The Connection Between Cognitive Activity, Brain Pathology, And Alzheimer’s


Welcome to Better Brain Fitness, hosted by doctors Josh Turknett and Tommy Wood. In this podcast, we will explore the frontiers of how to keep our brain fit and healthy so that we can perform at our best and do the things we love for as long as possible. Let’s go. Ok, welcome to another episode of the Better Brain Fitness podcast. I am joined again today by my salubrious cohost, doctor tommy Wood. Hello Tommy hello anything out there doesn’t know salubrious great adjective means health giving. So you know, what better way to describe Tommy than health, giving and all the knowledge?

00:48 : Well, that’s something that I can always aspire to yeah thanks. You bet. So Tommy is going to take the first crack at our question today which came in from Actually we have a couple questions the main one we’ll address here is from Mark in North Carolina who said I listened to your initial podcast where you laid out your thoughts on your theory of maintaining brain health through actively challenging your brain with new and varied learning tasks. I also understand how it would be difficult to control for and prove such a hypothesis. My question is whether there is any data from the field of pathology in the form of, say, autopsies, that might somewhat suggest that those who have been more engaged in work, challenging endeavors, and so forth, are found to demonstrate less of the pathology associated with dementia. If not, might such attempts to correlate pathology findings with age and some system to estimate cognitive challenge in a person’s life perhaps shed light on the relationship you propose. Great question mark and then we had another one kind of related which is what is demand function coupling with examples and that was the terminology and that we introduced in the in the paper and in the podcast that Mark talks about so tell me, what do you have to say about Mark’s question?

02:14 : It is a really good question and I’ll say that I hadn’t dug into that specific question much until. We read Mark’s question and I wanted to try and answer it. And I’ll say up front that the wording, I find the wording of Mark’s question interesting is because the way Mark words it is based on the assumption that pathology in the brain is the driver of Alzheimer’s disease, right? Because that’s you would assume that if cognitive function decreases dementia risk. That it does that through decreasing amyloid or Tau burden, because that’s the main cause, quote unquote cause of alzheimer’s disease.

03:00 : This is.

03:01 : A crucial point that you’re making. This is a crucial point that you’re making yeah and this is also what comes up in the majority of studies that the look at this question and there are there are some before we get into that i think we should say that depending on the pathology you look at where you look at it, how you look at it. The burden of pathology in the brain very poorly predicts either cognitive function, changing cognitive function over time or dementia risk. They are absolutely correlated. You know, if you if you do a statistical model and you find an average effect, yes, you will find a statistically significant association but that association is very weak and that has been seen, you know across hundreds if not thousands of studies at this at this point. And you know, we’ve. There have been lots of studies that say, you know, you’re you can find significant amyloid burden in somebody who’s cognitively completely normal, and vice versa you can, you can have a relatively low burden of those pathological hallmarks and still have cognitive decline or dementia. And I think this is particularly. Evident in just like one region of the brains, the hippocampus, which we know is preferentially or targeted and Alzheimer’s disease, you know, the hippocampal volume decreases that’s associated with changes in lots of aspects of memory function. The hippocampus doesn’t really get much amyloid in it, but you still see significant atrophy and loss of function so the associations across the brain with different cognitive functions and the pathology we see there. It’s pretty weak even though, yes, statistically significant but not like particularly strong it’s not, it’s not predicting the majority of the risk and that’s why we’re spending a bunch of time then looking for other risk factors. This is important because when some people have tried to answer this specific question, the marks ask cognitive activity, pathology in the brain, and then Congress decline or dementia risk. They may start with the assumption that pathology is the main factor. So a lot of the studies that I looked at come from the Rush Memory and Aging project, which was run primarily in Chicago. But they have a whole bunch of these kinds of data points, so they have cognitive activity at various stages of life. They have physical activity they have a whole bunch of blood tests. They have cognitive decline, so cognitive function, dementia and then they also did formal neuropathology in some in a subset of the individuals. So they have all of this information and some of the original studies tried to look at this so Wilson, that’s all this is in neurology, I think it was 10 years ago now. They looked at the paper was called lifespan, Cognitive activity, neuropathologic burden and cognitive aging that’s exactly the question that we’re trying to ask here. And what they looked at was how much cognitive activity, you know, prevents or prevents cognitive decline or protects cognitive function late in life after adjusting for pathology. So the so like the way they phrase the question is. Pathology is the main issue. Once we’ve taken a pathology into account, what’s the effect of cognitive activity? This doesn’t quite answer Mark’s question because if cognitive activity changes pathologic burden, the way that they structured that question can’t answer it because they’ve already made the assumption that the pathology is the key driving factor. Despite that in this study they find that cognitive activity predicts about 15 % of. The rate of cognitive decline. So and that’s after taking into account pathology burden and the conclusion of their abstract is more frequent cognitive activity across the lifespan has an association with slower late life cognitive decline that is independent of common your pathologic conditions and what they mean by independent is after is statistically independent after they adjust for pathology in the brain, they still see about 15 %. Is protected statistically significant by late life cognitive activity? Then there was another paper that also came out in neurology a little bit later that also looked to the same data from the same study and what was particularly interesting to me is that. They found no association between cognitive activity and pathology burden, right they’re just not related to one another at all. Among 102 persons who died and had a brain autopsy, neither global nor regionally specific measures of neuropathology were related to level of cognitive activity before the study onset or during the course of the study. And so in if we look at the like whole, like all the research in this area, we know that cognitive activity is protective against cognitive decline and decreases the risk of dementia, but it doesn’t affect pathology in the brain. And this is again I think more support to say that pathology is not the main driving force because protective factors for things that you care about, your cognitive function, your dementia risk, they don’t necessarily affect pathology burden at all. And the then another aspect that’s related to this and there was actually this is the study that kind of got me into looking at all the data that’s come out of the Rush memory and aging project is related to physical activity. So a more recent paper that came out of this came out of this like whole study. This is in the Journal of Neuroscience last year. Casaletto at all. What they did was they looked at their physical activity measures, so they have actigraphy, so how much these people, how much individuals moved and then later on they get to look at pathology in their brain after they died so it’s really nice you have this data on how they lived like good prospective data and then later on you follow them up and you get to look at their brains and what they found was a really strong protective factor of physical activity on. They looked at things like synapse integrity, so what are the number and the strength of the connections in the brain between neurons. And they also looked at measures of cognitive function. And what they found was that the more what they were looking at is these immune cells in the brain called microglia which become activated or inflamed in the setting of pathology in the brain. And that may be one of the reasons why those things are associated it’s actually this sort of inflammation in the brain that gets generated and then that’s actually what’s detrimental and across everybody. Physical activity had a significant effect on synapse integrity and cognitive function we know the physical activity is associated with improved cognitive function and decreased dementia risk, but what they found was that the more pathology you had in the brain, the more physical activity acted. By decreasing the way that these microglia respond to pathology, they become less activated you’re you. That’s one of the ways you might create resilience in the brain is because physical activity is kind of moderating some of these negative things that may happen in response to pathology and the more pathology there was, the more physical activity seemed to act through that pathway, even though the overall effect was still beneficial regardless of the amount of pathology in the brain. Another group looked at this, the same data from the same study, and what they found was I got to find the quote because this just I only read this morning and it blew my mind because I wasn’t expecting it but they said despite the consistent associations of a range of cognitive and social lifestyle factors with cognitive decline and dementia risk. The extant clinical pathologic data finds only a single risk factor in one cohort linguistic ability related to AD pathology so they looked at all like physical and cognitive activity and basically none of them except for one thing, linguistic ability predicts AD pathology. And then they said some factors such as cognitive activity, appear to bypass known pathologies, as if this is like. Oh, we did this doesn’t make sense because they’re not associated bypass known pathologies altogether suggesting a more direct association with biologic indices that promote person specific differences in reserve and resilience but basically what they’re saying is that these things that we know that are protected protective physical activity and cognitive activity, they don’t seem to act through pathology at all. And then the final, the final thing again that came out of this same study. They said physical activity was positively positively associated with Alzheimer’s disease burden. So in these people where physical activity is protective against cognitive function and cognitive the protects, cognitive function prevents cognitive decline. In this group where they saw that those who had higher physical activity also had higher Alzheimer’s pathology burden after adjusting for some other things so. It’s it may not even and I don’t know if this has been repeated elsewhere, but if something that is associated with improved cognitive function, decreased cognitive decline is also associated with increased pathology burden after adjusting for confounders, that again just like completely calls into question whether a pathology burden is the thing that we should really care about. Hey there, so if you like this podcast then I think you will enjoy the Brain Joe Connection newsletter. The Brain Joe Connection is a free newsletter sent out twice a month and is all about the science of how to keep our brain fit and healthy along with products, books, tools and resources for improving brain health and function that we use and recommend to subscribe. You can go to Brain Joe dot Academy forward slash connection or click the link in the podcast description. All right, now back to the show.

13:42 : To kind of tie all of this together and to go back to answering Mark’s question is that in general a lot of protective factors and so I’ve really looked at cognitive activity, but then also physical activity, they don’t appear to decrease pathology burden at all. I you know, I won’t say that physical activity increases pathology burden because it’s just like one paper. But in general, they aren’t associated with whatsoever, despite the fact that we know that they’re protective. It may be that other things are happening that sort of create this resilience to the negative effects of pathology so if you are going to generate a bunch of, you know, amyloid, are you going to accumulate all of amyloid in the brain? Then physical activity seems to help mitigate some of the negative effects of that in particular so you’re increasing resilience to this, to these pathologies. But even then the primary mode of action of these protective factors does not appear to be through pathology burden, which again supports the idea that maybe pathology burden is not the thing that we should be going for so Mark, to answer your question, yes, it seems, you know, seems like. Some good proportion of cognitive function is related to cognitive activity in that one paper it was 15 % which you know when you take into account all the facts in the system i think that’s a that’s a that’s a pretty good chunk of what we would expect. The pathology may not be the thing that we’re going after in cognitive function. You know, cognitive activity doesn’t seem to affect the burden of Alzheimer’s pathology in the brain and. This is kind of like a really fascinating dive for me into this. And there’s a lot of really great data from this study, in particular the memory and aging projects that sort of allow people to unpick different parts of this. Josh, what do you think?

15:47 : That was great answer. So interestingly I read this question too before episode and came up with kind of my own thoughts but we both fundamentally had the same kind of response to it which was the premise itself about the link between pathology and what we and the and what we care about in the clinical manifestations of it so I think in what you point out here is that if you look at the various observations and the research there you there are, there are complete logical inconsistencies that arise unless you remove the idea that the pathology that we have identified as being causative in Alzheimer’s is not right that’s the only way to resolve that’s the most sensible way to resolve that these logical inconsistencies that you just pointed out. And you know I would I would agree and so i’ll walk through kind of my what I thought you know my thought process after reading his question as well which I think is going to it’s along the same lines of what you described just you know from a slightly different vantage point and also may integrate the concept of demand coupling a little bit into it which was mentioned we had a question somebody asked about what that is and examples. So the so demand coupling itself, which is just the idea that the structure and function of our tissues is directly linked to the demands we placed on them. I think it’s so ubiquitous that it’s made that may be why we’ve missed just how significant a factor it is in our health. You know, we’ve over the years been consistently surprised like it’s just how powerful exercise is in terms of our health and kind of only recently started to come to a growing consistent consensus that it’s kind of the central driver of our health, like it matters more than anything. So you know, our capabilities are what directly determines our health, right we’ve talked about this before or our ability to maintain homeostasis across a range of conditions. And every species, every Organism can be characterized as a collection of capabilities that’s allowed them to survive and reproduce in certain environments. And we know unequivocally that our capabilities expand or contract in response to the demands that we place on them. So you can prove demand coupling to yourself quite easily. And you have many times over the course of your life, right Your knowledge, your skills, your strength, your endurance, all of those things are the result of this phenomenon of demand coupling. So you know, any individuals set of capabilities and function at any given time is a reflection of the physical and cognitive demands they’ve been placing on themselves over the course of their life. And since the engine of those capabilities is our biological machinery, the changes in those capabilities that occurred based on the demands we place on our tissues are going to be the result of functional and structural changes in that machinery. So again, anytime our capability changes, the machinery is going to change, right has to have changed to support them. So that’s demand coupling and that’s the fundamental driver of health. Now as your the question and your explanation and look into the research shows so well as we tend to focus heavily on the structural side of things. But what we care about, what is important is the function, right? All of organisms are fundamentally a process or this set of web of interconnected relationships that are always changing and structure can provide some insight and information about how that process is organized. It’s only a small part of the picture and we’re ultimately a process and not a thing. So for me, one of the key messages I think to convey here is that the function is what ultimately matters, right? For a variety of reasons, we’ve ended up in this place where I think it’s been, it’s commonplace now to think just the opposite and that bias is kind of reflected in this in the question, which isn’t our fault, the question or just a reflection of kind of where we are as a culture and how we think about these things. But it that’s it’s in the in the bias is that as if structural or pathological changes would somehow be a stronger form of evidence than actual function, when again the actual, the strongest form of evidence is going to be functional changes, right? And then in monitoring, some kind of structural or pathological finding is really just a proxy for the thing that we care about the most, which is function. You know, how is that particular capability doing? And there’s some, you know, if we’re monitoring some structural pathological change, the assumption there is that it’s somehow related. So I think overall, pathology is the wrong place to look, primarily right it’s 1 sliver of the picture. And in this particular case as you’ve just clearly demonstrated, we don’t really have a coherent picture of how the changes in brain tissue you know even relate to functional decline or the changes in the capabilities that we care about. So the most important research here is our is the research on function that we’ve outlined and the relationship of cognitive activity on that. And we have you know plenty of evidence that indicate that demands significantly influence our risk of cognitive decline and age-related dementia. All that being said, there is certainly lots of evidence where we do see structural changes in tissue, including brain tissue, in response to changes in demands. So one of the earliest findings in neuroscience related to this area that we discussed in the paper was from rodents in enriched environments versus impoverished environments. Or you see, ones that are raised in enriched environments with a lot of sensory stimuli end up having big, robust, healthy looking brains. And then ones that are in impoverished environments have smaller, sickly looking brains. You’re changing nothing there but the amount of sensory stimulation they’re given or the demands placed on the brain. And you see all of these differences, structural differences in brain tissue. Another one we mentioned, which is which was Doctor, which was done by Doctor Merznick, Michael Merznick and his colleagues taking adults, adult rats who had functional declines in multiple auditory capabilities compared to young rats with related structural changes in tissue. Had them do an auditory training protocol over the course of like a month. You know, teaching them to sort of sort of improve their discrimination abilities in multiple different auditory domains. And that ended up reversing 20 different functional over 20 functional parameters along with making the tissue itself look like young auditory cortex tissue again. And this is of course really well known in the musculoskeletal system, right, muscle tissue in particular so we know that bed rest causes rapid decline in muscle tissue, connective tissue and then you know dysfunction, loss of capability across multiple organ systems and wait that affect of reduction in demands on tissue health and particularly musculoskeletal system accelerates with age so that effect is going to be more prominent in a 70 year old versus a 20 year old. So again all sorts of evidence to indicate that this is that our demands both not only you know determine what we’re capable of doing but we can see that reflected in changes in tissue. So again it’s the functional changes that we ultimately care about and I think with rare exceptions chasing pathology is almost always going to be a red herring. And we can probably, we’ll probably talk more about this in an upcoming episode where we might talk about some recent research on the anti amyloid medications. One last point to make too is I think one of the limiting factors and a lot of the research on cognitive activity and its connection to brain health is that our definition of cognitive activity has been too narrow and limited. You know we tend to still think of it as the kind of stuff that we do in school rather than just thinking of it in terms of okay, what is what sorts of things place high demands on cerebral Cortex generally and that’s going to be far more than things in school. It’s going to involve a lot of the motor system etcetera so that’s another, you know, another kind of reason for this podcast and for the stuff we write and is to get that message out there because I think it’s an important oversight and I think we still underestimate the role of cognitive activity because we’ve too narrowly defined it. All right, That’s what I’ve got to say about that. Anything else, Tommy?

25:36 : No, I think so hopefully that answers the question i would love any follow-ups or anything that didn’t make sense on our part cuz I certainly gave a whistle stop tour of a few papers that if anybody has any follow-ups please do let us know. And again, you touched on an important point which is that even though we take issue with the phrasing of the initial question. That is how the research is currently framed that’s not like a the fault of Mark and his question that is absolutely how the field thinks about these things.

26:12 : So it’s completely appropriate in terms of how this stuff has been like that and it allows us the opportunity to point out that when you’re like you can have many, many years of research on a dead end if the underlying assumption is wrong and you’re like so it’s important to like be examining it could that be the issue here, you know, so we appreciate the question because it allows an opportunity to think through that and it’s you know based on the prevailing ideas, it is exactly the right kind of question to be asking. All right and I’ll put, we’ll put the links to the papers that Tommy mentioned in the show description so that if you guys want to take a look at those, I do too. All right. Well, thanks everybody for listening and we will see you guys in the next episode thank you, Tommy.

27:06 : Thank you.