SIO369: Stress Increases Alzheimer's Risk in Women... But Not Men?

Transcript

This transcript was generated automatically and may contain errors — the audio is the record.

0:00:15 Thomas: Hello and welcome to Serios Inquires Only. This is Episode 369! Twelve, fifteen, eighteen. That's a magic number. No, 369. I'm Thomas Smith. Today's episode is is about Alzheimer's, specifically some recent Alzheimer's research that may shed more light on why women tend to suffer from Alzheimer's more than men, as you'll hear. Some of that is women just live longer, but there's for that, there's still some amount that's not explained.

And today's guest, Hannah Edwards, is a grad student at Washington University and is part of the Cerrito Lab, which a peer -reviewed study suggesting suggesting that stress could be the difference there. It could, along the way, Hannah's going to explain some basics about Alzheimer's to us. I know this is weird, but I can't stop thinking of the movie, The Father. If you didn't see that movie, it is about Alzheimer's, or at least, I guess, dementia.

I'm not sure explicitly which, but, oh man, that is a great movie. It has nothing to do with the interview. I just, can't, I every time I talk about or think about this topic, that's my first thought. Such a great performance, such a brilliantly written movie. So that's my recommendation to go with this. Again, nothing to deal with Hannah or this episode in any way. I'd just hope that people saw that because it was really, really good. Right, let's see.

Some other total BS before, before getting to the interview with Hannah. It does look like the idea of doing what people have dubbed online Seriously Awful Movies. I don't know if I love that. Seriously Awful Movies, because it doesn't really play on anything. I mean, kind of. Serious Inquiries Only, Seriously Awful. But the Seriously Awful is only like it's it's like eight steps removed from the original source of the wordplay.

I don't know, maybe I'm exaggerating, it's a couple steps removed from that part of the wordplay, so to me it didn't strike me as the obvious name that some other people thought was really good, but maybe I'm wrong, maybe it is a good one. For now, I mean, I don't have a better one, so fine. Yeah, Seriously Awful Movies, anyway, uh, that does seem like it, it might be a very promising thing to do for the bonus content.

And we've already been talking some ones with some folks. And I want to encourage you, if you are an expert in something, feel free to email and pitch a movie idea if you wanted to maybe try this. I have to say, you got to be specific. I get too many emails, apologies, but I can't just have someone be like, hey, I'm a geologist, let me know, or something. That's a fake example.

But like, I, need I, you have a movie or two you think would be good, because it's just the volume of it. It's just too, you much to follow up on with all that. Uh, but I do really appreciate everyone who reaches out, contacts the show, thomasetseriespod .com if you'd like to email about that. Yeah, there's some fun ones.

And, uh, Lydia is on board to join in those kind of, maybe be more of the plot, plot summarizer person, which would be so much more organized than I would ever be on that. So I think that'll really help. I can't wait. That's going to be fun. We'll make sure one happens for July. Um, other news is, uh, you're listening to Where There's Woke, the new show, released part three of the NASA James Webb telescope controversy. And it is NASA's damned emails.

It's the FOIA emails that were not included in the New York Times coverage. There's a whole trove of emails painting a really dismal picture of what went on behind the scenes at NASA in that renaming controversy, not even nary a mention in the New York Times story. Just to, I know it just to give you an idea of how upsetting I found that New York Times coverage, uh, enough to start a whole podcast about it and other stuff.

And the fourth in final part of the NASA James Webb story will be coming out next week. So Monday night or Tuesday AM, I guess. So once again, a reminder to go check out Where There's Woke, just search it and edit in any pod thingy. Right, that said, let's get, get to our interview with Hannah Edwards and more about Alzheimer's and why stress and stress response may account for an increased Alzheimer's risk in female mice, but not mice, male mice that can't male mice.

0:04:19 Thomas: There's no reason that's funny. Yeah, how are you doing today?

0:04:22 Hannah: Great. How are you?

0:04:23 Thomas: Am doing well. I'm excited to speak to you. Feel like this is a topic where you might have to teach us some stuff because I don't know much about this, but I'm excited to hear about the new study, the new paper. In the meantime, can we start with some basics? Like, first of all, how did you get into this line of research?

0:04:42 Hannah: Um, so whenever I graduated from high school forever ago, I started working in hospice volunteering and hospice care. And it put me into a lot of retirement homes and memory care units. And that was my first real introduction to Alzheimer's disease. And it kind of sparked something in me. And I was really curious. So I started doing some research on my own time and came back with more questions than answers. And That really kind of drove my interest in dementia and neurodegeneration in general. Continued all through my undergrad research. And now as a graduate student, I am deep in the weeds of Alzheimer's Disease.

0:05:19 Thomas: It's a particularly heartbreaking and affecting thing, don't you think? I mean, it's really something, you know, it can be just an absolute punch in the gut to see sometimes, huh?

0:05:25 Hannah: Oh, Absolutely. And and it affects so many people and so many families. And it's a problem that's only going to continue to get worse as our population ages. They're expecting the numbers of patients with Alzheimer's type dementias to grow from what currently is at about 6 million to double that in 2050, just as the population ages, so there's a lot of interest in trying to understand the disease more.

0:05:50 Thomas: You mentioned you researched into it at first and found just more questions than answers kind of thing. What were some of those mysteries that you came across when you first started looking into it?

0:06:01 Hannah: Alzheimer's so disease is generally caused by two proteins, amyloid beta and tau proteins. Proteins we know a lot, well, not a lot, we know a good amount about, um, a beta is produced in the brain and what it does in a disease state, but we don't really know what its real biological purpose is, um. Also a lot of questions as to, uh, the pathology of the disease is causing the symptoms it does, end up leading to neurotoxicity and neuronal death in the brain, and that causes cognitive loss, but there's a lot lot of blank spaces in between. And understanding risk factors for developing the disease are also some pretty glaring holes.

0:06:18 Thomas: Hmm.

0:06:39 Thomas: Yeah. That. So, So this A, you said A beta, is that what you said? So is that amyloid beta? So are you saying It's something where we don't actually know what it's like. Does it have like a normal function and we don'T know what it is, but we only know when it goes wrong kind of thing.

0:06:43 Hannah: Yeah. Amyloid beta. Yeah, so yeah, A -beta is made in the brain just normally. In disease states, it kind of clumps together and forms these sticky plaques in the brain in the extracellular space. It's produced in normal healthy brains, but in a disease state, it starts misfolding and sticking together. In mouse models where they've completely knocked out the protein, nothing is wrong with the mice. They do sometimes have deafness, I believe, but other than that, yeah, nothing really wrong with it.

0:07:21 Hannah: And yeah, it's just an interesting protein. And

0:07:21 Thomas: That's weird, but like there's got to be something. You'd okay, if we knock it out in humans, I would be a little concerned kind of things, but you don'T we don'T KNOW exactly what it might do.

0:07:30 Hannah: Right. So there's a lot of research going into trying to understand what exactly this protein is doing in a normal, healthy functioning brain. I think the current consensus, well, not consensus, but thought is that it's just a byproduct, like a waste product that just ends up sticking around. But don't hold me to that. It's an evolving field.

0:07:37 Thomas: Yeah, interesting. Yeah, so do I need to start flossing my brain? Should I should I get the when routine. Do I stick the brush in there? Get it going? Of that?

0:07:57 Hannah: Definitely.

0:07:57 Thomas: No. Okay.

0:07:57 Hannah: Yeah. Just got to scrub it out.

0:07:59 Thomas: Yeah. Mouthwash, but for the brain, we'll figure it out. Is Is there a lot of stuff in, I mean, the brain is so complicated, obviously. Is There a Lot of Stuff in Neuroscience? It's like that. We're like, well, there's this thing and it's got to be important, but we don't really know what it does.

0:08:12 Hannah: From my experience, there are quite a few questions where we find some interesting protein or something that's happening and we don't understand what its normal function is. And so that's whole lab could be dedicated to trying to figure out what exactly this one protein does or yeah.

0:08:25 Thomas: Yeah, that's fascinating. And so, you did you end up finding answers to some of those questions or are those, are the questions that you initially came across, are they still just like big mysteries that everybody's working on with this.

0:08:37 Hannah: Mean, we have gotten some answers. There's evolving research every day and we're starting to understand more how different systems within the brain, like the immune system and the the glymphatic system, which is involved with a lot of fluid clearance, how those things are involved in regulating these proteins and how that can help fight disease and develop treatments in the future. I think the coolest late-breaking stuff in the Alzheimer's field is we've had a lot of positive clinical trial results lately with these different monoclonal antibody treatments that target A-beta specifically. And then we've also had a lot of advancements in biomarker testing. So looking at blood tests for Alzheimer's disease, that can help diagnose a patient before they start to get symptoms.

0:09:20 Thomas: Yeah. So are there like genetic risk factors and stuff? Is that what, like the biomarkers you're talking about?

0:09:27 Hannah: No, yes, there are genetic risk factors. The general late -onset type of Alzheimer's disease, there are some genetic risk actors, things like APOE, which is a, I can't remember off the top of my head, but that is one of the top genetic risk vectors for late -inset Alzheimer's disease. For familial Alzheimer's diseases, you're looking at a different set of genetic mutations, mostly that are involved in the production and clearance of amyloid beta. Blood tests are looking at levels of amnyloid protein in the blood.

0:09:56 Thomas: Okay. Yeah, that's scientifically kind of two different things, whether it's the late onset, which seems like pretty much everybody's at some sort of risk for, and then like an earlier onset, what's kind of the earliest range that that people tend to get this? Oh.

0:10:10 Hannah: The late onset type of Alzheimer's disease, I believe generally starts to pop up in the sixties and seventies age group. The early onset can start developing as early as the forties. Familial cases, it is insanely scary. Pretty genetically locked. So I know that there's research into some specific like family groups in different countries that have this early onset type of Alzheimer's disease. And interestingly, another population that is at risk and develops early onset Alzheimer's disease is people with Down syndrome. They have an extra copy of the gene that produces amyloid beta. It's the amyload precursor protein, and they just have an additional dose of that.

0:10:21 Thomas: That's So scary. So, Whether the early onset and kind of a later onset, it is it ultimately the same thing though, it just happens sooner, or is there like a different, any anything different going on, um, the disease? Okay.

0:11:02 Hannah: It's pretty much the same disease. The only difference is the time course. So,

0:11:05 Thomas: So it's more, it's about like developing that plaque earlier for some reason, it's not some different thing, that's, okay, that's interesting, okay. So thanks for the primer, primer on the Alzheimer's. Let's talk more about what you're looking into, which involves stress. Do you want to kind of start us off down that path?

0:11:12 Hannah: Exactly.

0:11:23 Hannah: Um. Stress in the body is regulated by something called the hypothalamic pituitary adrenal axis, the HPA axis. You know, whenever I like to give the example of like you're going through a haunted house and someone like jumps out and scares you, that rush of adrenaline and Epinephrine that you feel, your heart starts pounding. Epinephrin and norepinephrine are flooding into your bloodstream. And that's signaling to a part of your brain called the hypothalamus that, oh, my God, we're being chased by a monster, like have to go fight or flight. And so that ends up triggering this signaling cascade where the hypothalamus releases something called corticotro releasing factor, which signals to the pituitary gland to release something called ACTH, which then signals to the adrenal glands to release something call cortisol, which is the primary stress hormone that is found in humans. And this cortisol can do things like increase your blood pressure to push more blood into your muscles, it increases the amount of glucose in your blood so you have more energy to run away and

0:11:37 Thomas: Mm hmm.

0:12:20 Thomas: Yeah. Or if you're my dumb brain, it gives me just a feeling like I can't move or do anything. That's super helpful.

0:12:28 Hannah: Freeze Is also an acceptable response to being Startled.

0:12:28 Thomas: Yeah. Interest. That's so that's what my brain is doing. It's like stay very still. The bear won't see or something. I don't know. Maybe I was running from a T -Rex.

0:12:31 Hannah: Yeah. Yeah. Yeah. Exactly. If You stay, yeah.

0:12:38 Thomas: It's like, yeah, my genetics, we ran from a lot of T -Rexes. It was like, you need to just stay very still. Don't move at all.

0:12:39 Hannah: Right. Yeah. There's fight, flight, freeze, all, all three are acceptable. It just depends on your bio, like who you are as a person.

0:12:51 Thomas: Boy, yeah. Let's get an awareness campaign for freeze going on. You only always hear fight or flight. You never hear freeze. Okay. For legitimizing my response. Hashtag freeze awareness. All right.

0:12:57 Hannah: Yeah. But yeah, yeah, so whenever this cortisol is in your blood, it helps you run, get away from the stressor and in a normal healthy system, that cortisol feeds back onto the hypothalamus and kind of shuts the system off. Um, that works really well in an evolutionary sense. Like Like you're getting chased by a tiger or a bear or a T -Rex or whatever. But in our like modern society, you're not really often getting chased by a bear. You're more like stressed about your taxes or bills you have to pay or literally a million things.

0:13:26 Thomas: Yeah. Yeah. But if I'm really still, the taxes won't see me though, I think. If I'm very, IRS is like, I don't, we don't know where he went. He can't see.

0:13:36 Hannah: Exactly. Yeah, he disappeared. I have no idea.

0:13:42 Thomas: He's blending in with the curtains. I don't know. I guess he doesn't have to pay his taxes. It's fine.

0:13:46 Hannah: Yeah. But with these like longer stressors, people are having these increased levels of cortisol in their blood for a longer period of time, and that can have detrimental health effects. Effects. So things like increased blood pressure and hypertension, diabetes, those are all risk factors that come from having this.

0:14:02 Thomas: Damn. One of these days, I want something to be good about stress. Wouldn't that be nice if it was like, no, this is actually good. You should go on roller coasters and like all this stuff because it turns out it's good. Pretty much all bad, it seems like, the stress stuff. It's not all, yeah, okay. Well, that sucks.

0:14:06 Hannah: Yeah, no. Yeah. It's all bad. Yep. Yeah, and tying this into Alzheimer's disease, there were some studies done in like 2006-2007 which looked at the blood cortisol levels that were found in patients with Alzheimer's disease, and they found that patients with higher levels of blood cortisol had higher rates of symptoms, and they progressed to a worse state of dementia faster than patients with lower levels of cortisol.

0:14:40 Thomas: Hmm.

0:14:40 Hannah: And this was followed up with some preliminary work that ended up in a paper from my lab that showed that just doing this acute stressor can lead to an increased level of this amyloid beta protein in mice, so that kind of started us on this path of looking at stress and how that is impacting a-beta kinetics in the brain.

0:14:59 Thomas: Now, The experiment, do you have really bad mice taxes situation, you're like, hey mice, you fucking, you had a, you had an entity here that we didn't even know about, you're hiding from us, so your mouse taxes are like, how do you stress them out, you just mouse Clone Clowns Like around the corners of a mouse uh maze or something, right?

0:15:13 Hannah: We have a couple of different methods. Mean, like I suggested making a tiny mouse haunted house, but the animal committee kind of frowned upon that, but no, we use an acute stress model. So for the bulk of this paper, we're doing something called restraint stress, where we just kind of put the mouse in a really small environment for three hours and then let them out. And then we also did something called a predator olfactory stressor, which which is very high tech. We bought, no, we bought predator urine from just Bass Pro and used that on Kleenexes and changed it out every 30 minutes. And that led to the same increase in A -beta.

0:15:40 Thomas: Yeah. Put A cat in The room Oh, okay. Bass Pro Shop, yeah, I, I, you know, if you need predator urine I have some, but you know, Bass Pro Shops fine too, I get A killer Deal on it, though. It's just all kinds of cat piss that's in my house all the time from the oh.

0:15:59 Hannah: Right. Yeah. And what was really interesting about the predator urine setup was if we left just one predator in there the entire time, they didn't get stressed out, but if we switched it every 30 minutes so they weren't like getting habituated to it, that they were terrified, they hated it.

0:16:20 Thomas: Interesting.

0:16:20 Hannah: But Yeah, it was I It's just like they could smell it, but then they were like, oh, there's nothing coming, so I guess Maybe it just smells weird, but was An little quirk, yeah.

0:16:20 Thomas: So They're cool With One Predator, oh. Okay. I thought they had like a one predator's, okay, first predator's free, like that one's fine. Well, well, to the second predator, damn it. Yeah, yeah. And so this you ask the mice questions and see if they can remember their childhood, right? And then you see how well they do on that test.

0:16:48 Hannah: No, they don't, they aren't really big talkers, the mice. So we have to find other ways to kind of measure those things.

0:16:50 Thomas: Yeah. Know, actually, I say that and I'm just realizing maybe that's one thing to ask in the basics section. Know we're all familiar, I think, with or people have family or whatever, but I actually don't know anybody personally who has Alzheimer's that I'm aware of. What are the kinds of things you see? Typically, you know, memory loss is what's associated. Is there a kind of memory loss? Is there, you now, like I've heard things where it's like, oh, you remember your childhood forever, but then the later memories you forget. You want to talk about that a little bit to give us an idea?

0:17:21 Hannah: I can talk about it as much as I can. I'm not a clinician, but yeah.

0:17:22 Thomas: Sure. Oh, of course. Yeah, yeah. Just the basics. Yeah.

0:17:25 Hannah: So generally with Alzheimer's disease, the first kind of signs and symptoms you see is people misplacing things, like they can't find their keys or they're putting things in weird places, and they can't seem to really remember. And this starts to progress and get worse and worse, they tend to have problems with short-term memory. So you might come in and visit them one day and then you come back the next day and they're like, oh, well, you never come visit me and you were just there the last day. They just don't remember. Lot of times I do believe it's pretty true that the older the memories are and the longer it's been in their brain, it's some of the last ones to go. So Generally patients will remember their childhoods pretty well, and um, it seems to be like more episodic memory type issues. I've seen a lot of videos where um, Alzheimer's disease, who are musicians in their previous lives, they can still play music that they used to play back, and then whenever they were younger, just fine, but they can't remember their children. So

0:17:59 Thomas: Mm-hmm. Right. Yeah. That's so fascinating. So it's like, I guess it's like these, I mean, this is not scientific, but it's almost like you've worked these grooves into your memory really deep. Those kind of stay, but the stuff that's, you know, well, you say your children though, that's interesting. So when me, let me make sure I understood the episodic part more. What did, what did you mean by that? Because if you don't remember your children, I feel like those, your your children aren't episodic, are they?

0:18:21 Hannah: Yeah. Yeah. Yep.

0:18:43 Hannah: Well, yeah. I mean, memories like that are very formative. So like whenever you were a child and you formed these really deep, long lasting memories, but you might remember that you have children, but that's what they look like now. And you'll remember that you'll be married, but you don't remember that that's What your spouse looks like now?

0:18:47 Thomas: Okay. Oh, gotcha. Right. Okay. Gotcha. Yeah. That's so heartbreaking. Okay, so how do we tell that in mice? Are we asking them interview questions, or are we just checking their brain plaque?

0:19:02 Hannah: Yeah. Yeah. So in my lab, specifically, we use a technique called microdialysis. This is something that's been used in neuroscience for a long time, but we've kind of modified it to work in the Alzheimer's disease space. What you end up doing is you take a probe that has like a filter at the bottom of it and you place that into the mouse's brain, and then you push fluid through the probe, and that allows you to collect fluid that's floating around inside the brain, and with that all the proteins that are in there. And so we pull that out and we sample it, and we collect for an hour each time. And so we have a time course of samples that we can go through. And then we run tests on that to see how levels of these proteins, A -beta specifically in this case, are changing.

0:19:51 Thomas: Hmm. So we've got our experiment. We stressed out some poor, innocent mice. We've got urine all all over ourselves, just accidentally spilled the predator urine everywhere.

0:20:00 Hannah: Right. Yeah. It's piss everywhere.

0:20:02 Thomas: Yeah. But, and then we've, we've checked the brain plaque. We've got, so for a course of time, that's kind of how you're keeping it, I guess, consistent and getting a good reading of, of what the, what the brain plaque is. So tell us what you found, I gas, as long as I have all that right.

0:20:16 Hannah: Have these different time points. That way we can monitor the kinetics. And we found that whenever you stress a mouse and you put them in this little tube or this little container for three hours, in female mice they have a really rapid response to stress, the levels of a beta go up almost immediately, and they stay high for the entirety of the stressor, and they continue to stay high after they're removed from the stress environment. And in males, we don't see that. They don't have the same response there. They generally don't respond. I think maybe a quarter of males in our first experiments responded, which is super interesting.

There's, it's a big difference. Um, it turns out that the way that males and females process stress in their brain is slightly different. Females, there's this whole signaling cascade that starts to happen once the hypothalamus releases this CRF corticotrobe releasing, which ends up leading to more excitable neurons. So they start firing more, and that in turn ends up releasing more amyloid beta into the the extracellular space. Meanwhile, the male mice, they have a different signaling cascade happening, which involves another protein coming in within the cell and pulling the receptor off the membrane, stopping the stress signaling.

0:20:48 Thomas: Huh? Yeah.

0:21:30 Thomas: Okay. So that doesn't mean that the male mice aren't stressed, right? It just means that there's a different, are

0:21:35 Hannah: So both and females are definitely feeling the stress. Like during the course of these experiments, we're checking their cortisol levels or corticosterone in mice. We're checking Their levels, and they're both feeling the stress. They're both unhappy with this, but the male mice are just not responding in the same way.

0:21:39 Thomas: Interesting.

0:21:51 Thomas: So it's like it sounded like the the male mice, like the stress kind of, I don't know, cleans itself up or something, and then the with the female mice, it like it kind of retains something more, is that kind of what it was. Hmm.

0:21:57 Hannah: Yeah. Yeah, exactly. That's kind of the takeaway here. Like the female mice are having this longer signaling cascade and there's more happening evolutionarily, I guess, to maybe drive a memory in deeper to remember the stressful event. And meanwhile, the male mice are kind of blocking that signaling cascade. And moving past it faster, maybe, I don't know, that's an evolutionary biology question, right.

0:22:04 Thomas: Yeah.

0:22:22 Thomas: That. Is really I know, I'd be curious about the evolutionary biology of that. It's almost like you're dividing labor. It's like you want, you want one, you know, I don't know, I guess sex or whatever to be in charge of like, just being able to do the quick response of something or other. And then you're like other sex of mice is like you're You retain this knowledge for next time or something. I don'T know. It's kind of weird. Is but is that kind of what it seemed like is happening? Something like that. You Like, tell over time how affects the the mice and different in ways, or is it just, you just looked at kind of this one thing?

0:22:38 Hannah: Yeah. It is, yeah.

0:22:54 Hannah: So currently this paper we just focused on this one thing. I, there's stuff in the works to look at a more chronic setting, because that's a totally different can of worms. I there's a whole other set of signaling things that are happening there, but in this case, yeah, it

0:23:01 Thomas: Hmm. Oh, sure. Yeah. Let me ask this, I guess, was this something about stress people were already researching? And so then your, your lab was like, let's take a look at how that also might affect Alzheimer's or was this entirely something that you guys found or something?

0:23:23 Hannah: There's been research in the field previously that looked at how cortisol is interplaying with Alzheimer's disease. There's a paper in the, I think 2006, that came out looking at cortisol levels and disease progression in humans. And then there's a pretty decent sized body of literature looking at the sex differences in these signaling cascades when it comes to stress. But this was the first time we really tied together the signaling cascade part of it and the sex difference and Alzheimer's disease, and tried to kind of pick apart on a cellular level, what is happening here?

0:23:56 Thomas: Super fascinating. And thanks for, uh, entertaining my questions. I'm sure barely makes sense to you because because I don't, I'm not a scientist, but yeah, um, is this, I know we're talking mice here, but is this something that we know is similar in humans, like

0:24:02 Hannah: Oh, A great question. Yeah. So we, that women are more impacted by Alzheimer's disease. Whenever you control for age, because women generally live longer than men, women are still more highly impacted by disease. There's probably a lot of factors playing into to that. This could be one of those factors. Trying to work at doing like a more translational human focused side to this to see if this is the same story that we're seeing in mice is happening in humans, that this stress signaling cascade business is leading to an increase in females, but not males.

0:24:41 Thomas: Hmm. I mean, I know we always do the studies on mice, and I know that like frequently yields interesting results, but like how just in general do we expect mice brains and human brains to be be like very similar? Hmm.

0:24:55 Hannah: Mean, there's always a problem between like trying to translate what you find in an animal model into a actual living person. There's a lot of of differences there, but some the more biological processes should hold over. I mean, we do share quite a few genetics with our animal models, but it's always, I mean you see it a lot in like clinical trials where you'll see studies all the time post saying like, Oh, we cured cancer in this mouse model and they move it to a clinical trial and it just doesn't translate.

0:25:08 Thomas: Yeah. Yeah. Yeah.

0:25:23 Hannah: It's a gamble, but I really do think that this stress connection and this sex difference could definitely be a playing part in disease in women.

0:25:31 Thomas: I'll tell you, mouse health care better be amazing. Like, we better if am I if a mouse goes to the hospital, we're like, good news, we have studied you so fucking much, we know everything. Yeah.

0:25:36 Hannah: Yeah. Right. We can cure everything.

0:25:44 Thomas: What? Tell any just say the words squeak squeak the squeak and we we uh we got you too. Bad, we, I don't think a lot of people are like, I need to desperately want my mouse to live longer. I don't know how much of that. There's probably some of it, but it's not a ton.

0:25:45 Hannah: Yeah, right. Exactly. Right. I mean, if you have like a little baby pet mouse, yeah.

0:25:59 Thomas: Yeah. Well, that thing could live to a hundred now because we know everything about it.

0:26:04 Hannah: But yeah, I think once we start digging into the more translational aspect of our findings and looking into a human population and trying to answer some of these questions, I really do think that we'll see some overlap there, that we will see a lot of these same stress signaling pathways in humans. And hopefully, it will pan out that Yeah, that is the case in humans as well.

0:26:18 Thomas: Yeah, but I guess as you mentioned earlier, this is one challenge in all of science reporting and something that I'm trying to like do my small part of helping people with, which is is I always want to keep the perspective in mind here because the, because to the non -scientist idiot me, whenever, whenever I read, and it's not my fault, it's also reporters fault. Whenever I read these things, it'S like stress is the cause of the thing. Then in my mind, that's like, oh, okay. We a hundred percent figured out that all of Alzheimer's is because of stress. You know what I mean? But it's like it sounds like it's okay. No, there's like a nine 9 % difference that's not accounted for by the age, average life expectancy of, you Now, men versus women kind of thing. It's, this is, it's a pretty small factor of the difference, right? That you believe you found or put it in perspective for us, I guess.

0:26:56 Hannah: Right?

0:27:13 Hannah: Going back to like the Yeah, I, it's a huge problem.

0:27:19 Hannah: I think come out that are in an animal model, whatever model it happens to be, and they say like, oh, well, coffee, one cup of coffee a day reduces your cancer risk by this much. And they did a study in like 30 mice, and then they're trying to say that this is the case for all people whenever you don't really have proof for that.

0:27:27 Thomas: Yeah. Right. And in the small print is like, yeah, 0 .04 % fewer. You know, we just use words like less or greater or more or whatever. And it's so hard for us to know what that really means. Is that super significant? Is it like, Like, yeah, 100% of whatever. Or is it just a tiny little marginal thing?

0:27:34 Hannah: Um, it's yeah, for sure, yeah, it is a huge pet peeve of mine as a scientist that science communications isn't better about that, because it really ends up giving people people, right, yeah, exactly, it ends up giving people like this sense of hope, and like hope is good, but like a over-optimistic view of how things are going, whenever it's a much slower process, and like we're making huge strides all the time, every day, but yeah, it's

0:27:59 Thomas: Yeah, yeah. Well, let's do a better job here.

0:28:11 Thomas: Oh, yeah right. Well, that's interesting. This is a more meta question, but I'll be honest. I almost mentioned it. Like, I'm pretty sure in my daily life, just as a person reading things, I thought we cracked Alzheimer's like seven times before, you know, because I'll see these headlines. It's like, they got it. They fucking, they solved it. You know, it'll be, we did the mice, we talked to the mice. It's all taken care of. Don't worry about it anymore.

0:28:40 Thomas: But, you know, there's cancer. You mentioned the cancer one. There's that too, where I'm always like, oh, cool. It looks like they got that. They figured that all out. But it never, so it gives me almost the inverse sense. Like I start feeling on one hand, I'm like, oh man, we're solving everything. And then I see like, well, no, I guess not. Like, I Guess all those headlines were wrong. And so then I feel like we're resolving nothing. But that can't be right either. It sounds, you're saying we're still making strides. It's just, it's hard to know what those are with all the bad headlines and crap written articles, you know?

0:28:40 Hannah: Yeah, it, yeah, exactly, yeah, it, I think it makes people kind of more skeptical about science in general because they see all these headlines and it keeps getting pushed and pushed and pushed, like, oh, we're science cured in this population. All you have to do is drink a glass of red wine a day. And then like people are still getting sick. And then they're like, well, why should I listen to the scientists? They said that they did all this and people are Still Sick.

0:29:12 Thomas: Yeah. Right. Done. Doing it. I'm just drinking cases, of wine a night just to make sure I don't get all these diseases and it's, I guess it's not going to work. Yeah. And I'll tell you, and I know we're branching off, sorry, but, and, and now I'm just realizing too, I really think it made a big difference during the pandemic. I think there's so many people who, for different reasons, but this has got to be one one of them, one of the reasons that they think like, oh, you know, big pharma, they've cured all the diseases. You'll hear people say that. People from my hometown, you now, they, they have all the cure. They have an evolt. They got all the cures, but they keep us.

0:29:30 Hannah: Right. Yeah. Yeah.

0:29:49 Hannah: Hundred percent. Right? Yeah. They answered everything

0:29:55 Thomas: Yeah.

0:29:55 Hannah: Already.

0:29:56 Thomas: I wonder if this is a small part of that, 'cause it does feel like all the time you see the headlines. So, we haven't cracked it. This, this isn't like a hundred percent of Alzheimer's or anything, but give kind of numbers, what kinds of segment of, of people are we talking about here where this could be maybe the deciding factor or the difference between whether what age they get Alzheimer's or whatever?

0:30:16 Hannah: So in my personal opinion, I think that the risk for developing Alzheimer's disease and this like late onset type disease, it's due to a combination of things. It's not going to be just one part. This is just a piece of a much larger puzzle. I think we've seen other studies come out in the past 10, 15 years that look at things like diet in relation to Alzheimer's diabetes. A really interesting one that kind of ties into this is circadian rhythm dysfunction. So people who are working night shift and working weird hours of the day, and they're up all night, they have an increased risk of Alzheimer's disease.

I think that this stress finding and hopefully what we're working towards looking into a more translational area, it just adds another piece to the puzzle. And like, we know stress is bad for a lot of different conditions, it leads to hypertension, diabetes, bunch of other things. But understanding the risk that stress in particular plays and how that can potentially affect women specifically, I think will kind open up new avenues for treatment, possibly, and screening for disease. So maybe we can catch people at an earlier disease state.

0:30:44 Thomas: Yeah.

0:31:22 Thomas: Well, plus I imagine just broadening the understanding overall of Alzheimer's, maybe one day there is something like a cure that can be found. And I'm sure all these steps along the way of better understanding what's happening is part of that, right?

0:31:35 Hannah: Definitely. Yeah.

0:31:35 Thomas: Yeah, good.

0:31:36 Hannah: And it's, it's a large picture, but different labs all over the world are contributing just little bits and pieces here and there. And hopefully one day in the future, we'll have a more rounded understanding. I can only hope.

0:31:47 Thomas: Telling you, got to get my brain brainfloss going. That's my, I'm going to patent that. You know, the pharma companies, they have brainflass already in their vault. They got it. They flossed the plaque off their

0:31:50 Hannah: Exactly. Saw an article on Facebook about it. I'm pretty sure it's true.

0:31:56 Thomas: Yeah. But I guess, uh, one of the main things I wanted to just clarify, and I think we already did, but just to make sure when I initially read this, I wasn't sure what to make of like the stress part, like, Oh, do could, women be feeling more stress or undergoing more stress, and I was looking at it that way, but it sounds like irrespective of that question, it's more about like the chemical response to the stress than like the quantity of stress per se. That right?

0:32:26 Hannah: Right. Yeah, I think it's kind of maybe a bit of both. There is a different biological process happening in this whole signaling situation that we found, but I think the types of stress that women and men experience can be slightly different. Women, this is kind of an old sexist view of it, but women generally were more involved in taking care of the children and taking care of the household. And whenever somebody gets sick, they're the ones involved in takingcare of them. Just a lot of different stressors on women versus on men.

0:32:29 Thomas: Okay.

0:32:54 Thomas: Gotcha.

0:32:54 Hannah: So I think it's kind of a combination of both of them, so That's just speculation, though. I've, yeah, purely biological and chemical, yeah.

0:32:57 Thomas: Oh, okay. I see. Okay. As far as the mice go, it was purely just the chemical reaction though, right? Okay. Yeah, yeah. Just it'd be interesting to, I'm sure somebody's going to start looking at, if whoever, lab just researches stress and stuff like that, I am sure that'll be a very interesting question for them to look at.

0:33:17 Hannah: I mean, in the background, looking into this paper, whenever we started coming up with these ideas, is we also see that a lot of, um, cases of like depression, post-traumatic stress disorder, just disorders of stress in general, anxiety, I believe is another one, they're more highly diagnosed in women than in men. And so I think there is something there about how women experience stress as opposed to men.

0:33:37 Thomas: Yeah. So what, where do we go from here? What are you looking at next? What, What, you know, what's on the horizon for you?

0:33:37 Hannah: Yeah, yeah. So, um, we're currently looking at trying to do some translational stuff, looking to see if we can replicate these kind of results we saw in the mice in a different way, not putting probes in people's brains, but looking at levels of proteins in people. Right.

0:33:56 Thomas: Start collecting piss. Here we go.

0:34:00 Hannah: Yeah, looking at different levels of protein in patients and seeing how this cortisol thing relates to levels of a in patients. That's definitely a huge part of it. We're also wanting to look at more of a chronic stress situation because generally in people day-to-day lives, you aren't having this acute three-hour weird random stressor, you're stressed for a long period of time, like from the taxes or the bills, or the politics or whatever.

0:34:25 Thomas: Yeah. Unless you work in the haunted house. But then maybe you're immune. Maybe we should work in haunted houses. Then we'd all be...

0:34:31 Hannah: Although, then you're just stressed because you're just screaming, like, people are screaming all day, it's a stressful environment.

0:34:36 Thomas: Yeah, unless you get accustomed to it. Then you're, like, immunized, you now?

0:34:39 Hannah: Could Yeah.

0:34:40 Thomas: I don't know. Maybe. Or maybe you just worried about paying taxes on your fucking... Nah, damn it! Haunted house taxes! Back to the taxes. Can't get away from it. Stress and taxes, the two, yeah.

0:34:48 Hannah: But But It's just the basis of life, man, but, uh, yeah, looking at, um, more of a chronic setting rather than this acute setting. And then another thing, I know that somebody else in our group is wanting to look at is how the other protein involved in Alzheimer's disease, a protein called tau, how that's regulated with stress, are all big open questions that we're just starting to dig into. And me personally, I am working more on the sex difference side, looking at how hormones, specifically estrogen and progesterone, can impact the kinetics of these different proteins. Oh,

0:34:51 Thomas: Hmm.

0:35:22 Thomas: So? There a big rivalry in the proteins, the tau versus the a beta, Alzheimer protein. Yeah, it's big, a house.

0:35:25 Hannah: God. You have no idea. Yeah, there's, like, camps of scientists that

0:35:29 Thomas: Divided.

0:35:29 Hannah: Are, like, team a beta and team tau, and it's a whole thing. It is. Exactly, a house divided it

0:35:30 Thomas: Yeah. Yeah. You got to snap at each other while you're dancing, all that kind of stuff, stuff, yeah, so you're, we're solidly team a beta over here, is that what, is that, is that correct? I just want to make sure I have the right shirt on, right jersey.

0:35:37 Hannah: Can be, yeah, there're nerd fights that happen, it's stuff. I mean, yeah. Tau is very important, but a beta is also important. I'm kind of a neutral party.

0:35:46 Thomas: Oh, Yeah. Take nothing away from tau, yeah. I'm not, look, you won't catch me belittling tau, I just, in general, but, like, let's be real, like, we're a beta of it, no thanks for uh, following along with my nonsense. Let's, this has been really cool. Is there anything we should look out for from, from you or your lab? Is there the next, the next mice piss study thing, or, or, uh, or what?

0:35:51 Hannah: Yeah.

0:36:10 Hannah: I Um, I mean, it's all in progress, we're still working on stuff, um, yeah, we should have hopefully another paper out here in a year or so, looking more at stress and sex differences and why it sucks to be stressed and also to be a woman, so, yeah.

0:36:19 Thomas: Cool Yeah. Yeah, we'll have to ask the mice. They'll have some answers for us. No. Hey, Hannah, this was amazing. Seriously, great job. And thank you so much for explaining that all to us.

0:36:30 Hannah: Hopefully. Yeah, no problem, yeah.

0:36:38 Thomas: Was great. Thank you. And I hope maybe, you know, let us know if that paper new does come out. Maybe we can have you back. Ooh, is there anything you want to plug? I know probably not, but I asked just in case. Social media, website, blog, MySpace.

0:36:45 Hannah: Do a follow-up for sure, um, I mean, our lab has a website, ceritolab.com, you can check us out if you want, we love doing collaborations, working with people, if you're interested, we have all our publications up there, so, uh, yeah, you can check that out.

0:37:03 Thomas: Excellent. Yeah, I'll pop that link in the show notes. Once again, thanks so much for coming on.

0:37:08 Hannah: Thanks for having me. Oh,

0:37:25 Thomas: Start collecting piss. Here