Looking At Microplastics & Inflammation’s Impact on Brain Health | Jack Auty

When you look at it broadly, anything that increases your inflammatory response chronically in your body increases your risk of Alzheimer's disease and has this accelerated aging component to it as well.

Well, hey everybody, Dr. David Perlmutter here. Welcome again to The Empowering Neurologist. As fate would have it, I was watching YouTube videos at the gym on the treadmill, and I looked at one on microglia by a fellow by the name of Dr. Jack Oddi in Tasmania. Fascinating video, really explained what was going on in the brain and these immune cells. And I explored his work a little bit more deeply and discovered that he's doing some incredible work on brain inflammation in general, and specifically looking at what exposure to microplastics may be doing to our health and even considering how that might affect the brain. So I reached out to him and he is going to be our guest on the program today. Let me tell you a little bit more about him. Dr. Jack Audie is a lecturer in the Medical Sciences Division in the School of Medicine at the University of Tasmania. His research focus is really looking at how inflammation can contribute to disease with, I think, an emphasis on what's going on in the brain. He has a broad range of interests from microplastics and how they induce lung and gut inflammation to whether commonly used anti-inflammatories might actually be helpful in the treatment of Alzheimer's disease. His research group uses cell culture techniques, steps it up to rodent models, and ultimately human tissues, and even clinical data and statistical modeling in humans to follow the science from cells in a dish all the way to people. If you want to learn more about him, it's jackauty.com is his website. Let's get right to our interview with Dr. Auty. Well, hello, Dr. Audi. Audi rhymes with naughty, you told me. How are you doing today?

Good. How are you? How's it going?

Wonderful. What time is it in Tasmania?

It is now 11 PM at night, and I've just put my 2 kids to bed. And, well, you know, a wee while ago. And now hopefully they'll stay in bed. 9 AM for me.

So thank you for being up at 11 PM for me. That's probably not good for your health. I was, as I told you before we went to the recording, I was watching videos on microglia at the gym on the treadmill, as one of course would, and there you were, and beautiful explanation of microglial activation. So I explored you and realized that fundamentally you are really interested in the mechanism of inflammation, and that's very, very, you know, actually fundamental for the work that we do. And so that's why we reached out. So I know we're going to have a lot to talk about today. So let's first talk about what made you gravitate just to the mechanism of inflammation, and we'll unpack where that goes in terms of human health and disease. But why inflammation? What was it about inflammation that's so interesting for you?

Yeah, that's a great question. I've been studying sort of inflammation and neuroinflammation as a contributor to disease since my PhD. My PhD was focused on actually stroke, which is a blood clot or a bleed in the brain. And, there is a huge inflammatory response after that. And so, the question is, is that inflammatory response detrimental? And, you can imagine swelling in the brain following stroke, it's such a severe injury that the swelling in the brain swells up quite large. And, it's a bit like imagine rolling your ankle, that swells up really large. But inside the skull, there is nowhere for the brain to go. So, it starts to squish and the intracranial pressure builds up. And there was a general theory that this kind of swelling in the brain and this massive inflammatory response in the brain was detrimental. And so, I actually researched marijuana-like substances during my PhD. And so, marijuana-like substances, they actually are anti-inflammatory, they suppress the immune system, And they work through two— the cannabinoids, marijuana-like substances, work through two main receptors. One is predominantly on neurons, and that's what causes the getting high effect of marijuana. And the other one is actually predominantly on immune cells, and that's called cannabinoid receptor type 2. So the hypothesis was if you inhibit this, the immune response, by activating this cannabinoid receptor type 2 with synthetic compounds that were developed, we would suppress the immune system and hopefully have a beneficial response. Unfortunately, from my PhD, you know, it's one of these 4.5 years of work trying after trying after trying, we found no protective effect from it. And so, all I could really conclude from that is that the short-term inflammatory response following an injury in a healthy person may be adaptive. It may be a good inflammatory response at this stage. Those immune cells are cleaning up damage. They're doing what they're meant to do. This was sort of reinforced in a very famous clinical trial called the CRASH trial. Now, the CRASH trial was actually on head injury, not stroke, but it's a similar theory. If you whack your head, your brain swells up. We need to suppress that immune system. And they were using a much more potent and broad-spectrum anti-inflammatories, steroid-based anti-inflammatories. But they found an absolute increase in death rate of 3.8%, which is a huge increase in terms of absolute. So, that means if you had 100 people with a major head injury and you gave them all steroids, an extra 4 people would die basically because it's an absolute increase in 3.8%. And this was the CRASH trial. And the story goes with the CRASH trial is that they struggled to get doctors enrolled in the trial because it was standard clinical practice to give steroids as an anti-inflammatory in the brain during a head injury. And doctors were so sure that it worked that they didn't want to be enrolled in the trial where some of them would— some of the people would be getting a placebo. But it turned out getting a placebo was actually much better than getting a steroid anti-inflammatory. But one of the key things there is that we know that there's damaging processes that occur during inflammation. For example, there's an immune cell in your blood called neutrophils. It's the most common immune cell in your blood, and they are just packed full of broad damaging enzymes and molecules. So, they would release an enzyme called MPO that actually produces, once it's out of the cell, it produces bleach, hypochlorite. It actually generates bleach, these neutrophils. They also produce enzymes that chop up everything, proteases that chop up everything in the brain. So, we're talking synapses, everything. So, you can imagine that stopping those neutrophils doing what they do is probably a good idea, but maybe what they're doing is good in the short term but bad in the long term.

Exactly.

So, that's where a lot of our research shifted was that excessive inflammation or chronic inflammation is when inflammation gets really bad, really bad. You can imagine small amounts of bleach being released in your brain for 3 decades that might happen during Alzheimer's disease. is not a good thing for the brain, right? And so, that's where my research then headed. I first went into acute and severe inflammation in the form of sepsis. So, I did a postdoc on sepsis. And during sepsis, your whole body is infected and so, you have a whole body inflammatory response. And so, that's sort of that massive acute inflammatory response that might start to be damaging. And one of the big problems with sepsis is that one of the inflammatory responses is for your blood vessels to become leaky. That's why your ankle swells up when you roll it, is because your blood vessels become leaky. This allows your immune proteins out into the tissue, like your antibodies, but also your complement proteins can get out, and then your immune cells make their way out too through your blood vessels. But you imagine your whole body leaking blood is going to cause your blood pressure to crash to nothing and cause all sorts of problems. So there's a lot of research around trying to suppress some parts of the inflammatory response during sepsis, during acute inflammation during sepsis. But my bigger focus, and I spent probably the next 8 years of my life focusing on the role of chronic inflammation, in particular in Alzheimer's disease, but also in aging and accelerated aging in the brain and as we age in the brain. And when you look at it broadly, anything that increases your inflammatory response chronically in your body increases your risk of Alzheimer's disease and has this accelerated aging component to it as well. And so a lot of my research was focused on how do we reduce this chronic inflammation potentially as a treatment for these chronic conditions. I've looked at it, man. I've looked at— my research has spanned a huge spectrum of the scientific field. I've gone from researching proteins to cells, to animal models of Alzheimer's disease, and I know they have their shortcomings, even into human data. And so, I've done 2 or 3 large epidemiological studies in the roles of suppressing the immune system and looking at how reduced inflammatory response through anti-inflammatories or an increased inflammatory response through certain deficits in your diet can increase the risk of developing Alzheimer's disease as well as accelerate the progression. So a big part of my focus is a lot of epidemiological research has focused on the incidence. So how many people get Alzheimer's disease? But that has a whole bunch of issues with collinearity, but it also has issues with— that doesn't tell people who currently have Alzheimer's disease what to do because we only know how to stop you getting it perhaps, but what happens once you get it? So the slope, the decline was really interesting to me. in my epidemiological research. So what things could actually change the cognitive decline, the slope on the cognitive decline in these Alzheimer's patients using epidemiological research? So that's— oh boy, that was my whole life story.

Sorry, David. No, I didn't think we would be at a loss for things to talk about. So lots of thoughts come to my mind. And, you know, there have been interventional trials over the years using nonsteroidal anti-inflammatory drugs, to look at modulating the progression of Alzheimer's, and these have failed on the heels then of studies demonstrating actual increased risk of Alzheimer's in chronic users of these NSAIDs, and one might wonder why. And I think what we understand about the NSAIDs is they do modulate the complexion and functionality of the microbiome, the gut microbiome, and are indeed associated with increased gut permeability, hence actually in the long run, Hmm. increasing inflammation, which is, you know, based upon what you just described, that would be exactly what you don't want to do. And, you know, interestingly, when there is increased inflammation as a consequence of permeability of the gut or anything going on in the body itself, that does produce these inflammatory mediators that influence the phenotype and functionality of the brain's microglia. Yeah. And can keep them from reverting back to the helpful, supportive, good twin as opposed to the evil twin. I know you did a couple of really interesting YouTube videos that I watched several times on the treadmill, so I really know them well. That's— I think I learned better on the treadmill, I guess because of BDNF. Who knows? But that said, you know, I think ultimately where we come down to is focusing on reversing this activation of these microglial cells in the brain. that become activated with head trauma, activated with a stroke, activated chronically in the Alzheimer's patient as well, that they shift to becoming the assassin as opposed to the angel. And so much research, including looking at CBD, I might add, is looking at creative ways of shifting them back to being anti-inflammatory and supportive cells in the brain so that they can help with repair. And There are 3 ongoing studies right now looking at very popular GLP-1 agonist drugs. People would probably know the name Ozempic in that class. They're getting underway at this point. Some of them are going to take 3 years to complete, but the idea is reprogramming those immune cells in the brain via this GLP-1 receptor that they possess. To actually revert them back to being anti-inflammatory. Great study came out about 6 to 8 weeks ago in the New England Journal that showed cessation of progression in Parkinson's. It rested it dead in its tracks using over a 3-year period with a GLP-1 agonist. So, you know, that could be a game changer. So, you know, a lot of, I think, where you are going is really ultimately going to focus on that Those brain immune cells, the microglial cells, it seems like.

Yeah, it's a huge part. And I think part of the development of this field has been, firstly, the original plan was to just stop them doing what they need to be doing, stop them being bad. In fact, there have been clinical trials on drugs that kill your microglia. And actually, these are relatively recent, maybe 5 years ago, there have been clinical trials on phase 1 clinical trials on drugs to kill your microglia in the hope of preventing Alzheimer's disease. I think that the field has really moved on from this idea of shutting the microglia down, stopping them doing what they want to do, and instead trying to flick certain molecular switches to get them into the protective phenotype, the phagocytosing of debris, eating up the debris kind of phenotype, the repairing the synapses, repairing going into the repair mode. In fact, there's huge evidence now coming in with the interplay between microglia and blood flow and their involvement in restoring blood flow and maintaining good blood flow. So, I think that's where the field is heading, what molecular switches to flip. I think there is a tendency, I think every scientist does this, is that they start to see everything through the lens that they have spent their lives researching. So, I have spent my life researching inflammation. And so, every conference I go to, I go, somebody will be talking about cancer and I'll be thinking, ah, that's inflammation.

You bet.

And, they'll be talking about this and that. And, I think it's something I try and resist because it's a very complicated area. And, things like Alzheimer's disease are very polygenic. And so, I certainly think inflammation is one component and flipping those microglial switches is going to be important. But there's going to be many other pathways too, blood flow being a big part of it. In fact, there are many Alzheimer's researchers that are pushing for it to be almost called a vascular disease because studies have now shown around about 70% of Alzheimer's disease, once you actually look postmortem, have vascular pathology contributing to it. And so, we used to say vascular dementia, Alzheimer's disease, and now we're sort of slowly overlapping them more and more and more as we acknowledge the vascular component. So, I'm sure the vascular researchers out there will be screaming at the top of their lungs if I say it's all microglia. But yeah, conversely, if you try and say that it's all neuronal or blood vessels, I'm going to say, hang on, the microglia play a role there too. It's very polygenic.

Well, a couple things come to mind. There was a study done, I think, about 12 years ago that evaluated individuals in terms of their polygenic multiple genes influencing their Alzheimer's risk. And it found that even in those individuals who had high risk based upon their polygenic score, that markers of measurements of obesity and type 2 diabetes, or at least insulin resistance, were far more influential. And, you know, that kind of opens the door further for the notion that our lifestyle choices are really important levers to pull In terms of managing risk that you know we talk about presenilin one and ApoE, etc. But the real issues here and why we're seeing you know this virtual explosion in terms of prevalence of this of this disease really I believe relates to changes in metabolism and how metabolism and metabolic changes dysfunction affect. The immune system. And, you know, one study that comes to mind, we know that what one of the things that regulates the activity of the microglial cells are these what are called the TREM receptors, TREM1 and TREM2. Activity of the TREM2 receptor tends to favor good, healthy function of the microglia, supportive of the neurons, supportive of the synapses, able to phagocytize misfolded proteins. clean up debris, whereas activation of the TREM1 or overrepresentation of the TREM1 receptor does the opposite, favors the evil twin, if you will, if you will. Mm-hmm. But really interesting results of the study showed that the functionality of these receptors is hugely influenced by 2 factors: obesity and diabetes. And in the presence of both of those, obesity and diabetes, A significant overrepresentation of TREM1 in comparison to TREM2. They actually did the ratio of TREM1 to TREM2, which was markedly elevated, i.e., activating those microglia to do bad things in the brain as a result of being diabetic and overweight or obese. So, you know, whereas we are looking for various unique molecules to do interesting things, etc., All of us are. The notion that, you know, here it is in terms of lifestyle. It's what people have been saying all along. Yeah, cut back on your carbs, get more exercise, don't become diabetic, make sure you're not insulin resistant. And, you know, as it relates to blood flow, I think your point is very well taken that there is this unfortunate dichotomy between the microglial camps and the vascular perfusion camps and the insulin resistant camps. Mm, yeah. And the free radical mediated brain neuronal damage camps and inflammation mediated, et cetera. When, you know, ultimately, I think if you take a step back and do the work, you realize there are a lot of factors that tend to unify all of these issues as being related. And when we get to the notion that, for example, nitric oxide regulates blood flow, regulates insulin functionality, insulin, i.e., insulin resistance versus insulin sensitivity, and as such regulates brain metabolism, and as such regulates microglial metabolism. You know, everybody's really pretty much has a unique nuance of their language, but pretty much they're all speaking English with different accents, if you will. I guess that's an interesting metaphor, but, you know, it all comes together. And that's what's so exciting right now is The dots are being connected, and for us to have focused— I use the term us a little bit liberally— on beta amyloid as being the cause of this disease has been incredibly myopic and a disservice, I think, to the general population of Alzheimer's patients and their loved ones. It's not, in my opinion, just the accumulation of beta amyloid, which, you know, we see in teenagers now with metabolic issues. So, you know, what you're looking at then, I think, is a piece of the puzzle. But, you know, it seems to me you're taking a broader view. Well, hi, everyone. Dr. David Perlmutter here. We hope you're enjoying this content. And if you would do so, go ahead and hit the like button. And if you're not already a subscriber to our channel, please consider doing so. We're really grateful to have you as part of our community. So let's get right back to the presentation. And I want to go to an area that I think is really fascinating, and that is your work that relates the accumulation in the human body and in the brain, presumably, of these microplastics that tends to act as an instigator of inflammation and then downstream can activate these microglia. So how did that all get started, and what are you thinking about these days?

Yeah, so that's actually an interesting story. So, we were looking at the molecular switches that are turning these microglia on in general in Alzheimer's disease. And, one of these molecular switches has one of these names in biology that has one of these terrible names. It's called NLRP3. And, when you follow all those letters back, it ends up with more letters and more letters. And eventually, this often happens is it ends up in the fly researchers because the fly researchers, they're the ones that knock out a gene and find out what it does. So then, they get to name it and they will name it something terrible that doesn't correspond to what it does in the human body. But, it's a NOD-like receptor protein and that's where the NLRP3 comes from. NOD is a whole nother thing. And anyway, it's a protein switch that switches in response to an incredible wide range of stimuli. And when it switches, it causes one of the greatest inflammatory responses in the body. In fact, it's a little bit like the nuclear bomb. It releases a cytokine called IL-1. And IL-1 is so inflammatory that we don't actually use it in the clinic because it's so hard to detect at the levels that it gets to in our blood. And so, what we typically use is another one called IL-6. I think that's a complicated one because sometimes it's not just inflammatory, it's anti-inflammatory, but also another protein called CRP. So, we use those proteins often as a marker of inflammation in the blood, but those proteins are triggered by IL-1 release. So, IL-1 is sort of at the ground level, but it's such a potent molecule that we don't typically build up large levels of it in our blood because it would actually, it would be lethal to build up a large level. But so this molecular switch called NLRP3 flicks into— flicks on in response to a number of stimuli. And we were investigating it in terms of eating amyloid. And so I do want to go back to the amyloid hypothesis eventually at the end of this podcast. But so a microglia might come along and it eats an amyloid aggregate. Now, amyloid and amyloid aggregates are actually well known for creating holes in membranes. And some people actually think that this is part of its antibacterial properties of amyloid, because amyloid has been shown to create holes in the membranes of bacteria. And so, some people conclude that amyloid might be an antibacterial protein. The concentrations they use in those experiments are Excessive. So I'm not sure, but that is an interesting hypothesis. But we do know that if you drop a little bit of amyloid on a membrane, we see a transportation of ions through the membrane that shouldn't normally happen. So calcium flux might happen if you drop a tiny amyloid, like a really tiny amount of amyloid on a neuron. We'll see calcium move into the cell, which we don't normally do. So it's obvious that the amyloid has made a small hole in the membrane. So when the microglia eat these amyloid oligomers, they go into the microglia in what's called a phagosome, and it punctures holes in the phagosome. Now, that is one of the triggers for the NLRP3 receptor, and that causes the NLRP3 receptor to activate and cause the release of this incredibly inflammatory cytokine, IL-1. Now, there have been some excellent researchers out there. Michael Hennig is one of them. who's deleted the NLRP3 gene and then in mice and then crossed that with an Alzheimer's mouse model. And what he found was almost no cognitive decline in those mice at that time point. I wonder what would happen if he kept it out longer, but which says that at least in the early stages of the disease, the IL-1 release and the inflammation caused by the amyloid and the microglia is a massive contributor to the cognitive decline in these mice. And, it's important that we always say in these mice because mouse models do have their issues in Alzheimer's disease research. So, we were researching this NLRP3 receptor. And then, I was happening to watch a nature documentary by David Attenborough and he was talking about the microplastics in the ocean. And, he said nobody knows what that does to the body. And I said, "I bet you those microglia puncture holes in the phagosome and activate the NLRP3 receptor and cause IL-1B to release, which is that inflammatory cytokine." So I bet you, I bet you that's what happens. So then I went to the lab, and this is what we call a Friday afternoon experiment. It's when you're just mucking around in the lab, you've got some extra time, and you just chuck out an experiment. So. I took a little nail file, a little metal nail file, and I rubbed it against a piece of plastic that we had in the lab. It was just a tube that you store a sample in.

It sounds very sophisticated.

Very sophisticated. And then, I collected the microplastic, I sterilized it, and then I put it on some immune cells in a dish just to see what would happen. And, I actually got a greater inflammatory response in that dish than in the positive control. So, in every experiment, you often put something you know is inflammatory so you can compare it and make sure that all your experiments are working. And, this was actually way more inflammatory than our positive control, which is essentially a fine crystal powder silica, which causes a disease called silicosis. If you ever breathe in cut stone, that causes massive inflammation in the body. So, if you're ever cutting stone with an angle grinder, please wear a mask. It can absolutely kill you. Anyway, that's the positive control for NLRP3 activation, and the plastic was outperforming it. Now, obviously, that wasn't very scientific. So, my next step was to buy in a bunch of microplastics. And, there are companies that will provide you with microplastics.

Interesting.

And, they weren't inflammatory. And, I was confused. I was like, why aren't these new microplastics inflammatory? But, you look at them down the electron microscope, they're perfectly spherical. These microplastics that you buy from the company, which is not what you get out in the wild. So, I needed a way to engineer microplastics in a consistent way. And I actually went to the engineering department and they were making parts for space equipment. And so, they could actually mill metal down to submicron accuracy because they were designing parts to go on satellites as well as in airplanes. And I got them to mill plastic. down to submicron levels. And, when we did this, we found that we ended up with a more natural-looking microplastic fragment, which had edges and spikes, and these were back to being incredibly inflammatory. And, we went through the sterilization and everything just to check that it wasn't a contamination issue. And, we actually competed against other substances to see such as silicon. And, I've even tried Well, we tried rubber and rubber turned out to be quite inflammatory as well. We've now tried a huge range of plastics and actually, we're finding weird things like the color of the plastic is actually affecting how inflammatory it is, possibly because of the chemical contaminants that are inside it. Now, to share with you some research that hasn't been published yet, but it's very exciting and it actually involves a hormone that you just mentioned a wee while ago, We— I decided to take this research further abroad, and we know that wildlife are being exposed to plastic. In particular, birds are commonly eating plastic. And so I got in touch with some colleagues who were researching these birds that were eating plastic. And some birds like to eat plastic and some birds don't like to eat plastic. There seems to be this weird preference going on. And we got blood samples from these birds and we did proteomics, which looks at all the proteins in the blood. And you end up with a signature. You know, some proteins are up, some proteins are down, and you get the signature. And you can then upload that signature to a database and say, what does the signature look like compared to all the other uploaded signatures in the history of science kind of thing? And the number one hit it came back with was dementia. Now, these were young birds, but the young birds with plastic had a dementia signature compared to the young birds that hadn't eaten any plastic. And one of the key proteins that was identified that generated the signature was BDNF. And the BDNF levels were actually half of the control birds, the birds that didn't eat plastic compared to the birds. So now, and this is happening this week, I'm growing neurons in a dish and I'm growing microglia in a dish. And we're going to measure the BDNF levels that come off after we activate them with microplastics to see what's going on there.

Gosh, that implication is terrifying. Yeah. You know, I got a question yesterday on social media. What can I do to rid my body of microplastics? What kind of answer can you give a person like that? You know, how does one do that? Maybe, maybe you have an answer. I don't know. But, you know, I just said avoidance. Yeah, avoidance is the thing. You know, stop drinking out of plastic bottles and You know, all the things that you're hearing about, we should be avoiding. But it's interesting then that you're saying this NLRP3 inflammasome activation via— and we know that, you know, mechanistically what's going on back to the microglia is that, you know, these DAMP receptors and PAMP receptors and even RAGE receptors are all, you know, ultimately funneled through activation of NLRP3, Which ultimately leads to transcription, activating the transcriptome, and creation in the brain of these inflammatory mediators as well. And the notion that microplastics, which I guess can get through the blood-brain barrier, one wonders.

So there's been a few studies on that, and that's a question that we've yet to ask. Is it the chemicals that leach out of the plastic, or is it the microplastics themselves that are getting into the brain? And we don't actually know the answer to that question yet. There have been some studies that have taken those perfectly spherical microplastics that I was talking about and they'll load it up with a fluorescent dye and they've seen the fluorescent signal in the brain. So, they think that the microplastics are getting into the brain. However, a follow-up study said, hang on, we've actually noticed that in the body, the fluorescent dye that's in the plastic can leach out. So, maybe you're just looking at the leached-out fluorescent signal in the brain. They did try to follow it up with electron microscopy and showed. So, I think that these small microplastics can cross barriers. One of the reasons for that is the barriers in our body are largely made out of oils. So, our membranes of our cells are oils, right? So, they're phospholipid membranes. So, the lipid part is the barrier and that's most of the barriers in our body are made out of that. So, if you take something that's oily, it typically gets through all of our barriers in our body. So, cannabis oil is one of that. It can obviously get into the brain because it's oily and the barriers in our body. Apparently, I haven't actually done this, but apparently, if you crush garlic and rub it on your foot, because the smell of garlic is actually an oil called allicin, it can actually get up to your tongue and you will taste garlic if you rub it on your foot. I've never done that, but apparently, because it can get through the Well, you can do it with DMSO. Yeah. Oh yeah, that's definitely true.

Immediately, you can smell it and taste it. Rub it on your hand.

Yeah, for sure. And so, plastics are made out of oil. So, I don't think they're going to have that same problem of bumping up against it. They don't have that hydrophilic outer layer. They are pretty much a hydrophobic oil blob. And so, I think the membrane isn't going to— is going to accept the microplastic rather than reject it and try and propel it. I'm sure proteins will help because proteins are largely water-soluble. They will help prevent microplastics going everywhere. I will say, when we've done microplastic studies, we see them everywhere and we just never— you just— they just get into every organ. They do accumulate in the liver a lot, it seems. Yeah. And, that's partly what the liver does. It has this thing called the liver sieve, which is able to sieve out these microplastics. But yeah, in terms of avoiding them, I do have a couple of tips. Fabrics are the secret source of microplastics in the household. There have been several studies, one in Australia in fact, that showed that 40% of household dust is microplastics. And our fabrics are often sneakily just plastics, they are polyesters, polystyrenes, etc. So every time you take them off, put them back on, you're just shedding microplastics into the air. And your carpet is probably a nylon carpet, and that's going to be shedding microplastics. All those soft toys that people buy for babies, all those soft outer fluffy toys, those are all microplastics. And so I just strongly recommend people move to natural fibers on all of those because those are the sneaky source of microplastics in our house.

There's a lot to think about here. You know, it's going to be an interesting afternoon for me. There's a lot— you planted a lot of seeds. You know, study came out, I guess, 3 months ago. I'm sure you saw it, looking at measurements in carotid artery plaque that was removed at the time of endarterectomy. Hmm. And, you know, stratified versus low versus high levels of microplastics, and then followed these individuals over, I think it was 3 years. And found that those with higher levels of microplastics in their carotid artery plaque that was removed had a, I think, a 3.4-fold increased risk of major cardiac event, major adverse cardiac event during that 3-year period. So we, and one presumes that might have something to do with inflammation. And, you know, and back to the notion of getting into the brain, we know that with age, The competency of our blood-brain barrier declines, A, and B, that now we're recognizing that microglial cells themselves are playing a role in maintenance of the blood-brain barrier, and that is less effective as they phenotypically change to the M1 phenotype and are less able to be supportive of a good blood-brain barrier. So this is concerning. Let me shift gears a little bit. You've done a lot of work in terms of looking at lifestyle factors that relate to Alzheimer's risk, but you focused significantly, I think, on zinc. And why so, and what have you found?

Yeah, that's a great question. So I was actually brought over to do a postdoc. So for a postdoc research fellowship, some other researchers— this was Katherine Lawrence, David Brough, 2 of my favorite mentors in the world, excellent scientists that won a grant to look at the zinc, the role of zinc deficiency, um, in Alzheimer's disease. So I sort of came over to do that work and I really expanded it because I really wanted to look in the human datasets as well to support our animal work. Because I think, you know, science gets stronger the, the, the— from cells to animals to humans. If you can cross that spectrum, then you get stronger evidence and you can really accumulate up a clear picture. So I really also wanted to look into epidemiological datasets. So the general principle is, is that it was David Brough doing some cell experiments. He found that if you depleted the zinc from an immune cell, an innate immune cell like a macrophage or microglia, they became hypersensitive and they became inflammatory. In fact, you could actually, if you depleted them enough of zinc, the NLRP3 receptor would activate and you'd get IL-1 release.

Hmm.

So the idea was, well, perhaps, um, we know that NLRP3 is involved in activating and causing an inflammatory response in the condition of Alzheimer's disease. Perhaps zinc deficiency would further exacerbate that. And the reason why that's really important is zinc deficiency is actually the most common malnutrition in the world. They estimate 2 billion people on the planet is zinc deficient. And as we age, our ability to absorb zinc declines. And it seems to be both intestinal transport of zinc goes down. So, they've done— these were great studies in the '70s that I don't think you can get away with now where they used stable isotopes of zinc. So, this is a zinc with— it's a little bit different to naturally occurring zinc so you can measure it as it goes gets eliminated. And they feed people oat gruel with and without zinc dosing, and then they measured all the zinc that came out of them in the form of poo and pee to look at absorption over the period. It was a horrible period of like 2 to 4 weeks or something like that. And they found that basically as you age, your ability to absorb zinc across your intestine drops significantly, by about half. And we also know that elderly people are more vulnerable in terms of what foods that they get. Say they can get put in homes and these homes can have poor conditions with poor food being provided to them, particularly low zinc foods, which require sort of a diversity of reasonably expensive foods. Things like shellfish and nuts, which are more on the expensive ends of things, are high in zinc. So, we knew that elderly people were at risk of zinc deficiency. It's a very common malnutrition. And, we knew that microglia get sensitized and activated in the presence of zinc deficiency. So, we wanted to explore that question using animal models and clinical data. For the clinical data, I looked at people who are enrolled in a cohort called the ADNI cohort. And, they basically get psychologically tested and cognitively scored. Every 6 months for about 10 years. And we get— we record everything off them. And one of the things we record is what supplements they were taking. And what it turned out was the people that were taking zinc supplements had a significantly slower cognitive decline over that 10-year period. And the cool thing about this experiment is we got to compare it against other supplements, you know, people who were taking vitamin C or who were taking other mineral substances like iron or magnesium. And what's good about that is it acts as a little bit of a control. There's this problem in epidemiological research called the healthy user bias, and it's basically anyone that goes to try and improve their life by taking a supplement, they'll probably already care about their health more than the people not taking supplements. And this has really crowded and complicated epidemiological research. You mentioned NSAIDs earlier. I think this was one of the big problems in the NSAID research. If you look at people who are currently taking NSAIDs, you'll see a lower prevalence of Alzheimer's disease compared to people that aren't taking NSAIDs. But I suspect that's the healthy user bias. They're out there trying to treat the arthritis. They want to keep moving. They want to keep pushing through their potential pains. Where there are people that just sit on a couch and they don't want to take any treatments. They don't want to go for a walk, so they don't care about their arthritic ankles. And so I think that's one of the NSAID problems. But then when we went and did the clinical trials, the NSAIDs failed. And so the epidemiological data led us astray here. But the cool thing about that zinc study is we got to compare it against copper and iron and magnesium and calcium, which gets rid of that healthy user bias. It says if you were taking a supplement and you happen to take zinc, are you going to have a slower cognitive decline from old age or mild cognitive impairment or Alzheimer's disease. We actually tracked all 3 of those levels. Wow. And then, we repeated it, that study in the mice. So, these mice are genetically engineered to get Alzheimer's disease. And, it turns out if you make them zinc deficient, they get it much faster, they get their cognitive decline much faster. And, what was interesting is if you knock out NLRP3, they're less sensitive to being zinc deficient. which indicates that it is a potential mechanism of action of how the zinc was working. It was sensitizing the molecular switches in the microglia to make them. But whenever I say this to the public, I always say the answer isn't necessarily supplementation unless that's the last resort, unless you are in a home and you can't get access to a healthy diet. I always think seeking the healthy foods is the better approach because it comes with more than just zinc. It comes with all the other benefits of taking a broad and healthy diet.

The entourage effect.

Yeah, absolutely, absolutely. But I know we've talked a lot about lifestyle, but the one thing I'd say is that, um, and this happened a lot with lung cancer, where, where people who get lung cancer now feel personally responsible for their cancer because they smoked. Maybe, maybe they smoked for 10 years when they were 20 or something, and now they feel personally responsible for the lung cancer. And there's actually studies that showed that lung cancer gets less research funding because people blame the people with lung cancer for getting lung cancer. And I really want to be reticent about blaming lifestyle factors majorly for Alzheimer's disease. And one of the reasons for that is if we look, you know, over the last 30 years, I think you would agree, David, that in America and in Europe and in Australasia, people's diet have gotten worse on average. Obesity rates have gone up. And physical activity rates have gone down. But despite that, the number of 80-year-olds with Alzheimer's disease is going down. The number of 75-year-olds with Alzheimer's disease is going down. So while our diet is getting worse and our exercise is getting worse, for some reason, Alzheimer's incidence is going down if you adjust for age. We are living longer, So the total number of people with Alzheimer's disease is going up. But once you adjust for that and say, okay, if we've got 180-year-olds picked at random today, how many have Alzheimer's disease? It's probably around 30, and it probably was around 33 10 years ago, and probably around 36 20 years ago. So for some reason, the Alzheimer's incidences are going down. Now, the vascular people we were talking about— the vascular people will say the answer is statins. and beta blockers, um, because we're now controlling blood pressure better, we're controlling cholesterol better. So perhaps that's why, while obesity is going up, heart attacks are going down and Alzheimer's is going down, is because we're now more effectively controlling some of these problems with drugs. I don't think drugs is obviously the right way to go, and I think it would be way better if we just had naturally good low blood pressure and naturally good statins. But I just would warn against the idea that lifestyle factors are a 90% contributing factor to Alzheimer's disease. I wouldn't put it at that magnitude. I would put it much, much lower. And I know that probably goes against your thesis, David, but I just find it that— I just think I know plenty of fit people with Alzheimer's disease. I just think that blaming Blaming diet and gluten and other things is too— it's too overstating the effects of lifestyle factors. I don't know, what do you think about that?

Well, you know, I think that whether we're overstating it or understating it, it is a variable over which we have control. So, if it's 90% or it's 10%, doesn't matter to me. Even if it's 10%, if we can You know, get the messaging out that raising— that exercise is not only associated with reduced risk, but we see interventional trials that demonstrate better memory function, enlargement of the hippocampus over a 1-year period in exercisers, aerobic exercise versus stretching. So, you know, looking at sleep, looking at keeping blood sugar under control, I think these are levers to pull. Are they 90%? That's a big number. I don't know. But in the absence of anything else right now, you know, if there were, for example, an Alzheimer's drug that were effective well beyond this notion of targeting beta amyloid, I'd be all in. I would absolutely be all in. And I think that when, for example, there are 3 trials that are either ongoing now or scheduled to start this year looking at GLP-1 agonists in the treatment of existing Alzheimer's disease. Semaglutide study is 14 milligrams of semaglutide orally a day. That starts middle of this year. I'm all in if that, you know, does what I think it might do. And I, I'm actually very encouraged based upon the mechanisms that you and I have discussed today. So I'm all in as far as that goes. But I think absent any of that, What else do we have? You know, we're not going to modify our genome if you're APOE4 or 4/4. Yeah.

So, one example of a study that, you know, you probably like, you probably heard of it, the FINGER trial. Have you heard of the FINGER trial?

Yes.

It's the Finnish Lifestyle Trial. And so, for 2 years, these people had weekly meetings with dietitians and they had personal trainers given to them and they're over 65. And what they saw was a very tiny, kind of disappointing, but a tiny improvement in cognitive function over 2 years. And so, it was a little bit disappointing, but it was statistically significant, but it was only tiny. They're now repeating it in the SINGER trial, which will be in Singapore, and the POINTER trial. America decided to get away from the -inger suffix.

Of course.

So, the POINTER trial in America, they've gone off and done their own version, but it's all based on the fact that Let's give them dietitians and personal trainers and everything. But my— the cognitive result was disappointing. But I tell you what was excellent: the economic result. They did an economic study on these people that were in the FINGER trial, which was done in Finland. That's where the fin finger comes from. They did an economic study, and it cost a lot of money. They had to pay for dietitians and personal trainers, so it cost a lot of money to run the trial. But then once they did the economic study of it, they found that they saved the government money because there were fewer falls, there were fewer heart attacks, there were fewer prescriptions for antidepressants, fewer prescriptions for cardiovascular interventions. And so it actually, by spending the money to change the lifestyle factors, the government saved money by not having to provide other medical interventions. And that is my favorite result from the finger trial. And, you know, it might put me— we don't want to get political, but it might put me more into the socialist camp because it says to me that if everyone had access to healthy food, great advice, a free gym membership, you know, I think social sports are probably even better. We would save money.

I mean, I don't know if in Tasmania if you have pickleball, but pickleball has has taken over America. And when I go out to the pickleball courts, it's people my age. I'm going to be 70 and— or older. I'm not the oldest guy there. And they're talking and they're waiting for their next game and they're playing an aerobic sport that challenges their balance and their reaction time. God, what could be better?

Yeah, that actually reminds me of a study where they compared walking, I think it was 10,000 steps versus ping pong. And they actually found, they measured cortical thickness and they measured cognitive performance. They found that the ping pong was better than the walking.

Yeah.

And they said the social component, but they also said, this is what the authors are now extrapolating from their data, none of them had played ping pong before. So now they're doing a cardiovascular social exercise that requires a bit of learning, a bit of new motor pathways, reactivating that brain and trying something new.

Yeah, and reaction time and eye-hand coordination as well. So, you know, ping pong. I have a friend named Dr. Daniel Amen, and he is a huge, huge proponent of that. I wanna leave one last thing I wanted to mention, then I wanted to go on to talk about the Adrift Lab. Are you still working with the Adrift Lab? Okay.

Oh, yeah, we were just out there.

The notion of zinc, and, you know, I remember back in residency that Real zinc deficiency caused something called acrodermatitis enteropathica. I'm sorry, I remember that. But the enteropathica part is interesting because what we see is loss of tight junctions in the gut lining in people who are significantly zinc deficient. And you know, getting back to our discussion earlier, that permeability amplifies the availability of these inflammatory cytokines in the body, which influence in the brain. We, we do know that they make their way into the brain, um, the, the function of these microglia cells. So yet another mechanism whereby zinc deficiency may be an issue. Tell us if, uh, about the Adrift Lab. What goes on there and why do I want to visit?

Yeah, sure. Uh, oh, so the, the Adrift Lab is a group of scientists, um, Jennifer Lavers and Alex Bond and myself, and we always have a huge cohort of PhD students and honors students And we're researching the effects of plastic on this environment, on the environment and on health and the wildlife. And it's been a really interesting collaboration because basically Jennifer Lavers and Alex Bond are ecologists and environmental toxicologists. They're not people that have a deep knowledge of the proteins and the mRNA and all that kind of stuff that's going on inside the body. But I saw that they were researching plastics effects on birds across the world. And they also look at a number of other things like plastics in the environment, what it does to the soil, and all this kind of stuff. And I said, hey, why don't we collaborate? Because I know a lot about what's going to happen in the body with the inflammation, and you guys have years of experience working with all the animals that are getting exposed to the plastics. And so we collaborated, and we are— it's actually really tragic. These birds are called shearwater birds. They're supposed to go fly for 5 years. And if they're not healthy, they don't, they don't make it. They actually can't even make it out of the forest. And they, they're supposed to go fly above the ocean for 5 years. They go from Tasmania, they go from Lord Howe Island, which is near Australia, out to Japan. And what we find is they get washed up. They're so full of plastic, they get washed up. And we then humanely euthanize them. And then we study what's happening to them when these birds eat plastic. And we compare them against animals that are dying of— sometimes they die of starvation because the parents abandon them. Sometimes they die of roadkill, they might get hit by a car. So we compare them against that. And when we opened up the first bird and it was full of plastic, I said, that's massively inflamed. And Jean and Alex go, how do you know? How do you know? How do you know that's inflamed? But it was glossy and it was puffed up and it had all the signs of inflammation. But they haven't— they didn't have that experience. So their collaboration allowed us to make all these new discoveries. I actually designed an experiment on the spot. It's called the wet weight dry weight experiment. So if you weigh tissue and then you let it get bone dry and weigh it again, it'll tell you the water content of that tissue. And if it's inflamed, it'll have more water in it. And we immediately saw that, that the organs of these birds that had eaten plastic were more inflamed than the organs of birds that have died from being hit by a car, for example. So there's chronic inflammation going on in these birds that have eaten plastic. We've since had a really successful collaboration. We've done histology now, and we've shown fibrosis all throughout the liver, the kidneys, the stomach, and we've actually defined this as a new disease. We feel like it deserves a word that we can attach to it, and it's called plasticosis. And -osis is just a medical suffix that means a prolonged dysfunction. And so, it's often associated with a buildup of fibrous material. So, asbestosis, the alcoholics have probably heard the word cirrhosis, which is a fibrous chronic condition that affects your liver. And so, the -osis suffix is something that we attach to designate a prolonged dysfunction. And so, there are other diseases like silicosis, which is when you breathe in silica dust, Or asbestosis, which is when you breathe in asbestos dust. And so now we feel like we've got enough of a picture about what's going on in the body to define this new disease, plasticosis. And unfortunately, I think we're probably going through plasticosis right now in small levels, probably mainly in our lungs would be our first site of exposure where things get really damaged. I wouldn't be surprised if the gut was extra leaky. And inflamed because of plastics getting embedded in there and causing IL-1 release, tight junction breakdown, all of that kind of stuff. So, it's been a wonderful collaboration with the Adrift Lab. And, we're ongoing now. We think we've got a blood biomarker for plastic exposure, so we're now validating that. Can we just take a blood sample to know how much plastic you've got in you? And, we're now actually building out even more. We're getting human samples now. To see what's happening with the plastic exposure. We've got human samples, we've measured the BDNF, and now we just need to quantify the microplastics to see what's happening there.

So, you'll be able to correlate then a marker of plastics either actual or surrogate with BDNF?

Yep, yep. Wow. So, that's the next one on the cards there. We're applying for grants like mad because that one's actually quite an expensive one. It's quite expensive to measure Wow. Yeah, it's not a cheap experiment.

Well, Jack, I think it's clear we're going to have to touch bases in a period of time, maybe a year or two, to hear what you've discovered in all these interesting areas that you're looking at. And you're doing such great work, and it's well beyond the work. It's the fact that you have this presence in media to get this information out that I think is so powerful because it It changes people's perspective about what's going on around us. And I think that can be very motivating. So, I want to really thank you for spending time with us. It's probably close to midnight your time. So, that's very, very kind of you.

Well, thank you very much for your time, David.

Great. And we'll talk soon. Listen, how can people follow you? Where can they find you?

Well, I used to be on Twitter, but I'm finding it's just too hard to be around anymore. So, I would recommend going to the YouTube channel. I also have a website which is just jackauty.com. A-U-T-Y.com. A-U-T-Y. I'm very happy for anyone to email me as well. I spend a lot of time emailing the public as they come to me for advice about things.

I know that. I reached out to you cold call and you immediately responded. And I think you were on your way to do some kind of fieldwork, right?

Yeah, we were going out to an island with no internet to look at plastic-affected animals at that point in time. Yeah. So we had a bit of a media blackout. We sent an email and then we couldn't talk to each other because you were on a yacht and I was on a nearly deserted island. And so, yeah, is that right? You went, you went, you went yachting, is that right?

Uh, no, actually, the trip that I had told you I was going to take, I did not take because I had a back injury. I put it off and ended up going just, uh, very much more recently than that. But, uh, that wasn't— it was just a trip over to the Bahamas. Yeah.

Yeah, it was a peck of luck.

I wasn't looking for microplastics, actually. I was looking for something called Bonefish. But we'll talk about that another time. Again, thank you again, and we'll stay in touch. Well, we certainly got in the weeds today, and I think maybe I did this interview more for me than for everybody else because you can see there's a lot of interest on my part. But I think the take-home message is that, let's say, Inflammation is a cornerstone player as it relates to what makes a good brain go bad. That these brain immune cells, these microglial cells, can shift to being bad from good. They can shift from being friend to foe based upon things like inflammation, exposure to various chemicals, etc. Our mission is to try to shift them back to being helpful. And finally, that microplastics are a clear and present danger for which we don't have a real answer, with the exception of, of course, prevention. Again, Dr. Auty's website is jackauty.com. Thanks to him for staying up late in Tasmania to join us on the program, and thank you all for joining us today as well. I'm Dr. David Perlmutter for The Empowering Neurologist, and we will be back soon. Bye-bye.