BJKS Podcast

78. Gillian Coughlan: Dementia, spatial navigation, and menopause

October 27, 2023
BJKS Podcast
78. Gillian Coughlan: Dementia, spatial navigation, and menopause
Show Notes Transcript Chapter Markers

Gillian Coughlan is a postdoc whose work focuses on the role of spatial navigation in dementia. In this conversation, we talk about how Gillian went from Ireland to doing a PhD in the UK, different ways for diagnosing Alzheimer's disease, what beta-amyloid and tau are, what spatial navigation has to do with dementia, and whether early menopause can affect women's spatial navigation performance and risk of getting dementia.

BJKS Podcast is a podcast about neuroscience, psychology, and anything vaguely related, hosted by Benjamin James Kuper-Smith.

Support the show:

00:00: Playing the piano
07:13: How Gillian ended up doing her PhD with Michael Hornberger in Norwich
14:02: How to find a good mentor
16:48: Sea Hero Quest
22:28: Diagnosing Alzheimer's disease
32:37: The role of Beta-Amyloid and tau in dementia
34:41: Spatial navigation, the entorhinal cortex, and dementia
44:14: Does menopause affect spatial navigation and risk of dementia?
50:31: Book or paper more people should read
52:37: Something Gillain wishes she'd learnt sooner
55:31: Advice for PhD students and postdocs

Podcast links

Gillian's links

Ben's links

References and links

Episodes with Michael Hornberger and Hugo Spiers
Coughlan, DeSouza, Zhukovsky, Hornberger, Grady & Buckley (2023). Spatial cognition is associated with levels of phosphorylated-tau and β-amyloid in clinically normal older adults. Neurobiology of Aging.
Coughlan, ... Buckley (2023). Association of age at menopause and hormone therapy use with tau and β-amyloid positron emission tomography. JAMA Neurology.
Coughlan, Coutrot, Khondoker, Minihane, Spiers & Hornberger (2019). Toward personalized cognitive diagnostics of at-genetic-risk Alzheimer’s disease. PNAS.
Coughlan, Laczó, Hort, Minihane & Hornberger (2018). Spatial navigation deficits—overlooked cognitive marker for preclinical Alzheimer disease?. Nature Reviews Neurology.
Eger (2017). The Choice.
Pertesi, Coughlan, Puthusseryppady, Morris & Hornberger (2019). Menopause, cognition and dementia–A review. Post reproductive health.

(This is an automated transcript that contains many errors)

Benjamin James Kuper-Smith: [00:00:00] In my attempt to do some proper investigative journalism, I looked on your LinkedIn profile and, um, I saw you had a diploma in music, grade eight, and whenever I see something about music, I have to ask about it because I did a lot of it myself and thought I was going to be a professional musician for a while. 

Uh, so maybe what did your, what did you get your diploma in and maybe what is the grade eight system for people outside of the UK and Ireland, I guess. 

Gillian Coughlan: Okay. So that's a great question. And this is bringing back memories because I haven't played piano in quite a number of years. So in Ireland, we have a grading system where you do two years with a teacher, elementary and preliminary, and then you start going on to grades one, two, three, four. five, et cetera, once you've done those two kind of first years, once you start moving on to grades, then you're, um, have to be assessed at the end of the year by a external examiner. And so, you know, you have your piano teacher, in my case, I would go to her house, some people have it [00:01:00] in like a little business, but in my case, I was going to. The piano teacher's house and, uh, we would spend about an hour practicing. She also had other trainees, um, and then I would get homework to do at home. And for the first year or two, we didn't have a piano at home. And so my parents didn't want to buy one until they knew I was. I was invested in playing piano, so, uh, that was kind of difficult, but I, the first two years are quite easy. And so I managed without a piano at home. so I got, 

Benjamin James Kuper-Smith: Sorry, not to criticize your parents, but how exactly do they imagine you get into piano without having a piano? 

Gillian Coughlan: um, not sure, I suppose they felt that, you know, an hour a week was enough for Gillian to. Um, you know, get some basic skills in piano lessons. That's how they felt about it. Now, they are the ones who put me into piano in the first place. They love the idea of, you know, having a daughter who could do a party piece or, you know, be at, uh, [00:02:00] events or weddings or whatever, and, and be the one who's entertaining, let's say, um, personally. I liked piano, I didn't love it. I have to be quite honest. I was doing it initially because that's what my parents wanted me to do. anyway, got the piano started on, you know, grade one, two, three, et cetera. And, um, I did it for about eight years in total. And I think when I stopped was when things got very busy at university. 

So I initially started at kind of high school or. Secondary school, I'm not sure what the equivalent is in Germany, but I probably was 14 or 15 when I, when I had started. And then, yeah, as I got into about the second or third year of university, it became very difficult to keep up piano and do quite demanding curriculum at university, I was studying psychology. And then I also had a kind of small part time job. [00:03:00] So that's when I gave up piano and. After I gave up piano, I really didn't play very often after that. Um, and my, my partner, his youngest brother is almost a professional musician playing, um, piano and violin. And so sometimes when I'm at their house, there's a piano and I occasionally play just to, to reinvigorate that side of myself, but no, I certainly don't. I guess practice often and I, I probably don't use it in my general life, but I'm sure it was good for development and things like that. I would recommend it to parents out there if they want to get their children into other things. I do think music is a very, good way to kind of. you know, ignite children's interest in other things beyond, you know, sports and, and what kids are doing at school. 

Benjamin James Kuper-Smith: What you like to play when you, [00:04:00] I'm asking just because, and for those not interested in the piano and music, I'll keep this, I'll keep this relatively brief. Uh, but the piano was my kind of main instrument. I also started pretty late, but then really kind of fell into it almost. And, uh, so yeah, I'm curious, like, what do you, what do you like to play now when you, you know, see that piano occasionally? 

Gillian Coughlan: when I was training, I was given specific pieces to do that I would be assessed on. So I never really got to learn all of the party pieces, et cetera. Um, so what I play, When I play now is say, for example, if I was at my partner's house where there's a piano, I would play whatever is, um, in their piano books so I can read music and I will play that basically. And so when I play now, it's more about me trying to remember exactly what the notes are and, you know, remember the aspects of how you read music as opposed to doing it for fun. I think Beethoven was probably, uh, some of my favorite kind of [00:05:00] pieces that I played as, as a kid, but I wouldn't say that I have a specific genre of music that, um, I love to play. do you? 

Benjamin James Kuper-Smith: Uh, yeah, I mean, I, I mean, I think, uh, in a, in a sense, like what I like, I mean, so it was classical piano. Um, I never played any jazz or improvisation or anything like that, but I guess in a, in a sense, I think I like the. pretty much the standard kind of piano repertoire you might have. I'm not like, I don't have any particular unusual things like, you know, played a lot of Bach, played a lot of like Chopin, Rachmaninoff, Debussy, that kind of stuff. 

I didn't really like Mozart and the kind of first Viennese classical music that much, but yeah, kind of the, the, the stuff you might see in a, in a, at a concert basically. 

Gillian Coughlan: hmm. Mm 

Benjamin James Kuper-Smith: Um, Yeah, and it's kind of interesting to me that [00:06:00] in a way you, it seems like you kind of diligently did what you had to do almost, whereas for me it was just like I, it was funny to me when you said like I had these pieces I had to do. 

I was like, that's not me. I would like if my teacher would suggest something like I really try hard to play something else. Um, in Germany, we don't really have these kind of like, you know, grading system as you have in the UK. So I think if I'd been in the UK, I might've had to do more of that, but here it was just, you know, private tuition. 

And I was like, no, I'm playing this and yeah, then, 

Gillian Coughlan: long with my piano teacher, I don't think, um, you know, I think that's a better way to be, because playing what you want is important, uh, especially when you're young, you know, when you're kind of trying to follow your own interests. Not that it's important to be diligent, of course, as well, but I do think there's something to be said for following what you like, kudos to you. 

Benjamin James Kuper-Smith: yeah. And it obviously works a lot better if you're [00:07:00] so into it, that I actually practiced for like four hours every day, basically, because I was so into it. Right. So it was like a very, it's not like I would want to play a piece and then, you know, not practice it. Um, But yeah, anyway, we wanted to talk about dementia 

Gillian Coughlan: Yeah, dimension. 

Benjamin James Kuper-Smith: and spatial navigation. 

Yeah. I'm curious to kind of basically, uh, just start off, like, how did you get into that topic? Uh, I saw you had a bachelor's and master's in psychology, um, in Ireland, and then somehow you ended up in Norwich. How did that happen? 

Gillian Coughlan: yeah. So guess it was in 2014 that I graduated from clinical psychology and I had done kind of a master's in clinical psychology at Trinity College, Dublin in Ireland. The typical route for psychology graduates was to either go specialize in something else, like occupational health or, or go do medicine or something like that, or go do applied clinical psychology, you know, work in practice. 

And you could go down [00:08:00] a counseling route or a clinical psychology route. So they're both slightly different. And so I had done a bit of research throughout my undergrad and my master's and I really loved it, but there wasn't a traditional route for research in Ireland. So I kind of was like, well, maybe this isn't a realistic kind of, uh, And so I went after I had graduated in my master's to work in a secondary mental health clinic to get experience as a clinical psychologist. so I state 

Benjamin James Kuper-Smith: secondary mental health clinic. What does that mean? What's the. 

Gillian Coughlan: don't get better at primary health services. So when they first look for mental health services, if they. are not getting better with what they're first offered. They're usually moved on to secondary mental health services. So generally they'd be kind of seen as like a more, um, they would have a more severe condition or they have something that's treatment resistant. And so when I was [00:09:00] there, it was a very meaningful experience in that. I, I think I matured a lot, but. I felt that this doesn't bring me meaning in life. I didn't feel that I was making a huge difference there. I, I did find it challenging and in a good, and it's good to find things challenging. Um, but I just didn't feel that it was what I was supposed to do. So a friend of mine. Who had also done her master's at Trinity. And so we were friends because we studied together basically. She had gone to the University of Cambridge to do research. so we would keep in touch and she was like, Hey, look, there's a, we're looking for another research assistant here. 

Would you be interested? And I said, yes. And so we had, I had an interview with two people. They were like, great, come on over. And so then I moved from Ireland to England. Um, and I started working as a research assistant at the University of Cambridge. I knew straight away that this is kind of [00:10:00] more what I'm supposed to do. 

I just felt that I a very easy transition to that. Um, I also had friends that were there who were Irish and I made new friends. And so I was very happy with the decision I had made. But then I had another decision to make because to stay in research, you need to do a PhD. And so I hadn't really planned out whether or not I wanted to do a PhD when I had initially moved to England. 

And so. know, I had a lot of friends in Cambridge at this point. And so they were like, you really should just start looking straight away. Cause you know, you like your research. A lot of my friends had already started PhDs in Cambridge. And so I said, okay, I'll, I'll start looking. And so when I started looking, I had just missed the deadline to apply in Cambridge. 

And so I was looking all over the UK. And that's when I saw a PhD position advertised at Michael Hornberger's lab. And Michael had actually been in, well, he was in originally in [00:11:00] Australia. he had come to Cambridge with his wife and two, and two kids. And he worked there for a while. And then the university of Angola or Norwich medical school had offered him a professorship and a fantastic, you know, opportunity to open a lab there. So he had gone there. I didn't know him at this point. Like I didn't know Michael in Cambridge when I was there, but when I saw he was looking for a PhD student in Norwich Medical School, I was really interested in his area of research. So he was interested in preclinical stages of Alzheimer's disease, detecting Alzheimer's disease kind of at that asymptomatic stage, using very sophisticated cognitive tests. what also appealed to me is he had a collaboration with a basically research dietician who was interested in whether or not Omega trees could help people age well. And I, I was also interested in kind of the whole concept around aging. Well, that's always something I've been interested in. And so that really sold me. [00:12:00] So I applied for the position. I had also applied for another position in London. I did two interviews more or less at the same time. And, in, in Norwich, they just said, look, we'll give you all of the funding. We're very happy for you to come. Um, I had spoken to Michael over the phone and he just seemed like right kind of, the person I was kind of looking for, I guess, in a mentor, um, and in London. They were a little bit more like, Oh, we're not sure if funding can be secured or not. You know, it wasn't a hundred percent. Um, so I felt it was safer to go with, with our, my Norwich offer. And so I then moved, uh, basically to Norwich. Um, now I still had a partner in Cambridge. And so every second week I would commute to Cambridge and every second week he would commute to Norwich and that's how he, how he kind of did it. 

But, um. I think it was a great decision. I really think my PhD was a fantastic experience professionally and [00:13:00] personally, and so, um, I'm really basically happy with the decision I made there. Um, and sometimes I used to think, Oh, would it have been nice to live in London? But you know, when you're doing your PhD, can be quite busy for you. 

Um, You know, don't know what your experience with PhD was, but it certainly can get very busy at certain times of the year. And, you know, I think being somewhere like Norwich, where there's lots of nature, you know, it's a lovely kind of town or, or a small city. Um, and it's also close to London and Cambridge, if you want to get away, that was very advantageous. is great, but London is also, you know, there's a lot of sensory, uh, information coming at you when you're in London. And I just wonder. Would that have been the best environment when you're also trying to get a kind of a lot of work done and stay calm in stressful, stressful situations that sometimes come, et cetera. yeah, so that's kind of how I ended up doing [00:14:00] a PhD in art. 

Benjamin James Kuper-Smith: You mentioned that Michael was kind of what you were looking for in a mentor at the time. Uh, what, what were you looking for and kind of what makes a good mentor or how do you select the right one? Because it also sounds like you didn't spend a huge amount of time with Michael beforehand. 

Gillian Coughlan: hadn't. Yeah, that's a great question. So, and I suppose selecting the right major is something that has changed for me. I've developed, right, so what I need in a mentor now might necessarily been have what I need or been what I needed back then, or it mightn't be what I need in a few years because when you're opening your own lab, you still kind of have mentors. You know, that's kind of how it works in academia, right? I think particularly then when I had graduated my undergrad degree, and I was very lucky in my undergrad, I'd done research and actually was able to publish my undergrad thesis. I had a really supportive mentor there. Uh, who is also German, so I just seem to [00:15:00] collect German mentors. 

Um, but he, uh, he said to me, be very careful who you choose as your mentor. He said, you can be quite sensitive. It, that really struck me at the time. I was like, gosh, what does he mean by that? And I knew I kind of can be a sensitive person, but I was like, I didn't even think he had noticed that. And so. Uh, when I was talking to Michael initially about getting the, you know, getting or doing a PhD with him, something slightly reminded me of, uh, something in Michael reminded me of my previous undergrad, uh, mentor. And Michael also seemed quite upbeat. Sometimes in science, you can get a lot of people who are very serious, which can be okay, but me, I knew it was important to have someone who was kind of upbeat, who wouldn't get too cross. about things, for example, uh, if something wasn't going right. He seemed interested in training people. He, uh, was quite advanced [00:16:00] himself. So I knew he had climbed already to a certain level, which meant that if he was already at a certain level, he'd be interested in, in helping, uh, kind of other trainees get off that ladder, if you know what I mean. So that was another plus. And I, I suppose a lot of it was. intuition to, you know, I kind of just felt, Oh yeah, this is someone who I can chat with. This is someone I can ask for help if I need help. And so that's why, um, I think I, I, I knew that it would be a good fit. Mm hmm. Mm hmm. 

Benjamin James Kuper-Smith: Just before I forget it, I mean, I have a whole interview with Michael, if people are interested. Um, and there will be a fair amount of overlap, but I guess what I talked about with him and what we'll talk about now later. Um, I mean, if I... If I remember correctly, what you said you were going to do and what you ended up doing, was that exactly the same thing? 

Because it sounds to me then, I mean, with, with Michael, there was, I guess, around that time, he was doing the Sea Hero Quest game. [00:17:00] And I think that completely changed what he was doing. Um, again, I mean, I talked to Michael and Hugo Spears at length about Sea Hero Quest, um, but maybe briefly, what is Sea Hero Quest? 

And yeah, how did you get involved with it? 

Gillian Coughlan: hmm. So I did end up doing, uh, kind of what I had came to do, but CVRequests became a major part of what I was doing, and initially it wasn't a major part. I don't think it was even in... In the like, um, kind of proposal for my PhD project, but anyway, um, so when I arrived, they had just, finished collecting the benchmark population data from C Hero Quest. 

And the way they did that then is... They created a kind of online game, or you could use it on a phone or an iPad. And it's basically able to record how well people navigate space or solve orientation tasks. And so what they [00:18:00] wanted, what they initially wanted to do with this game was be able to record how people navigate in kind of a open arena or an open environment. Or how they, how well they remember certain spatial landmarks and that kind of thing. wanted to record that information and then they also recorded information from the players on, you know, what age they are, where they grew up, what their nationality was. It's kind of basic demographic information, I guess what, that's what you call it. The initial aim, at least I think for Sea Hero Quest was just to kind of understand how, how do humans navigate? Because we have a lot of information on, you know, human memory, how we remember things, people have been studying memory for a very long time, orientate space. Was a little less well and well understood. And there wasn't any kind of normative benchmarks on how people navigate. [00:19:00] men and women differ on how they navigate? There's kind of a stereotype that there is a difference between men and women, but is that true or not? We didn't know. And all of these kinds of things. become important when you about potentially using a spatial navigation task in a medical setting. if demographic factors influence how people perform, you need to take that into account when you're trying to potentially diagnose someone with spatial disorientation. So someone's 

Benjamin James Kuper-Smith: Sorry, just to briefly interrupt, um, just so we don't forget it, so for people who don't know, this wasn't like a small task, this was, uh, I mean, the task is retrograde forward, but it's basically as a game that people like playing, and they got, what, like, two and a half million people or something to play it. 

So it's, uh, As a foreman, yeah, but, but it's basically just to kind of put in context when we say we have some demographic areas like of a lot of people. So this is like conceptually very different from like a [00:20:00] typical study you might run online or something like that. Yeah. Sorry. 

Gillian Coughlan: yeah. And so if people want to know more about the origins of the game, they should listen to Hugo and Michael's discussion. Cause I'm sure it would be more informative than my own. I wasn't around for the development. I just kind of used the data when it came in, but it was. very, it was very successful in that it became available on the app store and the play store. 

And it was downloaded by more than 4 million people. And we were able to collect data on a large proportion of those people. who downloaded the game had to consent to their data being used by scientists. So some people could have downloaded it, for example, and just said, no, I'm not interested in, in the science. 

I just want to play it. you know, like they play Candy Crush or something like that. And so, um, yeah, that's just another thing. Another aspect of it, I guess. But I used to give it to my participants in my PhD study, PhD study, which we might talk about later. um, [00:21:00] thing that always struck me is how visually, stimulating the game was. 

So I think that's really what, what made it so successful was the game itself was very, like, even just the, you know, having it on your phone, it felt like an immersive experience. there was something very visually appealing about the game and it also felt like a game that you kind of pay for, if you know what I mean, it was just that level of good. Um, and. 

Benjamin James Kuper-Smith: Hmm. It wasn't like a, an experiment you do by scientists that just looks like someone coded it in three weeks. Yeah. 

Gillian Coughlan: it, you know, like those MATLAB, uh, 

Benjamin James Kuper-Smith: Yeah, yeah. 

Gillian Coughlan: um, 

Benjamin James Kuper-Smith: It's like toolbox or whatever. 

Gillian Coughlan: Yeah. So it was very sophisticated. Um, I think there's another program called Unity. Game or something that Michael used to talk about that can make something similar, but to see hero quest, but they had actually hired a gaming company. 

I think it was glitchers Inc in London to do this game for them. [00:22:00] So, you know, they really had experts basically working on this. Um, and as you probably know, it was also sponsored and financed by Deutsche Telekom. Um, and so Deutsche Telekom were interested in doing something for science. So had kind of asked Michael, Oh, we're interested in giving money for something that, can do good. Um, and so that's how, um, Michael and Hugo ended up kind of developing the game. 

Benjamin James Kuper-Smith: Yeah. Uh, so how did you end up using it for Alzheimer's? 

Gillian Coughlan: Yeah. So I suppose. Michael was always a dementia researcher, and so when he had initially pitched to understand how people navigate space in the normal population, which we were learning with C Hero Quest, had wanted to know that so that it could help him inform how we best develop tests to diagnose Alzheimer's disease. how do we make them sensitive and [00:23:00] personalized? Do we need to make these tests, like, of spatial navigation personalized to the individual based on their gender, their age, et cetera? so, this is kind of a question that my PhD then sought to answer is, can we use the information we've collected from the global population on navigation ability to make a more sensitive cognitive test Alzheimer's disease? so, um, I suppose just to go, I think you mentioned you want to discuss the review and the P& S paper. So what we first did is we just decided to write a review on spatial navigation in Alzheimer's disease. And so. Some people had worked in this in that some people had looked at spatial navigation in people with mild cognitive impairment, people with dementia, people who are already clinically diagnosed, but very little to nowhere could be done on spatial navigation tools in a preclinical [00:24:00] population. 

So preclinical is just defined as people who have of Alzheimer's disease pathology in the brain, but they don't have any cognitive symptoms. They're going about their daily life well. They're functioning well, they might have some degree of subjective cognitive decline, um, but not enough to warrant a clinical diagnosis of mild cognitive impairment. And that diagnosis comes before a diagnosis of Alzheimer's disease dementia. 

Benjamin James Kuper-Smith: So brief, uh, question here. Um, how, I mean, this also relates to kind of the whole, like, I guess the whole point of like developing these early diagnostics is to find the people who, you know, who, who don't have full blown Alzheimer's when it's too late. Um, so I'm curious, like, how do you, for example, maybe how is dementia usually. 

diagnosed and in the case of people who are preclinical, how do you find someone with neural, you know, pre stages, let's say of Alzheimer's without them really having any behavioral or cognitive [00:25:00] problems? How do you find those people? 

Gillian Coughlan: Yeah, so that's what most of the Alzheimer's disease field are working on at the moment. Um, and so I guess. How we find them is we look at biomarkers. So what we do is if someone suspects that they might be having some cognitive issues and they're concerned about dementia and Alzheimer's disease, they'll come into a memory clinic. what we can do there is we can. measure Alzheimer's disease in the CSF. So we know that Alzheimer's disease is caused by two neurotoxic proteins, or the deposition of these proteins in the brain. One is beta amyloid and the other is neurotoxic tau, right? So we have these amyloid and tau proteins that we know cause Alzheimer's disease. And so we can take a sample from the CSF and measure them there. If we do that, It can be a little bit invasive, so taking a lumbar puncture to get a CSF sample can cause [00:26:00] headaches, um, in the worst case you can get infections and things, um, as a result of it, which is not that common, but it happens. So it comes with a certain degree of risk and generally people don't like getting lumbar So the next option is, you know, um, a positron emission tomography scan, which is quite. expensive brain scan, and we need to inject contrast into the individual. So what that contrast do is, so it's injected, you have two different contrasts for amyloid beta and tau, and that contrast kind of moves into the brain, and it binds to that neurotoxic that's depositing, right? And once it binds, we can image that on MRI. These scans are really, really valuable because what we can then do is look, not only does the person have Alzheimer's disease, but exactly where is it? Because that's also important, uh, for diagnosing Alzheimer's disease. You know, where are these neurotoxic proteins depositing in the brain? that's the second way, but that's [00:27:00] expensive. And it's not, it's usually not part of the coverage that people have in different countries. So, you know, it's not your standard. Like assessment and so if you wanted to get something like a positron emission tomography first scan You'd firstly have to find a hospital that's willing to do it or who does it as standard and then you'd probably have to pay Quite a bit to get that done unless you're doing it for research But if you're doing it for research, you don't usually don't get your results. 

So, you know And so in the past five years Blood base biomarkers for Alzheimer's disease have come online and they really transform the field Now, they haven't really made it into clinical practice yet because there's many different assays that are used to measure how much Alzheimer's disease we have in the blood. we're still working on creating cutoffs for what's abnormal and what's not abnormal. And those cutoffs will vary depending on [00:28:00] the type of assay and the machine you're using to measure Alzheimer's disease in the blood. That field in blood based biomarkers is rapidly progressing and developing, but it's not at the, we're not at the place where we can roll it out to the GP, for example, it's just not there yet, but I expect it will be maybe in the next 5 to 10 years at least, and so what blood based biomarkers do, so far, they're very good at measuring levels of beta amyloid, in the brain. 

So we know that, um, if we measure Alzheimer's disease in the blood, what we're seeing is that it correlates very well with, um, beta amyloid as measured with a, a PET scan. So that more expensive measure I, I kind of mentioned just previously. What it doesn't do though, is a blood based biomarker doesn't correlate so well with levels of tau measured with PET [00:29:00] scans. the blood based biomarkers seem to be a good proxy for how much beta amyloid an individual has. But it's not as good a proxy for how much tau an individual has. Is that a problem or is it not? I, I don't think there's a, there's a, a firm consensus around if that's a problem or not. But just to contextualize this a bit more. we age, we all deposit a certain amount of beta amyloid. It's not that uncommon for you to start accumulating amyloid in your 70s, for example. is a bit more abnormal to start accumulating amyloid, um, in your 50s, you know. So timing, the time you accumulate can be important. But anyway, suffice to say, the real thing that seems to be problematic for cognition is when we deposit tau as well. we have a certain level of beta amyloid, [00:30:00] usually we can measure that first. We can see that coming online first with a scan, for example, and then we get tau. Now, When we can see a significant amount of tau depositing in the medial temporal lobe, so usually it's first found in the entorhinal cortex, the, the, um, find it hard to measure in the hippocampus, but in the medial temporal kind of area, and then it kind of projects up into kind of more parietal regions. 

And so that's the typical course of spread. And so when we see tau in the medial temporal lobe, and when that tau starts to move outside the medial temporal lobe, Temporal lobe is when people are super vulnerable to cognitive decline. So they'll usually, you know, go down a slope very quickly. Once tau is in these areas of the brain. so when we're measuring amyloid with a, a kind of a blood sample, still very informative kind of in that. Okay. So if we see people are having abnormal levels of beta amyloid, [00:31:00] that's important. We know they're at their risk. But if we don't know what their levels of tau are, it's kind of. I suppose a slightly missing piece and so I think what people who are developing these blood based biomarkers are trying to do is see if we can get a biomarker for tau as well and so that would, that would be important because then we can look at Vote levels of beta amyloid and tau in the blood and make inferences about what we think is happening in the brain. So at the moment, as I said, we can really only make inferences around how much beta amyloid is kind of in the brain. 

Benjamin James Kuper-Smith: You've kind of already, I want to ask kind of what the differences are between bit and tau, and you explained some of it, but I think it might be useful to go into a little bit more detail. Do you, for example, I mean, I'm assuming from what you said that they, for example, don't really correlate with each other, um, or not particularly highly, but I'm curious, like what kind of, what are the, um, in, in the context of dimension Alzheimer's, like kind of what are the [00:32:00] differentiating factors between the two? 

Gillian Coughlan: beta amyloid and 

Benjamin James Kuper-Smith: Or maybe also for spatial navigation. Yeah, exactly. 

Gillian Coughlan: um, so what's the difference? So they do correlate, they just don't have amazing, uh, like there's not like a one to one correlation, if you know what I 

Benjamin James Kuper-Smith: Yeah. 

Gillian Coughlan: So it's really interesting. As many people might know, some people... Can deposit amyloid to, um, you know, a significant amount of amyloid and they can also deposit a significant amount of tau and never get symptoms of Alzheimer's disease, right? 

We call these people resistant to the implications of having this disease in their brain. And so there's a lot of people studying that. I work with people studying that to try and understand what is it about these people that help them to stay cognitively well. despite these deposits. And so that's really important to understand because that can inform treatment, obviously. some people deposit beta amyloid, but it takes them a long time to get kind of [00:33:00] deposit tau. And if they don't deposit tau, then, you know, they're not so at risk for cognitive decline. And so that's another interesting piece is, okay, so some people are resistant to tau, but not so much amyloid. And so what's happening there. And, but in the general course of Alzheimer's disease, if you're, if you have a very typical patient, you will see a correlation between amyloid and tau such that amyloid accumulates. It kind of, it spreads and then you get accumulation of tau in the medial temporal lobe and then amyloid hits a threshold where it kind of stays at the same level across the brain but tau rapidly increases and so as tau increases then You know, your, your cognition declines. 

And so amyloid is interesting because when it goes up, when, or when amyloid, um, starts depositing or, or increasing in the brain, it kind of increases everywhere. It doesn't follow a very typical spatial pattern like [00:34:00] tau does. Like tau is very specific kind of where it spreads, but amyloid is a bit more. Kind of spread so I guess that's why people might also say that they're not the correlation between these two proteins Isn't so high because they're actually moving in the brain and when they're moving in the brain It is not really the same or it's not characterized the same way for both these these proteins if you look at the typical course of Alzheimer's disease you will see a correlation such that once you hit a significant threshold of amyloid you get a very significant increase in tau as well. 

Benjamin James Kuper-Smith: Maybe I want to ask a little bit about kind of what, why spatial navigation is particularly relevant for Alzheimer's. Um, and maybe you could link that to why the entorhinal cortex and tau is a particularly relevant area. 

Gillian Coughlan: So why spatial navigation? [00:35:00] Typically we use memory tests in the clinic to diagnose someone with probable Alzheimer's disease or probable, uh, mild cognitive impairment. So with memory tests are that memory typically in normal aging. So even if our brain is aging at a kind of typical pace, we're still getting a decline in our memory performance. so that's one issue. How do we differentiate between normal aging and what's a very early stage of Alzheimer's disease. When people come to memory clinics, where we pick, where we typically, you know, kind of diagnose dementia and things, they come saying, my memory has declined. I'm having problems with my memory, right? 

They never really talk about orientation and how, how well they're doing there. so, [00:36:00] uh, what orientation then allows us to do is kind of, we, we can assess it in the lab and we could see, well, how well are people doing on their spatial orientation? Because typically people's spatial orientation, some would say might not be as vulnerable to the normal aging process as episodic memory is, which is our gold standard test for Alzheimer's disease that we typically use. the other issue with memory is it's very much. Kind of sensitive to someone's education level. So how, you know, sophisticated their level of, um, education is will partly determine how well their, or how good their memory is in later life. That's less the case for spatial navigation. So your education, know, educational attainment typically doesn't predict how well you orientate. 

space. And so we typically in, if we were to use spatial navigation tasks in the memory clinic, then [00:37:00] we'd have to worry slightly less something like a socioeconomic status or education, kind of muddying the waters on your assessment. And then the final thing is that it doesn't rely on a certain language, spatial orientation doesn't rely on speaking a certain language or being from a certain country or, or anything like that. 

Like many memory tests do, they're, they're, you know. They're kind of designed for English speaking languages or maybe they're validated in Spanish, but maybe they're not, et cetera. With spatial orientation tasks, it really doesn't matter, you know, how fluent you are in a certain language or whether or not you have the language at all, as long as you could read one or two questions or the translator is there to translate one or two questions. And so it's very advantageous for that reason. So if you think of low and middle income countries in particular, you can see that spatial orientation tasks would have a lot of Um, utility there because it's very difficult to use memory tests [00:38:00] in illiterate populations or populations you just don't have, um, English. Now the issue with spatial navigation is that it's not yet understood how well it correlates with Alzheimer's disease in the brain. I've done a little bit of work on this. So initially. In my PhD, we looked at people who are genetically at risk for Alzheimer's disease, who are likely to have Alzheimer's disease in the brain. And so these people who are genetically at risk were performing slightly more poorly C HeroQuest, but also other spatial navigation tasks. And I, I, I just did a really big study in, I think it was three, yeah, 3000 people who are part of a European Alzheimer's disease registrar. And we looked at how their spatial navigation performance correlates with levels of amyloid and tau in the CSF. So we took, [00:39:00] say, or the study team took, uh, lumbar punctures, we measured Alzheimer's disease, and we correlated with spatial navigation tasks. And unfortunately, we didn't see a ter terribly strong association here. So, I think two things that could be happening here. Our spatial navigation tasks that we used in that particular study were not as sophisticated as some of our other tasks that require a little bit more learning or a little bit more kind of work with the participant. Or, that our these particular tasks we have are correlating well. With something to do with Alzheimer's disease, maybe it could be neuroinflammation, maybe it could be, you know, some other pathological change that happens in kind of genetically at risk people, but for some reason, they're just not capturing amyloid and tau at that very early stage. so. [00:40:00] We're still working on this, basically. We're still working on really understanding how well spatial navigation does track biomarkers of Alzheimer's disease. And this is really important for translating spatial navigation tasks to the clinic. Because if, if we know that they don't correlate very well with the biomarkers, then that... That's a problem, but there's a lot of people working on this. It's not just, um, me or it's just not, not just Michael's lab. I mean, there's a lot of people, particularly in Germany, actually, um, who are working on this, um, and understanding if we can make slightly more sensitive or specific kind of spatial navigation tasks that can track levels of beta amyloid and tau, but it's sort of an evolving field. And the reason we're interested in. Using cognitive tasks like this is just that they're very easy and inexpensive. So we can screen thousands and thousands of people for preclinical Alzheimer's disease using cognitive tests, not a huge cost and not a huge effort. If you wanted to use a [00:41:00] PET scan, you'd be, you know, it's, we're talking huge cost here, which isn't realistic for most countries, lumbar as I said, have their own issues. Blood tests are much more promising. But we're still haven't a fully validated blood test with an abnormal cutoff that can be used in the clinic. And so that's why people are still working on kind of developing cognitive tests to sort of track, uh, the disease process. 

Benjamin James Kuper-Smith: I guess, interesting. I, from what you just described, it seems to me, if I understood you correctly, that kind of the aim really is to have a cheaper alternative for the traditional biomarkers, the more expensive ones. My initial assumption actually was kind of that it was supposed to be also somewhat complementary to it. 

So, um, where, I mean, I guess you can have different, some are complementary, some just measures the same thing quicker and cheaper. But I'm curious, like, how complementary are the spatial navigation tasks, or do they pretty much just tell you what the [00:42:00] biomarkers tell you at a cheaper cost? 

Gillian Coughlan: And that's a great, um, point. So there was kind of a discussion about this among the people who usually set out the diagnostic criteria for Alzheimer's and Dementia, like how important are cognitive tests now? And so they concluded that cognitive tests are still very important because we have these people who are sometimes resistant To amyloid and tau such that they don't experience, um, cognitive decline or cognitive changes, right? And so even if we just had the biomarker alone, so if we know, okay, this person has high amyloid or this person has high amyloid and tau, if that is not translating at all to a poor performance on a cognitive task, even if it's subtle, even if it's a subtly poor score, then we have to question. Is this really Alzheimer's disease because we know really what Alzheimer's disease [00:43:00] is someone who is you know, has a poor short term memory, has a poor spatial disorientation, is prone to getting lost, and in the later stages has difficulty, uh, family members and might have hallucinations, et cetera. So if an individual who we think is preclinical Alzheimer's disease and has high beta biomarkers, Um, or who has high levels of the disease in the brain is not showing any decrements in cognitive performance, then we have to question, is our diagnosis correct? does this person just need to be tracked for a lot longer, basically? cognitive tests are still important for that reason, as you said, as a complementary to biomarkers, but certainly I would say the Alzheimer's disease field probably put more emphasis on biomarkers now, like they want to understand, is that disease in the brain or not? [00:44:00] Cognitive tests are still important. A lot of the Alzheimer's disease research these days is focused on developing biomarkers or getting biomarkers translated into clinic. 

Benjamin James Kuper-Smith: In a sense, last question, or last topic kind of about special navigation and dementia. Uh, what's the role of menopause in, uh, special navigation? So I didn't, uh, I hadn't really heard anything about this until I saw that you had, uh, a few articles on this. 

Gillian Coughlan: Yeah. 

Benjamin James Kuper-Smith: And maybe what exactly is menopause? 

Gillian Coughlan: menopause, yeah. So menopause is, uh, something that happens for every woman, right. And it usually happens at the age of 51. And so what happens uh, levels of estrogen. Decline, uh, levels of follicles simulating hormone go up, um, and that leads to a very different hormonal situation. for the, that woman, and that induces menopause. So menopause is when [00:45:00] woman is no longer able to have children, for example, once they're going through menopause. Now, menopause also causes a lot of, can cause a lot of fairly, uh, undesirable symptoms for a woman. So, um, difficulty sleeping, um, mood swings, depression, hot flashes are a very common one. It can, it can, interrupt daily living, it can interrupt performance at work, it can have issues, and it can last typically for up to seven years in some women, so that's quite a long time. what we've seen in our data at least is that It's not just the menopause transition that seems to put women at risk of dementia because women, women are more vulnerable to Alzheimer's, dementia than men, just based on epidemiological studies. We can see that women seem to get a diagnosis of Alzheimer's disease more than men do. Some people say that survival bias because women live longer. Some people say it's not, but generally speaking, what we've seen is that women, if, if women move into a menopause [00:46:00] earlier. So if they have a premature or early menopause, they are more at risk of Alzheimer's disease, dementia, and later life. Is this something to do with the fact that their hormones are declining earlier? 

We're working on understanding if that's the case. Or is it just that the early menopause is a marker of accelerated aging in general? And it's not necessarily the early menopause, but it's just that they're, you know, they're aging quicker for some reason, then they're, they're for more at risk of age related diseases, right? 

Like dementia, it could be that too. And so this is actually a topic that's really only opened up again in the past few years. so what we did in our recent study is that we, we actually looked at how women with early menopause are. Are kind of doing in terms of their biomarkers about 15 or 17 years after they had their early menopause or their premature menopause. And we [00:47:00] saw that the women with the early and premature menopause are showing higher levels of that bad tau we were talking about. So that neurotoxic tau protein that we know is particularly important for cognitive decline. And we measured this on a PET scan as well. So there does seem to be a link between early and premature menopause and greater risk of Alzheimer's disease, dementia, and later life. And so if hormones are the cause of that, we're not sure. Like if a hormone, early hormonal fluctuation, they're the cause of that, or if it's something else, but hormones do play a big role in brain health and brain function. I mean, that's very basic kind of science. Um, and that has been done and looked at in rodents and in humans. So hormones could be the link here. But they also might not be. And so this is something we're kind of investigating. And we're also looking at what are the implications of using hormone therapy. So giving women, prescribing women, women hormones. How does that [00:48:00] change this relationship between early menopause and Alzheimer's disease, dementia? Alzheimer's disease is a very prominent. disease in women, but it's less prominent in men. So, you know, up to two thirds of our whole AD population are women and one third, third is men. And so there seems to be, definitely some sex divergence here. So there must be some factors in women that are putting them at a higher risk of developing this disease. 

And that's why we're looking at menopause. Now, there are other things that we could look at, and another interesting thing that, sorry if this is a bit off topic, but we know that Parkinson's disease is much more common in men. So about 70 percent of men, right, have Parkinson's disease, and about percent of women have Parkinson's disease in that 

Benjamin James Kuper-Smith: Sorry, dude, you mean... Ah, okay, yeah. I was saying not 70 percent of all men, yeah, yeah. It's... [00:49:00] It's 

Gillian Coughlan: uh, I think that's really interesting, like, we really don't understand why that is either. You know, why is, is Parkinson's disease so much more common in men? Parkinson's disease typically onsets earlier than, Then Alzheimer's disease does, what does that mean? Alzheimer's disease is theorized to start in the gut. Could that have, give us some clues why men are more at risk? Um, I think these are really interesting questions and they're not really understood at the moment. So, um, so this is what I'm working on at the moment. 

Benjamin James Kuper-Smith: good to have a topic where you know you'll have, uh, what's it called? Career? Uh, I don't know, what's the word? Uh, basically you know you can... You can spend a while on this topic. 

Gillian Coughlan: Yeah, I guess, 

Benjamin James Kuper-Smith: It's maybe not so nice for the clinical population, but it's nice as a scientist, maybe. 

Gillian Coughlan: yeah, well, hopefully it will translate to treatment, right, uh, in, cause then the other question I guess is if there's [00:50:00] really stark differences in how women get to Alzheimer's disease versus how men get to Alzheimer's disease, that then mean that we should be using more, more personalized approaches based on. And so I think that this is something that's really interesting, um, and, and, um, it's really important to understand. 

Benjamin James Kuper-Smith: Yeah, definitely. Um, okay. So at the end of each episode, now recurring questions, uh, the first is kind of what is a book or paper, uh, that you think more people should read? Uh, this can be, you know, something you discovered in an archive somewhere. No one else has ever heard of. It can be a famous article that lots of people know and they should read again. 

Uh, do you have anything? 

Gillian Coughlan: Um, yeah, so it's hard to, well, I'm going to go in a book. Um, and it's hard to pin down just one book cause I think a lot of books can be very influential in our lives. Um, I think one that was really important for me was [00:51:00] The Choice, uh, by Edith Eger. So she was, um. She was actually in the concentration camps in World War II, um, and then her and her and her sister were there and it documents her, her life during that period, how they kind of escaped that situation and then they kind of fled to America and she became a clinical psychologist and now she's very famous and she helps a lot of people and the title, the choice is kind of her trying to say that We can be in certain situations and we can have certain traumas and we can have very challenging environmental situations. to a large extent for a lot of us, at some stage there comes a choice. Am I going to be a victim of all this or am I going to try and take what I've learned and do something good with it? And so she kind of documents her experience with that with a lot of real life examples. And I found it really Such a captivating read, I think whenever life gets [00:52:00] difficult, I sort of think about, you know, her story, um, and some other books I've read as well. 

And I just. Kind of, it, it helps put things in context, I guess, about what's difficult and what's, what you're, what you're just perceiving as difficult. And, um, you know, life is challenging. You get thrown with a lot of, um, things that are unexpected. And so to have stories like this that we're aware of, or that we can even just refer back to in challenging times, I think is very important for us. So that's one that's, I think, very standing out for me. 

Benjamin James Kuper-Smith: Very nice. Second question is something you wish you'd learned sooner and maybe how you. Dealt with it or, yeah. 

Gillian Coughlan: Um, yeah, so, well, there's lots of things here, um, but, um, I think I have two actually very important ones. So the first one is, um, try not to be perfectionistic about things. This is something I learned, I think only [00:53:00] relatively recently, actually, um, but when you can. embrace the noise, or you can embrace zigzag path. 

You can still achieve what you want to achieve, but you can achieve it with a lot more kind of well being and a lot more, um, energy and a lot more, kind of, give when you get there, if you know what I mean, if you just accept that the path To, or the way, or the obstacle is how it should be. Things aren't perfect. 

You know, things are not terribly straightforward in life. And so I think it's very important to just accept you know, everything is not going to plan or there is going to be, um, you know, some things that you didn't expect to prop up and just being okay with that and not being too perfectionistic about. Certain, you know, things related to work, but also person life. Um, and I think that if you do lose kind of a very high standard approach, sometimes the [00:54:00] results. Ends up being the exact same. It's just that you might have a higher wellbeing at the end of it than if you took a very perfectionistic approach to it. And I think the other thing is of things aren't always as they seem. I think this is important to remember, not just at work and, but for personal life too, is, you know, things aren't always as they seem. And so flexible again is very important and a very, um, important kind of way. To go through life or kind of progress up the ladder, because if you're not flexible or if you're not willing to accept that, you know, something you taught before was one way and it's actually another way, then that can really deter you and it can hold you back. So I think, you know, when I say things aren't always as they seem, I just mean, uh, [00:55:00] be okay with things not. exactly as you had expected them to be basically. And sometimes people, you know, can have a lot of difficulty, but I think with accepting the things, Oh, this isn't actually how I thought it was, or this person isn't who I thought they were, that kind of thing. But I think if you can just, you know, accept that and keep moving through life, it's, it's very helpful and it's a very helpful way of kind of just, you know, being happy and being able to again, deal with any kind of setbacks you might have. 

Benjamin James Kuper-Smith: Great. And the final question is, uh, so I just finished my postdoc soon. Uh, any advice? I mean, I guess your last two questions kind of, uh, maybe we're already some sort of advice, but, uh, maybe for people kind of in this like early postdoc position, let's say, uh, any, or, or maybe people were just about to finish a PhD. 

Uh, any advice? 

Gillian Coughlan: Um, Oh, I think. what I would say is just make sure that you're working with or the, the [00:56:00] goals of the person that you're working with align with your own goals. So usually I think things go very smoothly, uh, at work when everyone's goals align and we're looking for the same and our end game is the same. I think, um, that's important when we have, when we're moving to a postdoc or moving to a new position, it's just that, um, the people we're working with have, have the same, you know, goals at work as we do in terms of the same product to be produced. Uh, so that's, I think what I would say is important, uh, when transitioning to, um, a new kind of position. 

Benjamin James Kuper-Smith: Very good point. Yeah, yeah. Yeah, you can avoid a lot of conflict by just knowing that both of you want the same thing anyway. That does sound like it makes things a bit easier. 

Gillian Coughlan: Yeah, it definitely does. And, you know, sometimes, you know, you might get on very well on a personal level with someone. But if, if your goals don't [00:57:00] align at work, there can be problems and vice versa. If your goals align at work, but you don't personally get on with a person, it might not matter that much if you don't. Personally, really like each other. If you still have the same goal that you're trying to achieve, things can just be totally fine. Like you just go ahead and you try to achieve that. Um, so yeah, that's why I think it's very important. 

Benjamin James Kuper-Smith: Okay, great.

Playing the piano
How Gillian ended up doing her PhD with Michael Hornberger in Norwich
How to find a good mentor
Sea Hero Quest
Diagnosing Alzheimer's disease
The role of Beta-Amyloid and tau in dementia
Spatial navigation, the entorhinal cortex, and dementia
Does menopause affect spatial navigation and risk of dementia?
Book or paper more people should read
Something Gillain wishes she'd learnt sooner
Advice for PhD students and postdocs