TRANSCRIPT
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. Hello everybody and welcome to another episode of the Better Brain Fitness podcast. My name is Tommy Wood and I’m joined by my magnanimous cohost, Dr josh Turkner hello Josh.
00:31 : Hello Tommy. I’ll try to be as magnanimous as I can today, Stretch. So Josh is going to field our question today, which comes from Ted Olson in St paul, minnesota. Ted says type 3 diabetes is a term that has sometimes been used to describe Alzheimer’s disease and dementia. Can you address this, Josh, can you? I will try. So yes, type 3 diabetes is a term that some people may have heard of in reference to Alzheimer’s disease.
01:05 : It arose, I don’t know it’s been around maybe a decade or so ago from research indicating that there was evidence of insulin resistance in neurons in Alzheimer’s. So that was kind of the main finding so it which kind of parallels the type 2 diabetes in the body which were that’s the hallmark of which is insulin resistance in the tissues. So here we’re seeing evidence of insulin resistance in the brain. There’s also evidence showing that there’s an increased risk of cognitive decline and Alzheimer’s in those who have diabetes, estimated around maybe 1 7-5 times more likely is also about two times in the increase of risk of vascular dementia and those with diabetes, which is not surprising, as we know diabetes especially harmful to the vasculature, but again also a significant increase in the risk of Alzheimer’s.
02:04 : So again, this providing evidence that metabolic dysfunction seems to be involved in some way in the pathophysiology of Alzheimer’s, at least in some instances. There’s also other kinds of similarities between Alzheimer’s and diabetes in terms of pathological findings so in both you see systemic inflammation. There’s also evidence of blood blood brain barrier breakdown, but I think that the key point here is that insulin resistance in brain cells is one of the physiological deteriorations seen in Alzheimer’s, at least in some cases, which leads to an impair impairment in the utilization of glucose in brain cells.
02:47 : Also a potential mechanistic reason why a ketogenic diet could be helpful in Alzheimer’s disease, as if there’s an impairment and utilizing glucose for energy, you can provide another substrate in ketones instead of the glucose. However, you know it doesn’t. It’s not clear if this is true in all cases it doesn’t it so it doesn’t appear that it’s necessary or sufficient for, you know, for a clinical diagnosis of Alzheimer’s. And I think All in all of this seems very confusing and even contradictory if we are looking for a single smoking gun for Alzheimer’s or a single cause or even that Alzheimer’s is one thing with one single pathological signature.
03:33 : But people often talk about these sorts of things in either or terms, as in Alzheimer’s disease when this type 3 diabetes thing came along, people were saying we really should be thinking of diabetes now as a I mean as of Alzheimer’s now as a metabolic disorder, and we should be calling it Type 3 diabetes to reflect that. And still others say no, it’s really a disorder of amyloid. And then others saying no, it’s really about neural inflammation and then others saying no, it may be infectious and so on.
04:00 : And the assumption with all this is that these are mutually exclusive explanations or that they can only be one. And what we’d say, as we discussed in our paper, is that this is only confusing if you’re trying to explain Alzheimer’s at this level of biological organization so if you’re looking for a single smoking gun, a single cause at the level of biological molecules. And this confusion and these apparent contradictions kind of fade away when you zoom out and start from a different level of organization at the level of the whole Organism and its interaction with the environment to create a model of Alzheimer’s pathogenesis.
04:45 : And as we’ve discussed, we think the most parsimonious model is that it is a mismatch disease in other words, you see deterioration of the neural substrates of cognition resulting from environmental mismatch and a reduction in the cognitive demands placed on the brain over the lifespan. And so because it is or if it is a condition that’s driven by lifestyle and environment, then the specific pathological findings are going to be idiomatic or unique to each person because every lifestyle is unique. So you wouldn’t expect any single pathological signature, which is kind of what we see, right. This is unlike something like meningococcal meningitis where the cause in every person is the meningococcus bacteria and so the pathology in every case is going to be the same from one brain to the next other on the other hand, each case of Alzheimer’s will be pathologically unique because it isn’t from any one thing, but rather the cumulative impact of multiple factors that are upstream from the level of biological molecules and the pathology we see in the brain is resulting from those upstream factors.
05:58 : So which means that pathology can be determined by lifestyle plus genetic factors that shape the impact of those lifestyle factors of their particular ways they manifest. And so the specific pathology that you see in any given individual and then the specific areas that are most commonly affected first are likely those that are most vulnerable to these mismatches such as the medial temporal lobe where, which is what seems to which, what accounts for kind of the early symptoms in most cases. So going back to this original topic of type 3 diabetes or insulin resistance in the brain, we know that mismatches in our modern diet and lifestyle, in particular our consumption of refined carbohydrates and reduction in physical activity.
06:50 : We know those things impair metabolic health, and we have evidence that impairments in metabolic health can lead to deterioration in the neural substrates of cognition, among other things. So it’s definitely something to be mindful of for sure, to maintain a fit brain over the course of a lifespan, lifespan. So it’s part of the story, but just not the whole story. And for me, the most important point here is that none of this stuff is either or, even though it’s commonly discussed like it is.
07:21 : And you know the Alzheimer’s Research project is still usually framed as the search for the cause. This podcast is brought to you by the Brain Joe Academy. The Brain Joe Academy provides brain boosting whole brain stimulation in the form of neuroscience based musical instruction designed for adult brains and with no prior musical experience required. Start your brain boosting musical journey today at Brain Joe dot Academy. The last point I’ll make is as we’ve mentioned, maintaining cognitive activity is also likely a key piece in maintaining brain health and preventing cognitive decline.
08:07 : And just as if you don’t have a lot of energy, it’s going to compromise a physical workout. The same is likely true of the brain. If it’s ability to utilize energy is impaired, then that will constrain the demands that we can place upon it which can then lead to further reduction in growth and repair mechanisms which then can lead to further deterioration. So this is how also the phenomenon of demand coupling could play into this impairment and metabolic health.
08:32 : And illustrating the fact that none of these things are working in isolation if we seem naturally inclined to want to kind of find a single cause and it’s really hard to kind of hold a multifactorial model in our head and I think that’s why we’re often so predisposed towards trying to sort of make a nice tight, clean story. But everything points to that not being the case here with Alzheimer’s. Tommy, anything you have to add to that? Yeah, I think that was a very nice, nice overview and I think that you know, really puts it to context all these different you know, single causes that they clearly aren’t the single cause of Alzheimer’s disease or dementia.
09:19 : However, as it as it pertains in particular to this idea of Type 3 diabetes, I think we can even look at proximal causes of this that sort of fit into this model and a part of the things that you just mentioned so I’ve done a whole bunch of work in insulin resistance previously trying to model the various upstream things that may account for it or cause it and you know previously or there are several people out there who’ll say like insulin resistance is the root cause of all these diseases you know non communicable diseases of modern society but it’s the resistance doesn’t just like happen right there are things that are upstream of that and so give us some examples.
10:04 : Insulin resistance as I think about it is essentially A regulated process where it sells a cell says I can’t take up any more energy i already have more than I need. And that’s either because that cell isn’t using that energy or it doesn’t have the capacity to use, it doesn’t have, say mitochondrial function to process that energy as it comes in so it turns off the transporters that uptake energy into the into that cell it’s a regulated process and so things like oxidative stress cause insulin resistance. Oxy stress directly acts at the insulin receptor to affect uptake of glucose into cells. But inflammation is another one so we know there are all these things that we get exposed to it could be either some kind of pollutants or toxins they can cause Oxy, stress, air pollution or they could be inflammatory.
10:54 : And in the setting of inflammation, we get this whole body insulin resistance and it’s on purpose because you’re shutting glucose to the immune system your other cells say I’ll hold up when using glucose right now because my immune cells really need it, right this is a normal part of a response to an infection so part of this, you know, could be some inflammatory response in the brain that then purposefully as part of a regulated response causes INS resistance in certain cells.
11:22 : Another part of it is the demand side itself. So to give another example of where we compare the brain to muscle tissue, we know that if you don’t use muscle tissue, it becomes insulin resistant because it’s not using that energy so it says I don’t need anymore, It turns off uptake. And this is most obvious or evident in those who have some kind of significant, say, spinal cord injury they can no longer move their legs, you know, under an endogenous control and those muscles become very insulin resistant because then and not using that energy. So you can imagine a scenario where if you’re not using your brain tissue, it says well do you know what, I don’t need any glucose because there’s nothing happening here.
12:03 : So I’m not going to take up anymore. And one of the ways that we look at glucose uptaking into the brain with our PET scans, you know that’s one of the signatures or of Alzheimer’s disease is decreased glucose uptake into areas like the medial temporal lobe. If there is less demand in those areas, you will automatically take up less glucose so it’s not necessarily that you know this is all driven by instant resistance it could just be driven by decreased demand as one of the many options that may lead into what people are calling Type 3 diabetes.
12:39 : And then there may be several other examples where that doesn’t happen and glucose uptake looks relatively normal, but there’s still damage or change occurring in those areas of the brain which then leads into this sort of multifactorial mismatch model. That’s interesting yeah. So it’s not easy to distinguish between pathological versus functional similar assistance, right i mean like as you say there may be scenarios where it’s a perfectly logical and response and a way of maintaining homeostasis versus it being a broken system and you can’t all you can’t just tell what which is which but that’s really interesting.
13:20 : All right well, thanks Tom for that question. If you guys have any others for us, feel free to send them our way at brainjo.academy/questions and we will do our best to answer. All right thanks Tommy. Thank you.