to have this supply of substrate. You want to have good function. You want to make sure you allow that area to rest and recover. You want to avoid things that then may impact those processes.
And then what I think is driving a lot of this is the amount that we actually ask those regions of the brain to do, which does decline naturally over time, based on how we currently structure our lifespan. So with all the things you said there, I think the one that we're going to click on first, I guess, would be this idea of demand and what we ask of the system. So in certain areas, as you point out, it's pretty intuitive. You cannot maintain muscle mass without putting the muscles under significant demand.
That is so strenuous that you wouldn't be able to maintain it indefinitely, right? If I look at the workout I did this morning, I wouldn't be able to do that to my muscles or to my heart indefinitely. You can do it for a few hours. But as you point out that if nothing else through sleep, but even more than that, there were just days when you wouldn't push that hard.
In other words, you think of exercise as a hormetic stress. Now I haven't thought about it this way, but there are certain organs for which I would guess that that's not true. Does the liver need to be stressed? Do the hepatocytes need to feel the insult of ethanol to otherwise perform well?
I guess I haven't thought about it through the lens of kidneys and the liver and stuff. What do we know about other organs and their need to do? What say the heart does or skeletal muscle does? I've thought about the liver in particular, and I think you can say that the case holds, particularly with alcohol exposure, as the example, that's what you said, and that's what I think of as well.
Not that the liver doesn't function without alcohol exposure, but if it wants to optimally deal with a certain type of product to say ethanol, you want to metabolize it, then we know that with chronic alcohol exposure before, we get to the point where we damage the liver, you see an upregulation in size-frame P450-2E1, you see an upregulation in aldehyde, the hydrogenase, you see an upregulation of mitochondrial function and metabolism to regenerate NAD, which is the rate limiting step for alcohol detoxification. So yes, if you stress the liver with alcohol, it will upregulate its function in order to have a greater capacity when the next drinking session occurs. So I think there are sort of parallels across multiple organ systems. Yeah, and it just makes your listeners aren't hearing us and thinking, oh, he's telling us to drink more, to drink more now, I think what you're saying is, and we would all agree that the health benefits of alcohol are none, but you're saying, before you get to destroying your liver with alcohol, irreversibly vis-a-vis cirrhosis, if your goal is to be able to drink two drinks a day, you have to drink daily.
Like, you're gonna have a better job tolerating two drinks if you occasionally have a drink, as opposed to if you never have a drink. I mean, that's sort of what you're basically saying. Yeah, that's right. And so if you want an organ system to function in a specific way, so you want your brain to function, improve its function in a specific domain, or you want your body, or your skeletal muscle, or your vascular system to function better, in a specific domain, you wanna train from Earth at all, you want to be a capacity-powered actor.
You apply a relevant stressor, that's, like you said, it's all metric, and you give time to recover and adapt to it, and then you get an increased capacity later. And so I think that that's very relevant for the brain, but I might use exercise as a way for people to better understand it, because you can kind of see that happening. But then to kind of draw that analogy out, you might say, okay, there are other organ systems where there's evidence that that's the case as well. So let's go back to the brain and talk about what might be a difference between kind of a positive versus a negative demand.
So I'm sure most people listening to this podcast right now are under some cognitive demand. Not just sitting here idly shooting the breeze, we're talking about stuff that for most of us requires some thought, some concentration to pay attention to this. So is listening to this podcast for different people, producing different levels of cognitive demand, for example, depending on their level of familiarity with this subject? Yes, absolutely.
And again, I think that the idea of cognitive demand is relative to the individual, as well as what they want their brain to function best at. However, when we think about cognitive demand, I think there's multiple different ways that you can come at it. So when I think about generating skills, or maybe just brain development more broadly to start with, you might think about how does a toddler interact with their environment such that they're developing motor skills, language skills, social skills. And it's often this concerted effort for a short period of time where you are right at the limit of your current capacity, being able to stand, being able to walk, being able to climb a tree, being able to pronounce a certain word.
And then maybe you could put a time frame on it, maybe some of it may be something between 20 or 30 minutes, something like that, adults may be able to do this one more. Right, the edge of your skill set. And then probably there's some failure in there because the process of failure sort of up regulates the process of focusing attention as well, up to a point before we get frustrated. And then there's some rest and recovery your toddler is gonna sleep a bunch after they spend a lot of time exploring the environment, trying to improve their motor skills.
And I think that kind of provides an idea of the type of focused attention that you put into something that then drives past degree organization, which is what we care about. We want to try and drive an increase in functional capacity in some domain of cognitive function. And so it's probably going to be something that looks like that. And there are benefits to continually doing things at the level of your current capacity, right?
If you're an athlete, you're not always pushing the boundaries, you're not always doing a red line session that drives a bunch of adaptation. And I think the brain is similar. But that's very different from how most adults perform in their day to day work, where yes, it's very, it feels cognitively demanding, but you're multi-tasking task switching. So you're never providing focused attention on a specific subject.
And you're also not really providing that stimulus to increase skill in a specific area, necessarily. Even though you feel busy, even though something feels cognitive demanding, I don't think that those stimuli are the same in terms of what's driving a functional change in some area of the brain. Yeah, it's a very important point you raise. And of course, always begs the question that I have when people tell me, or when I feel this way myself, that I just can't remember things.
I'm just not as facile cognitively. And I always just wonder where distraction and lack of focus fits into the mix. So are there any kind of heuristics for what is too much task switching? What is too much distraction?
Because as you said, you feel very busy sometimes. And I actually went through a little bow to this yesterday. I was really trying to get a lot of things done. And then one more thing I put on my plate.
And I had this window of 10 minutes where I accomplished literally nothing by toggling back and forth between three different emails, text, WhatsApp, and a document I was trying to work on. And I just couldn't get anything done. To be that debilitated is pretty unusual for me. But in that 10 minutes, I accomplished exactly zero.
I would have been better off for 10 minutes, literally just walking around the house or walking around the block. So clearly, there was sort of a threshold there. But do you have any way to think about what that looks like and where you've crossed a line into being busy and unproductive rather than busy and productive or focused and productive? I would probably make the argument that humans in general cannot multitask in the way that you describe it.
And again, we can celebrate this out. There are probably two different types of multitasking. One is the automatic performance of learned subroutines that kind of just happen. And you can do multiple of them at the same time.
So say you're a dancer and you're running subroutines that steps you've learned interacting with a partner, listening to the music, you are technically multitasking. But those are all learned subroutines that are essentially happening automatically or subconsciously. What you're describing as multitasking is that process of focusing on one thing and another thing and another thing. And we know that there's a loss function in terms of the time it takes to get back onto a new task from the previous task.
And it's something in the order of, people have said 20-something seconds, right? For you to refocus onto something. So say you're switching your focus every minute or two. The amount of time you actually have to focus on one specific task is dramatically reduced because a significant portion of that is just spent with your brain, figuring out what it is you're asking it to do.
So in that setting, say you're doing things that allow you to enact learned subroutines in your work, you can probably do that continuously. And there's less of this sort of stressful demand on your attention. But if you're needing to directly focus on multiple things at the same time, then switching from one to the other, I would argue that the majority of people cannot do that well, even though they may think that they can. Yeah, one way that I think about this in terms of exercises, if I'm doing a steady state or aerobic efficiency, we've called a zone two workout on a stationary bike, I can listen to a podcast and an audio book and be completely focused on it.
I can still manage to be on a bike and pedal, not often we're about traffic or anything like that. And I can be focused. But if I'm doing a higher intensity cardio workout, or if I'm lifting weights, I can't listen to podcasts and books, those tasks just demand a little bit more of my attention, either to not get hurt or just to focus on the movement. In other words, they're not as presumably automatic as just holding 90 RPM at a fixed wattage riding around.
Would you say that that's kind of an example of something that's really automatic versus something that's just a high enough order processing where you can really only do that one thing? Yeah, I think that's a good way to think about it. And more broadly, I think that traditional work-based multitasking is probably the point where there's this biggest gap between perceived demand and the amount of beneficial cognitive stimulus you're actually getting. And it reminds me of something that former colleague of mine at Hinsa, James Hewitt, he also used to be a professional cyclist and he calls this the cognitive middle gear.
And it's this point where effort is high, but sort of the end product is minimally useful. If you can think about athletes who may go out and thrash themselves threshold for an hour and do that every day, it's very hard. It feels really hard. But in terms of physiological adaptations that improve performance, there's a big gap between how hard it is and benefit.
And I think this kind of multitasking is the same. Yeah, it's a physiologic no-man's land. Exactly, yeah. It's too hard to give them the wide aerobic base and not hard enough to give them that peak performance.
Well, this is actually kind of a nice quick way to segue and I want to come back to this, but just talk about Formula One for a second. So you and I have been fans of this sport for a very long time, but I think a lot of people listening to this have become fans of F1 through Netflix's drive to survive series. Of course, if you're listening to this and you don't know what drive to survive is, I recommend you go back and watch the last two seasons, at least. But I think anybody who's watched the sport will appreciate how much they need to be able to do while driving.
And on a personal level, this is something I can relate to because I spend a lot of time in a car and in a simulator and I am nowhere near being able to do what a driver does. So for folks to get a sense of this, first of all, they're traveling at speeds that are simply unbelievable, right? Their straight line speed is 200 to 220 miles an hour, depending on the setup they have for that race. And the amount of things that they have control over on this computer that masks arrayed as a steering wheel in front of them is unbelievable, right?
So between every corner, they're making some adjustment. They're switching the brake bias with one knob, which shifts the emphasis or force between how much brake is on the front wheels versus the rear. They're altering the slip angle of the differential, which is allowing inner wheels versus outer wheels when they're going around corners to move at different relative speeds. They're obviously adjusting drag reduction system when appropriate.
They're adjusting access to battery power if they're passing or overtaking or trying to defend. They're simply no shortage of things. And by the way, they're pushing a radio button to talk to the engineer who's talking to them the whole while. So I will just say, Tommy, I have been driving for nine years.
I can't come close to managing all of these variables in the simulator even, let alone. I mean, the most I can handle when I'm driving is driving and talking and maybe adjusting brake bias here and there, but I'm just so beyond my capacity to do anymore. So how do these guys do so much? And I think more importantly, for those of us who can't, what do we need to do to get better at that capacity?
Or is it just so sport specific? And because these guys have been driving carts since they were five, things that I have to think about while driving, they don't. Is that simply what it comes down to? I honestly think that's a lot of it.
Many of the things they're doing, like we talked about this idea of multitasking being running several learn subroutines at the same time, which the human brain is very good at. That's essentially what they're doing for a lot of those functions. And if you spend your entire life as a racing driver, which they have as a driving driver, then casting since they were young kids, these guys, then when the computer set up changes or there are new things on the car based on new regulations, they're just stripping off a top layer and adding on a new one. So what they have to learn is very minimal compared to everything else that's probably happening automatically.
So yes, I mean, there's a huge cognitive demand. And then probably a lot of what they're actually using their brain power for in the moment is reacting to others. Right? You can't learn that.
Yes, race craft. Yeah, exactly. And so that's where most of their attention is. And everything else is happening automatically.
Now, when you have drivers that move up the ranks, and there's a pretty big jump from F3 to F2 from a complexity of the car standpoint, and again, from F2 to F1, are there things that coaches will do with the drivers during those big transition years to really help them get up to speed? I'll give you an example. I don't think this is an example of what I'm accomplishing. But just people aren't probably very familiar with watching before races play sort of half physical, half cognitive games, where they have little lights on a board and they have to touch them or they're playing catch or juggling or doing all these sorts of things.
Are those things doing anything to sharpen their brain? Or do they just look cool? Probably a bit of both. But I would argue that for some drivers, it seems to be beneficial.
And it's very different from drivers to driver. However, there are definitely drivers who, when they move up the ranks or even those who've been in for a long time, they'll have a dummy steering wheel. So they can move through the patterns of doing everything, even if they're not on track. And this is often the same as when we were learning.
Subroutine, so you're learning a new dance. You'll do the steps one by one without music, then you'll start to string them together, then you'll add complexity. And it's the same thing. So there are multiple opportunities for them to practice some of these skills, even though they don't get a huge amount of time actually racing on the track.
When you're thinking about the sort of reaction games that some drivers are doing, and some of them may do it in terms of practicing starts, and again, they'll have sort of a dummy set up to do that, or balls and reacting to somebody throwing something. Something may be placebo, right? It helps them feel like they're getting ready, which is great. Anything you can do to improve that, you would welcome.
But then the other part of it may be moving you onto the appropriate part of the Yerkes-Dolls and Arousle curve, which basically says that there's this U-shape, or inverted U-shape curve of how aroused you are and how you perform. And that curve is different based on the sport. And so some period where you're having to focus and react, but also remain relatively relaxed, because that's incredibly important, right? You wanna be fast off the start line, but then the first thing you have to do is get into turn one and then you have eight guys around you trying to navigate the same thing and you have to react to them.
So if you were very tense, that would decrease your performance in that setting. So I think some of it is just getting you to the point where you're focused, but then also relaxed, if you're doing it with some kind of skill-based thing that requires you to also be relatively fluid, so it can be like catching a ball suddenly, right? You can't do that if you're very stiff and tense. So I think it's not about this balance of getting into the right mindset before you then you have to do something once you get into the car.
Now most of us, we're never gonna be professional drivers or athletes and certainly as we're aging, the need for really complex motor skills and cognitive skills may go down, but what is the equivalent that you think about for a person as they reach middle life and they're thinking about transitioning, you know, or what lies ahead of them as they transition into into older age? In other words, what is that apex set of skills that they need to be able to have, to give them the highest amount of physiologic headroom that's possible to avoid or minimize this age-related decline and more importantly, potentially even avoid the pathologic stuff that we haven't talked about yet, but we'll come to. I think a lot of it again is probably quite individual. If you want to be able to perform a specific task, you want to be able to drive cars for as long as you're able, right?
The next four or five decades. So then you would want to push your skills as far as you can in that arena while you're able. And then you have, like you said, maybe we'll talk about more about this idea of headroom. You cannot, at least not yet, we cannot completely stop the aging process, but you may be able to slow the decline and, or if you increase your level of capacity, it will take longer to get to a point where function is lost, that you can no longer engage in that activity.
When you're thinking about the brain, there's a whole bunch of things related to language skills. Obviously, memory is important, but how you interact with your environment, and I think social interaction is critically important and something that is probably under-discussed in relation to long-term cognitive functions as a critical aspect as well, particularly as people spend less time with others because of societal effects. But when you think broadly about how cognitive functions decline to age, it seems to mirror very closely the amount of demand that we put on our brains, and again, how society is constructed, because cognitive function essentially increases from birth to some peak in late teens or in your early 20s, which is the period of formal education. It is your job to learn.
It's your job to develop skills. That's when most sports are learned, that's when languages are learned, that's when skills are learned. And then after that, you essentially spend a bunch of time doing the same thing over and over, or you become hyper-specialized in one specific skill, and that's rewarded in a number of jobs, and so you're a surgeon, you want a lot of those processes to be automatic, you don't want to have to think about all of them continuously, so it's been a special thing to do a very good job. But there's much less room for that period of skill building or putting in effort into developing or providing those kinds of stimuli that then drive plastic reorganization and bring them an increased headroom.
So I think some of that natural decline with aging is a function of how we use our brains in general in society, and then there's a drop-off when we retire, and you can see that in various different types of datasets where those who retire earlier seem to experience cognitive decline sooner. And that's probably because the cognitive demand that we do get in our daily lives, the majority of that comes from work. So an important answer, I think, is, trying to maintain a basic set of cognitive functions is to actively work on ways to increase headroom, increase absolute capacity throughout the lifespan. Because at some point, capacity will decrease, but you want to push that out as far as you can, hopefully you'll die of something else before you lose the majority of cognitive processes.
Yeah, I mean, again, I think everybody's aware of the anecdote, right, where boy, Sally was just sharp at this attack, and then she retired, and all of a sudden it all went to hell and a handbasket, but you hear this so many times that you realize there must be something to this. It can't just be an observational phenomenon that's best explained by something else. There may be other contributors to it. Maybe people who are retiring younger also have more health challenges.
Maybe they're of lower socioeconomic status. I mean, you can come up with a lot of confounders that could explain this, but I suspect that there is also a signal there. There's some fire in the presence of that smoke that says, if you retire and in its place add nothing cognitively, you could expect to see a decline. I also can't help but wonder how much of this has to do with sense of purpose, which again, I think maybe falls outside of, we're getting really warm and fuzzy outside of the scientific discussion, but the question I always have is look, retirement should be thought of maybe as a financial decision, maybe retiring means I no longer need to work for money, but I'm gonna work on something else.
And if that's something else is not as cognitively demanding, right, let's say you go from being an accountant, where it's pretty cognitively demanding, you're in a spreadsheet all day, and you say, well, look, I'm 65, I'm done with that, and I don't need to work anymore. But now I'm gonna go and do something philanthropic where I'm gonna work for, I'm really interested in homelessness as an example. I'm gonna go and do X, Y and Z. You probably have more sense of purpose, you might derive more satisfaction from that, even though it's not as cognitively challenging.
We have any sense of how that factors into it or is that just so far outside of our ability to kind of understand risk. The majority of studies that have looked at this, I guess they fall into two camps, which partially answer your question, but don't necessarily answer it fully. The first is looking at the removal of that stimulus through retirement, that's been done in several population-based studies, they usually account for medical conditions that might cause you to retire, at least as an important confounder. And when you look at other studies, there's evidence that suggests that late in life cognitive activity, so whether you regularly play chess or you dance or you do something else that's cognitive stimulating, that's protective against incident adventure or cognitive decline.
So the two parts of that would say that removal of work as a major cognitive stimulus increases risk, but that adding some other kind of cognitive stimulus mitigates that risk. And there are several studies where you do some kind of cognitive training, maybe it's a computer-based brain training in older adults in their 70s, you can see significant improvements in cognitive function. And if you think about all the things that are most protective in terms of preventing cognitive decline, there was a big mess of that was done by Gintai Yu's Professor Shanghai, looking at all the different potentially modifiable factors for cognitive decline. The two most important protective ones were early in life education, which I think of as increasing headroom to the more you learn and skills you develop early in life and the longer you do that for, the greater headroom you have.
And then late in life cognitive activity, which then provides that protective factor. So I think there's enough evidence, as much as we can right now, and most of this is observation, although there are some intentional trials in older adults, you can say that if you're no longer working, if you replace it with cognitive stimulating activities, you're probably mitigating all of that risk, always most of it. And we've discussed this a little bit in the podcast in the past that not all cognitive tasks are created equal. So for example, my reading of literature, there wasn't any evidence that doing crossword puzzles is necessarily going to do anything for you, other than make you better at doing crossword puzzles.
But dancing, no, that's a bit different actually, because no two steps are ever exactly the same. You're always sort of problem solving, especially if it's sort of complicated dance. Solving a business problem is more elaborate than doing Suduko or whatever it's called, where it's just sort of little predictable word games. And so would you agree that maybe what you replace it with, there's also some variability in the complexity of that.
And the less color by numbers or paint by numbers it is, the more likely it is to, well, let's use that example, painting by numbers versus painting. You're both painting, but in one case, it's a much higher level of cognitive load. Yeah, and I think there are two streams of evidence that maybe support this. So one is around cognitive activities performed on computer.
So there are a number of different ways to do online brain training. There's a system called Brain HQ, which probably has the best evidence and support. It was actually developed by one of the researchers who sort of did a whole bunch of the primary basic research in terms of how we learned the first place, I'm back in the 90s. They have some nice data that shows that if you do these complex training games, which are often reacting to something or shifting focus, they require you to be very interactive, then you can see parallel improvements in things like verbal memory and executive functions.
So things that you actually care about in real life, you're not just getting better at the game, you're getting better at certain cognitive functions, which is what you really care about. And that program is called what? Brain HQ. And that's something that people would do online.
That's like a game you would play online. Yeah, it's a subscription service. I have no relationship with it. But in terms of online brain training systems, it's been used in a bunch of clinical studies.
It's probably the best evidence one in terms of creating translational improvements in function. And then related to that, there are also studies using video games where if you randomize people to play solitaire versus angry birds versus Mario 3D, the 3D game results in better improvements in working memory. And there is some responsive, inefficient version of executive function. So the more complex, the more interactive something is, seems to be the greater the improvement in cognitive function associated with it.
Then related to that is work in physical activity. So you mentioned dancing. There are studies that have compared dancing to circuit training that is as cardiovascularly challenging, but obviously without that element of social interaction, music, movement steps, reacting, and you see better improvements in the dancing group. And some people have termed this open skill versus closed skill physical activity.
So closed skill is unidirectional, doing the same thing again again. So by sitting on an exercise bike inside, you're not doing anything else at the same time. So maybe this is a podcast versus table test or badminton. So the physical nature of it, the cardiovascular stimulus is the same, but you're not reacting to the environment and other people.
And when you do those open skill type of physical activities, you seem to see some greater improvements in cognitive abilities. So there are those various things that say that the more domains or the more complex interaction associated with the activity, the greater the associated improvements. Yeah. The more variability there is, right?
It's to be able to walk outside on an uneven surface where the slope is constantly changing and you kind of have to be able to physically and cognitively be aware of what's beneath your feet. It's going to be a lot better for you than walking on a treadmill or even walking around a track in circles. So let's talk a little bit now about the pathology side of this thing. So again, I think listeners to this podcast have a decent understanding about Alzheimer's season all-time or season all-time we've certainly had a number of podcasts on the topic.
But maybe let's just kind of refresh people's memories on the difference between Alzheimer's disease specifically and perhaps other kinds of dementia, such as vascular dementia, frontal temporal dementia, luobody dementia for that matter. And maybe even forms a dementia that don't necessarily fit neatly into these boxes. Like I said, those are probably the four main types of dementia, although there are other ones that then are associated with maybe other neurodegenerative conditions, or the types of dementia associated with Parkinson's disease or ALS. They can be sort of complex and multi-domain.
You might see changes in different areas of the brain. The main thing that ties together outside of this disease, and this is something that's worth getting into because I think both the genesis of the eponym as well as how we now use it, is very interesting. But the thing that kind of ties together forms about Alzheimer's disease, and there were two as we think about them early on-set Alzheimer's disease and late on-set Alzheimer's disease. But what really ties them together is the neuropathology, which is if you slice somebody's brain open, particularly, again, within the medial temporal lobe, that's where the primary atrophy and pathology seems to exist, although it can be throughout the brain, is amyloid plaques and tau-tangles, hyperphosphorulated tau within the neurons.
And this was how the disease was originally classified. There was an initial case, August D, who, Alzheimer, treated in an asylum for several years, and then looked at her brain after she died, and he saw these things under a microscope, then collected other cases where they saw similar things. And this was done right at the beginning of biological psychiatry, where trying to find biology that explained psychiatric symptoms. And one of the things you could do at the beginning of the 20th century was look at things under a microscope, after that person had died, and that's how they classified it.
However, whenever you want to, we can get into how, actually, these pathological hallmarks correlate very poorly with somebody's symptom burden and disease progression. And the reasons why they accumulate may be very different from person to person, and may matter much less from one person. So the next, however, is these pathological hallmarks that created the classification of what we call Alzheimer's disease? That's why I wrote about this story in my chapter on Alzheimer's disease, and pointed out that many years later, they exhumed, I guess, part of her brain.
And lo and behold, she actually didn't have the sort of typical Alzheimer's disease that we see today, which is the disease that 99% of people with Alzheimer's disease had a very small subset. She was in that subset, get a variant of the disease that is genetically predetermined. And I can't remember which one she had. I think she had PSCN1, or did she have APP?
It was PSCN1, but that's actually quite hotly disputed. There's a paper in Lancet, neurology 2013, where they sequenced their brain, and they supposedly found the mutation, but then another group got another sample of their brain and couldn't find any mutations associated with familial early-on-site Alzheimer's disease. Though, if you did have early-on-set, a monogenic orthonormontal mutation, some people have looked into her family history afterwards, and her children didn't seem to get it. So even if she had a spontaneous mutation, it didn't seem to be passed on.
So there are a lot of people who think that actually there's no evidence that she had a mutation. That may be the first correction I need to make in the second edition of my book, because I noted that she in fact did have it in her PSCN1, and as a result, it may be a different disease entirely. It may be that PSCN1 mutation, PSCN2, APP mutations, which are all these, essentially, autosomal dominant deterministic mutations that result in people getting this disease and getting it very early. I mean, this is not uncommon for someone to be stricken in their 40s and certainly be dead before they're 60.
What is the alternative explanation? If in fact she did not have any of those mutations, what is the best case explanation for her disease, its severity, and the histologic findings? By some telling of the story, after examining her brain, Alzheimer's encouraged supposedly by his mentor, Emil Kraplin, to gather together cases to build this idea of this common pathology process. And again, you're recounting history, so it depends on who's telling it.
But some people say that actually Alzheimer was quite reluctant to try and group these people together, because they were so different. And I know you've mentioned that famous line, which is that once you've seen one case of Alzheimer's, you've seen one case of Alzheimer's, right? Yes, they're also very different. And apparently this is something that Alzheimer's felt as well, he wasn't sure that they should be grouped together.
In the version of the story where she doesn't have an orthonormutation in PSM1, it's that she did have some kind of decrease in her cognitive faculties. There are a whole bunch of environmental factors that could play into that, and you can certainly talk about that. But it led her husband to then put her into an asylum. And we know that one of the fastest ways to trigger cognitive impairment or cognitive decline is to basically remove somebody from their environment and completely remove all stimulus and interaction and all the things that ground them in who they are.
So that version of the story says that because of the asylum that she was put in and the way that she was completely disconnected from her normal environment, that then triggered an acceleration in her cognitive decline, which then maybe a sort of maximized version of what we might see in individuals nowadays to experience cognitive impairment and dementia. Do we know her APO E4 status when they were looking for PSEN1? Did they check APO E? That's a good question, but I don't know if they check that or if they haven't seen it.
Let's sort of talk about the current state of affairs with Alzheimer's disease. And let's go back to a point you made earlier. Do you know what the discordance is between the presence of amyloid beta on a histologic sample, obviously taken postmortem, and the presence of and or even severity of dementia related symptoms in that person while they were alive. And the contrapositive of that, which is to say, the severity of symptoms in a person while they were alive and the absence of amyloid beta on a pathologic specimen after they've died.
Because in an ideal world, it would be a one to one mapping that is 100% concordant. Anyone who has symptoms will have amyloid beta on autopsy and nobody who doesn't have symptoms will, and anybody who doesn't have symptoms never has it and nobody who doesn't have symptoms will have amyloid. It's a perfect one to one mapping. Well, it's clearly not that.
So how messy is it? It would be nice if we could put an R squared or an R value on this to see how tightly correlated we are. I think I have to reach deep into the depths of my memory. And if people have tried to do that kind of correlation, the R is somewhere around 0.1 or something.
Which just means for people it's virtually uncorrelated. Yeah, there's a couple of percentage points, maybe, in the variability and cognitive functions is explained by the variability in all the amount of amyloid that you have. And that's very clearly described in animal models as well as in humans. And we also, there are several studies where they've made some very good drugs that can decrease plaque burden in the brain, but that doesn't seem to then correlate with laser cognitive functions and may have a high risk of side effects, although that's a whole other story that we won't be getting to today.
So pretty much anybody who dies with dementia or experiences to mention will have some burn of amyloid plaque and towels. I don't think I know of a case where somebody had that without any, but we also know that these things naturally accumulate over time. And you can have people, there are multiple cases where they've looked at the pathology where you have significant burn of these neuropathological hallmarks with no decrease in cognitive function or beyond what might be expected given that person's age. And so there's a possibility that there's some other factor of people are now thinking about other things that may come into play here.
So microglial function phenotype. So microglial, the main immune cells in the brain needs are now being increasingly interrogated in Alzheimer's disease dementia. Other processes might be important. So lysosomal function is potentially important as well, which is basically processes proteins for breakdown and that gets impaired and that makes sure that some of the accumulation of some of these things.
But the alternative is to maybe think that some of these hallmarks may be epiphenomenal. They just accumulate in the face of neuronal stresses. Speaking about this largely or pretty much only in the case of late on-sourinesis disease. Your brain is going to get exposed to a bunch of things, be that decreasing metabolic function, be that smoking vascular disease.
And then as neurons get stressed, they start to secrete some of these proteins or accumulate some of them. And there are some lines of evidence that suggest that some of it's actually a beneficial response. So animaloid beta has some antimicrobial and metal collating effects. So it may be this actually response to a stress that's then supposed to be protective.
You get to a point, and they've shown this very clearly in animal models, where if you can force animaloid parks to accumulate in large numbers, where they do start to become damaging in their own right. But up to that point, it may be more of an epiphenomenom or a response to neuronal stress rather than this core sort of underlying pathological process. Yeah, there's so much there to think about. So on the one hand, you could say, well, look, is amyloid beta necessary but not sufficient for amyloid plaque?
So the classic example that would be ApoB. ApoB is necessary, but not sufficient for atherosclerosis. You have to have it, but by itself, it's not enough. You also have to have inflammation and ethereal damage or dysfunction for the ApoB particle to get in there and cause damage.
But ApoB is causally related, and that's why reducing ApoB reduces events. It's necessary, but not sufficient. If that were true of amyloid, could it explain part of the observation that lots of people have amyloid without symptoms, because it's only necessary, but by itself, it's not sufficient. It's not that wouldn't necessarily imply causality, because it would, to have causality, you would have to say, removing amyloid, because it is necessary, though not sufficient, removes the disease.
And as of yet, to your point, we don't really have evidence of amyloid reducing strategies working. Now, the flip side to that, which I know people will argue, is it might be because those, and I don't know where I stand on this, I'm very confused by this. It might be that, well, we're applying those therapies too late. And if you applied amyloid reducing therapies earlier, if we knew how to target people long before they were at the doorstop of MCI, maybe we could do something about it.
In this sense, it's sort of like saying, well, lowering APOB a week or a month or even a year before someone has an MI probably isn't going to help, but doing so 10 years before will. So how do you think about the causality and the necessary but not sufficient argument, and also this temporal argument of if, in fact, APOB is playing a role, we may be way outside of our window to do anything about it. I'm open to that idea still, though I am skeptical, based on the range of animal and human evidence so far. It's possible that amyloid is necessary, but if it is necessary, we don't know what evidence that it is sufficient to cause to mending processes.
There's been some recent work in this area that I feel supports the idea that maybe it may not even be necessary or sufficient, which is this process called pantheos, pathological andthos, which is pathological flower, as was published by Ralph Nixon's group out of NYU last year. And what they showed was that in a specific knockout model in mice, when we traditionally think about amyloid plaque accumulating, we think about it accumulating outside the neuron. And it's sort of like this whole bunch of protein that's kind of just sticking together. And eventually that is injuring the neurons around it, which is being secreted, is accumulating, aggregating, and then it's causing damage that way.
What they show with some really nice techniques is that what's actually happening, at least in this model, is that amyloid is accumulating inside the neuron. It is aggregation inside failing lysosomes, which are supposed to process proteins. And they aggregate within the neuron, which then lyses. The cell dies, it disappears, and you leave a plaque in its place.
It's sort of like burst the neuron open. And so in that setting, there's a nice quote by Nixon that says that if you're trying to remove amyloid, it's the same thing to try and treat Alzheimer's disease. It's the same thing as trying to revive somebody from the dead by removing their tombstone. That's essentially what is the plaque is the tombstone of a previous neuron that failed its ability to process protein and then left this in its place.
There's still a lot of work to be done to say is this was actually happening in humans, which haven't been sort of genetically manipulated as we do with a lot of mouse moles. But that's a very stark concept, right? That's a very stark concept because it implies that amyloid is an absolute marker for something horrible, just as walking through a town and seeing lots of tombstones tells you if they occurred over a short enough period of time, something bad happened in this town. But removing the tombstones does nothing to erase what just happened in that town.
What is the critical response to their model? So the people that would be on the amyloid is at a minimum necessary, maybe even sufficient, how would they be critical of Nixon's work? So I think you could say that, even if that's the case, even if this is not, if this is interesting, there accumulation, all you've done is you move the site of initial accumulation. If it does hold in humans, and then maybe that would be the first major question that shows that this happens in humans.
And I think that they're working on some pathological samples to see, but this is the case. You could say, well, okay, first show this is how it works in humans. And then you could say, well, even if that's the case, all you've done is you've moved the amyloid from outside the cell to inside the cell, where it first is humanly. So it doesn't then stop it causing damage being a primary cause factor, because once that first and you're on itself and then the structures around it could still be damaged.
Or because then you might get, micro-vacivation, right, you get this new response, right, back and then trigger some of the necessary processes. So I think there's still possibility that even if that's the process as it happens, you could still say, oh well, everything else is still the same. So let's talk about some of the other ideas, Tony, and we can talk about some of them broadly. But I'd like to also hear if you were all sign-res are for a day and it was your job to allocate funding for both prevention and treatment.
If you were gonna allocate those types of dollars, presumably you'd wanna have a strong sense of where to put those resources. But what are some of the other theories, right? Sort of vascular, metabolic, obviously there's a genetic component. So just tell me where you think it sort of shakes down and then we can go from there as to what the implication is from where maybe we ought to be spending our resources.
We've gotten this far, I've talked a lot about that, sometimes it's important for me to mention that a lot of the work and thought I've done in the Serena is not on my own. I primarily have worked a lot with Dr. Josh Tuchner, who is a neurologist, which I'm not. And obviously has a lot of front facing experience in this.
And so a lot of these ideas as they come together, we've wrote a paper about the demand model, that's where some of this discussion comes from. But it's very much a collaboration with PM and others. So I won't pretend that I suddenly figured anything out by myself because I certainly didn't. Nor can I say that I figured it out or else I'd be getting an invite from the King of Sweden sometimes going, let's go and meet him.
But when we look at late onset Alzheimer's disease, I think we've gotten to the point where there's such a broad number of environmental and lifestyle-based risk factors that seem to be critically important. That's really where I would focus my efforts. And you can definitely say that, even if the brain is responding to neurological stresses or the absence of expected inputs with the accumulation of certain pathological hallmarks, there's still some upstream process that's driving that. And that's where I would want to focus.
And I think our best evidence so far is in factors around diet, lifestyle and peripheral cardiovascular health being an important one. There was a Lancet Commission report in 2020 that looked at dementia broadly and tried to estimate what amount of dementia, what proportion of dementia would be preventable. And they estimated that 40% of dementia is preventable based on population of trippable risk and a bunch of different risk factors, looking at physical activity, body concentration, diet quality, smoking, hearing loss, which I think of as a cognitive demand, which has lost educational status. And my guess is that this is actually an underestimate because they didn't include sleep.
They didn't include nutrient status, particularly homocysteine status, which other individuals have suggested has a population of trippable risk of around 20% for late onset Alzheimer's disease. And then they also, when you do these kind of assessments, and you've written about this recently, you do a population of trippable risk or population of trippable fraction, you say, if we remove this entirely, what proportion of that disease would disappear. And we have a mounting body of evidence that says that these risk factors interact. So when you do a population of trippable risk, you say, this is a linear effect, it's additive.
Based on top of this, but in reality, we know that they're actually, they're actually interested. Now, they're creative. Yeah. So I think if you're talking to account other risk factors and more complex interactions between them, my guess is that the majority is probably preventable by focusing on some of those lifestyle environmental factors.
Can you say more about the homocysteine one? We definitely manage homocysteine very aggressively. So we're very liberal with our use of methylated B vitamins to keep homocysteine down. We typically target eight or nine as the upper limit.
We want to see, even though the lab reference range says up to 13 or 14 is normal. Do you have thoughts on that? And I guess also tell me about the mechanisms. Our concern is mostly through cardiovascular, by the way, because I think there we have pretty good evidence that homocysteine impairs the clearance of two molecules, SDMA and ADMA, that impaired nitric oxide synthase, which obviously has an important role in the cardiovascular endothelial world.
Perhaps it doesn't, the brain is well, I'm just unaware. So a lot of the work in this arena, I think we have to be indebted to somebody called David Smith, Professor David Smith, who's a former chair and head of the Department of Pharmacology at the University of Oxford, who's done a huge amount of work on homocysteine and cognitive decline. And actually this dementia charity in the UK that I'm on the advisory board of, he is the chair of their scientific advisory board. He has done a number of interventional studies, looking at this, the main one is the visor cog study, where they randomized individuals with elevated homocysteine to a B vitamins supplement, it was a B12 and further catted.
And then looked at rate of cognitive decline and rate of brain atrophy. And they showed that if you could reduce homocysteine and the greatest risk is with those with a homocysteine of 13, there's also an elevated risk in those with a homocysteine of about 11. So the cut off that I use for cognitive decline that's based on hard evidence in the political literature is 11. And you can slow cognitive decline and brain atrophy if you decrease homocysteine beyond that point.
There's a number of potential reasons for this. The first is there may be a direct mechanistic effect related to the neuropathological hallmarks. So homocysteine seems to activate CDK5, which phosphorylates tau, and then also inhibit phosphatase 2A, which dephosphorylates tau. So it may contribute to the accumulation of tau of tau-tangles, high-phorylated tau in neurons.
But then sort of more broadly in where, I think the majority of the action is, and sort of excluding cardiovascular, is the importance of the methylation cycle in creating functional neuronal membranes. And the reason why I think this is because of evidence of how homocysteine level or B-vitamin supplementation interacts with omega-3 status. We know that if you want to try and put, particularly, a molecule of DHA into a lipid membrane, you need to attach it or you need to create a phospholibid. And that process of creating phosphodilicoline, say, which then attaches to your DHA so it can sit in your membrane, it's very lethal intensive, right?
So it requires, there are several methylation steps that require that to happen. When you look at, there are actually sub-analyses of several randomisochemical trials that show, so in the Vicercoc study, what they showed was that the rate of brain atrophy was only slowed in those who had in the highest turtial of omega-3 status. There was a study in the Netherlands, the bee-proof study, where they also showed that the benefit was greatest in those who had the highest levels of DHA. And then there's also the omega-AD study, where they supplemented with EPA and DHA, but then they saw benefit in those where the lowest levels of homocysteine.
So there seems to be an interaction between B-vitamin status and omega-3 status in terms of cognitive decline and brain atrophy. And the best way to think about that is, is probably both are required in order for DHA to be inserted in a functional way into your own membrane. Let's pause there for one second, Tommy, because I just wanna make sure people understand what it is you're saying here, which is, if you lower your homocysteine from 13 or 14 to nine or 10, all the while, maybe taking some DHA, and we haven't talked about doses, but what do we be thinking, one to two grams of DHA? One to two grams a day, yeah.
Doing those two things together, which don't require any medical care. I mean, I've never seen a person who, with the right amount of methyl phylate, methyl B12, sometimes some B6 is needed. You can pretty much always get your homocysteine into that zone, coupled with a high quality DHA, no affiliation with any of these companies, but I like Carlsen's and Nordic Naturals as the two. What would you say is the risk reduction?
Would you say that that's a 20% risk reduction in all-cause dementia, just doing something like that? That's what others have suggested. They've calculated population of risks, and it's actually, it's more than that. Yeah, that was just the homocysteine.
That was just the homocysteine. Another 20% has been attributed to four omega-3 status. So this is kind of frustrating, because I know that there are literally hundreds of thousands of people listening to SB right now, whose homocysteine is elevated, whose DHA is low, DHA is low, and they are unaware, and their doctors are unaware of everything you just said. And there's no drug, including a $30,000 a month drug, that is going to come close to that level of prevention.
So why do you think there is such a disconnect in how we think about prevention? And we haven't even talked about the obvious stuff. Like I'm just gonna leave the obvious FSI. You should sleep.
Sleep is important, exercise is important. Not having type 2 diabetes is important. Controlling blood pressure is important, not smoking is important. I'm gonna take this off the table.
They're enormously important, but they're so obvious we're not gonna talk about them. But the homocysteine thing is not that obvious. And yet, a 20% risk reduction when you're starting with an absolute risk that's as high as AD is, that's like having a winning lottery ticket in your pocket and just not knowing it. I can't explain why this is not better understood.
When I've talked to physicians about this, when I've had old age psychiatrists, who are like, I'm immediately gonna start measuring homocysteine and supplementing beatings, plus the minus omega-3s. And I know David Smith a little, particularly from the work sort of through this charity. And I think he's gone to the point where he's incredibly frustrated. I don't wanna speak for him.
But it's basically this pretty significant body of randomized clinical trials showing these improved outcomes has not been incorporated into, Frenching guidelines has not been incorporated into things like the Lancet Commission report, which looked at population and triple risk. But based on the information we have, and this is cheap, it's easy to measure, I'm just thinking it's easy to measure on a mega-3 index if you need to assess the DHA intake in your diet. I think there's, I can't say to certain, I think there's massive potential benefit. Even if it's not 40% with the combination, right?
Huge potential benefit here. Again, with high quality and then it's full to. I think there's just a bias in the medical community against non-pharmacologic interventions. And I mean, look, there are few people that are gonna stand here and be more critical of the supplement industry than I am.
I really think it is a filthy industry, especially in the United States. I think it's disgusting everywhere, but in this country it's especially disgusting. And the total lack of regulation, the complete predatory nature of it, and the total lack of quality control means that on average it's filthy. However, that doesn't mean every supplement is a bad idea.
And I probably take a dozen supplements a day, at least nine or 10 if I were to release it there and tally them up, including obviously, methyl phthalate, methyl B12, B6, EPA, and DHA. So right off the bat, there's five. So probably take another five. But I can't help but think that there's a systemic bias in the medical community against supplements.
And some of that I think is probably well-founded because I know how frustrated if I'm just going to be completely honest, I get when patients show up in the practice and they have a list of 40 supplements. And I can tell just looking at them because I've done this exercise a thousand times, that 37 of them are garbage. But three of them are worth it. And I don't know what the answer is.
I don't know what it takes to bridge that gap, but I guess this is just an example of where you might just have to bypass your doctor and sort of say, look, I need to know what my home assisting level is, I need to know what my EPA DHA levels are. And I can fix this on my own. And by the way, since I'm in the process of telling people what supplements I like, especially given that I have no affiliation, I'm very happy to do this. So I prefer the Jarrow supplement for methyl phthalate and methyl B12.
I just find Jarrow to be a very high quality supplement in general. I'm sure there are many others out there. I also like the pure encapsulations, B6. So those are kind of the variants I'm using.
Do you have any supplements that you've tested or found to be particularly trustworthy as far as manufacturers go? For a lot of the supplements that I take, I like for one, just because I know they have a high, a very stringent regulatory process and there's multiple points in the process where they test for impurities or contaminants. They also have a subset. So if I'm working with a tested athlete, if you recommend a supplement, it has to be an example for sports certified or similar.
So you know there's no band products in there and they have a line like that. Pure encapsulations, I think, is good. Mementis do some good supplements. I think part of the problem here is that, it depends on the medical system that you're working in, right?
If you're in the UK, you're in the National Healthcare system, if you're in the US, obviously, could be several different types of systems. You need to be able to prescribe it. So that needs to be built into a system. So in the UK, you can prescribe things like this indeed.
In the UK, you need to have a physician prescribe those supplements to you? No, but if you're a doctor and you want your patient to take it, then it's very hard. There's a big gray area where you then start recommending your patient go to the pharmacy to buy a supplement. I think part of it is this gray area, whereas you're protected if it's in some respects, if it's this indication that the National Institutes of Clinical Excellence nice have said, this indication, you can prescribe it or it's available, right?
There's kind of guidelines around it. And so I think that's missing, that's part of it. But even other physicians, so I work with a bunch of physicians who are interested in lifestyle medicine. In lifestyle medicine, I don't want to tell multiple people with the same, every with the same brush, but they're very against supplements.
They're like, lifestyle medicine doesn't include supplements. We don't do that. And anybody who does recommend supplements is sort of not allowed in the club, which is hugely problematic because, again, you have good evidence to say that there's benefit there. So some of it may be regulatory or the system and how you can get your patient these things, or whether you'll get in trouble if you start getting home assisting tests on everybody, which they can be tricky to do right there.
They can process quickly. It's a slightly more expensive blood test compared to some other blood tests. And then there's also the, like you said, I think there's some bias in there in terms of what people think supplements are allowed or not. It's really frustrating.
All right, let's move on from the topic that is disappointing to me, which is, one, having a winning lottery ticket in your pocket and not playing it. And two, being such a Puritan in one's view that you wouldn't think everything is on the table, right? I mean, my view is like Alzheimer's disease and dementia in general, very, very complicated, formidable opponent. Ideally, have as many things as possible in your quiver.
You should have a jab. You should have a right cross. You should have a left hook. You should have a net workout.
You should have all of the above to somehow suggest we only want lifestyle or we only want supplements. We only want drugs. I've never understood that rationale. But you're right.
It permeates into cardiovascular medicine, permeates into cancer, permeates into everything. And it's just created a bunch of silos of people who each have probably some truth and some expertise that are equally limited by their blind spots. So let's go back to pathology again just really quickly. What is sort of your unifying theory on these things?
So whether it is the homocysteine, the limitation of omega-3 marine-based fatty acids, we didn't even get into glucose hypometabolism, but it's something we've discussed a lot in the podcast. I think people are very familiar with hypometabolism, whether we talk about low-grade ischemia and microvascular disease, do you think it's all working its way through a final common pathway of neuronal damage, which leaves the tombstone in its wake? And that's the only thing that's basically common to them is that they leave the same tombstone. Yes.
That essentially summarizes my current thought process. And so again, working with others, I think including David Smith, Josh Turkner, I didn't tell you, I mentioned earlier, he did a big mess analysis on what viable factors were factors for cognitive decline. And trying to build this systems approach to cognitive decline or late onset Alzheimer's disease. And so then my current thought process is that all of these things are necessary, healthy vascular supply, some kind of metabolic substrate that is taken up and available to neurons in the brain, that you have the nutrients required to build quality structure, that you have the absence of things that may impair some repair process.
You mentioned a bunch of them, which are a clear risk factor like smoking. And then to tie everything together, you require demand on the system that drives and creates a stimulus for adaptation. Those things are required in order to respond to that stimulus, and then you have a period of recovery and adaptation that allows for consolidation and plasticity. And any individual may have an issue in one or more of those areas, but then what ties them together is the tombstone that they leave in their wake.
But the exact way that looks, the exact number of tombstones, say, or how those tombstones look, what else is going on, is probably an expression of things like genetics and other factors, which they explain some of their variability. But that's kind of, yes, it's maybe the final, common pathway, but everything that's important is happening upstream with that. Before we leave dementia, I'd like to talk a little bit about one of the strongest associations I've ever seen with mitigating risk, which is strength. So this is often demonstrated with simple, measurable things like grip strength.
But I don't think it's the strength of your grip and the ability to open a jar is particularly important. It's just that very high levels of grip strength, very low levels of grip strength, variability here is a great proxy for overall strength. People with a very strong grip, they're able to carry really heavy things and that requires strength all the way up and down their chain. Why do you think strength has such an important bearing on both the avoidance of dementia, so from an incidence standpoint, and also survivability?
So just to give people some numbers, when you compare the top 10% or so of people from a strength perspective to the bottom 10%, it's about a 70, 70% reduction in both incidence and mortality associated with all-cause dementia. When you start to think of things that we have some control over, this also rises to the top of the list. I'm not suggesting that someone at the bottom can be at the top within a year. But if you think about this over the course of your life, this is something we can all aspire to.
What do you think from a physiologic standpoint explains such a stark relationship? So my experience of talking about muscle mass and muscle strength with hard outcomes, say dementia or all-cause mortality, usually the response is, all right, calm down, bro. Clearly you like to lift weights and therefore you think that that's the answer to everything. And people who are healthier are stronger and that's just the confounding factor.
But I think we have good evidence that that's not the case. The main one being that you can take individuals in their 70s, you can put them on a very basic resistance training program, and you can see improvements both in white mass productivity, you can do them or ICANN, or you can test them on various test-apocalyptic function and you see improvements as a result of this training program. So then if you wanna think about potential reasons why, the simplest is that some kind of novel movement is a direct neuromuscular stimulus. You are stimulating the brain to create new connections, driving plasticity because the recruiting of most fibers that that motor skill is in itself a stimulus, a cognitive stimulus.
But then we also know that the muscle that you have and the amount that you move it, it's an important glucose sync. So if you think about blood sugar regulation, and we know that pre-lapse and type two diabetes, like you said, are significant risk factors for cognitive decline in dementia. So it may be increasing glucose flux that helps regulate blood sugar. We also, if you're moving your muscles, there's this still exploding area looking at myokines.
So things released by the Tissue that may support brain function, by Gf1, veg, BDNA, brain deriving, or a terrific factor that may support neuronal function, sort of survival factors to keep neurons around. We know that exercise is also through a hometic process and inflammatory, so chronic inflammatory conditions we kind of mentioned earlier, but can be associated with increased risk of dementia and you're decreasing systemic inflammation through physical activity. So that kind of group of things, I think all of those are playing a role. I don't know exactly which is most important, if any.
Frankly, I'm not sure I really care that much because I know that it's a very important invention. So again, it's documented that you can actually work and you can implement it pretty much at any stage. So one of these is why it's so beneficial is because it has these multiple pleidropic effects and they're probably at least additive if not synergistic. As well as, yes, there will be a certain amount which says that the healthy you are, the stronger you are.
So there's a little bit of that. But then there's a whole bunch of things on top of that. When I met with similar resistance, no pun intended to the idea of the importance of strength in muscle mass, I usually respond with something which is look, even if strength training, meaning have a high degree of strength in muscle mass and cardiovascular refactories, even if all of those things didn't add a single day to your life, in fact, even if they shortened your life by six months, they would still more than be worth it in terms of the quality of your life, especially in that final decade, which is something that most people, unfortunately, don't want to pay attention to until they're in that marginal decade, as I call it. And you realize that at that point, having poor movement, being in pain, having low strength, limits your capacity for doing just about everything that people would find pleasuring, whether it be playing with their kids, or simply going for a walk, or carrying out any basic activity of daily living at the extreme level.
So it's a fitting way to end our discussion on this before we transition. So the only thing I'm gonna talk about, Tommy, is another area where you have a great amount of expertise and that is around head injury. About 10 years ago, I had a friend that suffered very significant head injury, riding a bike down the street and a jogger bolted out between some parked cars, didn't notice him riding, and they hit head to head. The jogger got the worst of it because he was wearing a helmet, but nevertheless, they were both devastated by this.
He was going about 40 kilometers an hour. She sustained multiple fractures to her head. But he sustained a concussion that was so bad that basically he wasn't himself for about two years. He's more or less himself now.
Can you explain what a concussion is? Even this, the idea of what concussion is, is quite hotly debated. But in general, you would classify a concussion as a mild traumatic brain injury, with more severe traumatic brain injury, you might think of complete open skull fractures and direct penetrating to trauma to the brain, things like that. So this is the skull remains intact, but there has been some transmission of force or a blast wave, say if it's a blast injury, that's been transferred to the brain.
Then at some level, in order to have symptoms of a concussion, you have some kind of disturbance of neuronal function, and that can either be because of abrupt loss. So there are some significant head impacts. In particular, where you can get shearing of axons, direct axon injury of neurons, and then that cell is essentially lost as you sort of ripped it apart. But even more milder impacts may cause disturbances that include a neuron firing when it shouldn't.
This can then sort of create this pattern of activation, again, that's not expected, or in an area of the brain where it wouldn't normally occur, in a way that it wouldn't normally occur. And then this can then cause these downstream processes within cells that can cause a much more severe damage, swelling, you then might see the accumulation of certain pathological proteins. So tau is just like you see. And sometimes dementia is also a response to direct neuronal injury in a concussion.
I work with a neurosurgeon whose definition of concussion is any impact or force to the brain that causes the disturbance of function of one neuron. Unfortunately, that's not something that we can measure, because you probably need multiple or large sections of the brain to have aberrant function for you to be able to actually measure it or detect it. But those are the various processes that are going on when you get ahead of it. So it could be as quote unquote mild as just a headache for a few days following a head trauma, or it could be in the case of this friend of years, they had a lot of photosensitivity, they had a lot of auditory sensitivity, they had difficulty processing things, they were much more irritable.
How common are those types of more severe symptoms than just a headache for a few days after a hit to the head? So in reality, it's quite difficult to say how common things are because millions of concussions happen every year in the US alone, most of which probably go unreported. And so it's only when you see more significant symptoms or something's happened in front of a pseplank sport, it's happened in front of a doctor, you get a form assessment. And the downstream effects are varied, can be around verbal effects, photosensitivity, noise sensitivity, effects of memory, focus, reaction time, depending on how you're measuring things.