Charting the Mysteries of the Mind - Unraveling Alzheimer's and Dementia

Dr. Biology: 0:00

This is Ask A Biologist, a program about the living world, and I'm Dr Biology. This episode is, well to be honest, personal for me because we're going to be talking about dementia, including Alzheimer's. It's personal for me because my mother had Alzheimer's. In the early stages, when we weren't aware of her condition, she lived a few miles from our home and then later, when it became clear that she was having some challenges, we moved her into our home. For about a year and a half, both my wife and I looked after her, and I'll say right now that we also had the help of some great in-home caregivers. Now that we also had the help of some great in-home caregivers. After that, there came a time we had to make the difficult decision to move her into a memory care facility and, to be honest, even though that was difficult, my mother, as I had known her all my life was really gone. Now, our experience is not unique by any means.

Dr. Biology: 1:05

In case you don't know, according to the World Health Organization, more than 55 million people worldwide have dementia in some form, and there are nearly 10 million new cases that are added each year. At that rate, the number of cases is estimated to increase to well over 130 million by the year 2050. So what research is going on in this area and are scientists making progress? You might have heard about a new drug that's out for Alzheimer's. We're going to talk a little bit about that. We'll also talk a little bit about what we might do in the future, because one of the biggest challenges with dementia is diagnosing it early Now.

Dr. Biology: 1:50

For our guest today, we have Kimberly Olney from the Mayo Clinic in Scottsdale, Arizona, where she's a bioinformatics scientist in the lab of Dr John Fryer. Kimberly is also an alumna of ASU and the School of Life Sciences. She received her PhD in 2021, and her research was done in the lab of computational evolutionary biologist Melissa Wilson, who has also been a guest on this program. Since then, she's been studying Alzheimer's and another type of dementia called Lewy body dementia, using her skills in bioinformatics. This is a big topic and one that requires certainly more than one podcast episode to cover all that's happening in this area, but we'll at least give it our best effort to introduce you to these diseases, if you don't know about them, and also the challenges we face with dementia. Kimberly, thank you so much for taking time out to sit down and talk with me on Ask a Biologist.

Kimberly: 2:56

Well, thank you so much for having me here.

Dr. Biology: 2:58

Before we begin, let's start with some basic brain anatomy, because everybody knows we have a brain,  but we don't all know what the different parts are. You want to just break it down? We're not going to go into an anatomy lesson, but we are going to talk about some basic parts.

Kimberly: 3:13

So, if you were to place your palm on your forehead and move it all the way back, that would be the cerebral cortex and that is the largest part of the brain and that is involved in language, decision making, and then all the way in the back of your head you can feel it kind of where your neck meets. Your brain is the cerebellum and that's involved in motor functions, so being able to move your hands and things like that. So those are the two main parts.

Dr. Biology: 3:41

Right, and so there's more. 

Kimberly: 3:44

Yes, there's a lot more.

Dr. Biology: 3:45

And so, as a reminder, we have a great story about the nervous system, including the brain, on Ask A Biologist and it's called A Nervous Journey, so you can go check that out. It even has a fun activity that you can do at home or in the classroom, and it doesn't cost anything. A Paperclip, a ruler, and we give you the sheet to work with. All right, so now we have a basic understanding of some of the parts of the brain. Let's also talk about a few terms that get used and how they might be a bit different. There's this global term, dementia, and then there are these more specific types so, for example, Alzheimer’s. So, let's talk about, maybe, some of the different kinds of dementia.

Kimberly: 4:29

Yeah, so dementia is an umbrella term and it's used to describe a set of diseases like Alzheimer's disease or Lewy body disease, and all of those diseases are comprised of symptoms that individuals have, which then get categorized as dementia. And all of those diseases are comprised of symptoms that individuals have which then get categorized as dementia, and those symptoms are cognitive impairment, such as short-term memory, like what did you have for breakfast this morning? And if you're not able to answer that, that might be an indication of early signs of dementia. What kind of dementia depends on the pathology that you have, and pathology, that's a big term. 

So, what is pathology? That is where you have different proteins that build up inside your brain, and that's what distinguishes individuals that have Alzheimer's disease because they have a certain set of pathology, versus individuals that might have Lewy body disease, where they have a different set of pathology.

Dr. Biology: 5:25

Right. So different causes in the brain for it not to be working just right.

Kimberly: 5:31

That's correct.

Dr. Biology: 5:32

And for those of you that don't remember what you had for breakfast this morning, don't worry, you're probably not suffering from Alzheimer's.

Kimberly: 5:40

No, the greatest risk for Alzheimer's disease is age. So, as we age the body doesn't function quite normally and these proteins build up in the brain, so it's really a disease of the age. There are rare cases where individuals under the age of 65 can get Alzheimer's disease, but it's very uncommon. More likely over the age of 65.

Dr. Biology: 6:04

Right, you know some people worry about inheriting dementia. Is that something a person can inherit?

Kimberly: 6:19

There are certain genetic risk factors that make you more likely to have Alzheimer's disease, but the vast majority of individuals have what is called sporadic Alzheimer's disease. That's not an inherited form. It's a combination of both genetic and environmental factors that aren't completely understood. So, there are genetic mutations that you can inherit that do put you at a greater risk of developing Alzheimer's disease, but it's just a greater risk. It doesn't necessarily mean that you will.

Dr. Biology: 6:43

Ah, so in the case of my mother that I spoke about, I don't have to be thinking that automatically that I might have some form of dementia. And, to be clear, I say she had Alzheimer's, but we really never looked inside of her brain after she passed away, which is really the only way you really know if you have Alzheimer's, right, or maybe any of these other kinds of dementia right?

Kimberly: 7:06

To be able to definitively tell, you need to be able to look at the brain post-mortem that means after death and look to see if these misfolded proteins are in certain parts of the brain and that can give you an indication of what kind of disease that they had, whether it was Lewy body, dementia or Alzheimer's disease.

Dr. Biology: 7:28

All right. So, we know about the brain, we know about the different kinds of dementia, but we really don't know what's going on. You mentioned these proteins. Let's talk about what's not working to cause someone to have dementia. 

Kimberly: 7:49

One of the early stages is called amyloid beta plaques. So, there is this protein in your brain, amyloid, and it's supposed to be there. It has a normal function and it normally gets dissolved in the brain after it's done doing its normal function. But what happens in Alzheimer's disease is that it is no longer in this like single form. It has almost like a double form of itself, which makes it really sticky. And then it sticks to other amyloids that are around that didn't dissolve, and then that's what creates the amyloid beta plaques, which don't dissolve. 

So, then they form up and accumulate in the brain. When that happens, they can interfere with the neurons communicating with each other, and when the neurons can't communicate with each other anymore, the neurons then begin to break down, and that's not good, because the neurons are really what makes up the brain and does all the communication and signals, what tells us how to even speak right now or move our hands. So,   when the neurons start to break down, that's when you start seeing the symptoms of Alzheimer's disease.

Dr. Biology: 8:57

All right, we have these proteins that are usually there for a reason, but they break down, they disassemble, no problem. But if you're having a problem with dementia, you probably have these proteins that aren't breaking down and they're actually clumping together with other proteins.

Kimberly: 9:16

Yep. 

Dr. Biology: 9:17

And so that interferes with the neurons and then, once the neurons are not working properly, they begin to shut down. Do they deteriorate? What's going on?

Kimberly: 9:28

Yeah, so inside the neurons is almost a skeleton-like structure. They're called microtubules (micro, small) tubules almost like a tube, and there is a protein inside there called the tau protein, and that no longer sticks to the microtubules. So, then the microtubules break down, which then causes the nerve to break down, and then you've got these neurofibular tangles, and the combination of amyloid beta plaques and neurofibular tangles is what defines the pathology of Alzheimer's disease.

Dr. Biology: 10:06

Wow, that was quite a road we're on. So,  I suppose the challenge for scientists right now is first diagnose. Second is actually start to repair or slow down the process before those neurons start to break down, because once they break down, I assume you're not getting them back.

Kimberly: 10:32

That's correct.

Dr. Biology: 10:33

Okay, this is where we enter into something that's good. Right, we have a new drug that's on the market. It's the first one that's been out there to help treat Alzheimer's. Does it only work for Alzheimer's?

Kimberly: 10:47

That's correct. It's only for the treatment of Alzheimer's disease. There is currently no cure for Alzheimer's disease, so these drugs are anti-amyloid. So, they're anti-amyloid beta blocks, which are the first hallmark of the Alzheimer's disease. So, essentially, if you give individuals that have early indications of having Alzheimer's disease, of having these amyloid beta plaques which they do have to confirm with like an image of the brain or looking at spinal fluid to confirm that there are amyloid beta plaques in the brain then they can give them this drug that has anti-amyloid. And what the drug does is it targets these amyloid beta plaques to help break them down so that there's less buildup of the amyloid beta plaques. And what the clinical trial has shown is that individuals that received the anti-amyloid treatment versus those that received placebo, essentially no drug, showed slight improvement over the cognitive decline compared to the group that didn't receive the treatment.

Dr. Biology: 11:52

So, it slowed the progress. 

Kimberly: 11:53

It slowed the progress. 

Dr. Biology: 11:55

You know, we've talked about just the basics of a few parts of the brain. How about we dig a little deeper, right? So, what else is going on in the brain? I mean neurons. Okay, You're going to tell me neurons are cells, but what else? What's going on?

Kimberly: 12:13

So, another major cell type in the brain are called glial cells, which is for the Greek word glue. And glial cells have a very important function in that they help to protect the neurons, and the neurons are really important for transmitting signals to other neurons, so that you're able to talk and walk and do all the things that you can do. So, protecting those neurons, those glial cells, those glue cells, help to make the neurons continue to function correctly.

Dr. Biology: 12:43 

All right, and are they involved at all in any of these diseases?

Kimberly: 12:48

Yes, what happens in some of these diseases is that there's a sheath that covers the neurons it's called a myelin sheath and that degrades in these neurodegenerative disorders. So, when that happens, then the neurons can't send the signals as well, because they're not protected as well.

Dr. Biology: 13:08

We've talked a lot about Alzheimer's. What about Lewy body disease? How is that different 

Kimberly: 13:14

Yeah, so in Alzheimer's disease you have amyloid beta plaques and you have neurofibular tangles. In Lewy body disease they often also have amyloid beta plaques and, in some cases, these neurofibular tangles. But what they also have is called Lewy bodies, which is a different type of misfolded protein that forms in the brain, and it's extremely challenging to diagnose individuals with Lewy body disease, as they have symptoms that are very similar to Parkinson's disease. Those symptoms include jittering, motor movement issues. So, they have those symptoms, but they can also have symptoms that are very similar to Alzheimer's disease, such as cognitive impairment. But what really distinguishes the symptoms of Lewy body disease is hallucinations and sleep disturbance. So, they don't sleep very well at night. They get horrific nightmares, and they have hallucinations where they think they see something that isn't there.

Dr. Biology: 14:16

Does it affect the same part of the brain?

Kimberly: 14:19

So, with all of these different diseases, there's different progressions of them, where they start in certain parts of the brain and then they work their way towards other parts of the brain, and it's not one size fits all. Every individual is different of what part of the brain was or was not impaired.

Dr. Biology: 14:39

So, it doesn't always start in the same place.

Kimberly: 14:42

Not necessarily because you can have a different degree of amyloid beta plaques that start in one part of the brain and work their way everywhere, but the neurofibular tangles may be concentrated to only one other part of the brain, but there are stages and phases of these that typically follow a similar pattern.

Dr. Biology: 15:03

Now your area of expertise is in bioinformatics. We use that term a lot. So, in general we're using computers. We have the term bio in there, so it must be something about biology, life and in general you collect and you store and you analyze a lot of information. That's just a thousand foot view. Let's talk a little bit about a life of a bioinformatics scientist, especially the one that's studying Alzheimer's and Lewy body disease.

Kimberly: 15:40

Yeah, so my typical day involves reading literature to see what others are talking about in the field, what they have found. And then a large chunk of my day is also involved in processing and analyzing data, which I do need computers for. If we tried to do this by hand it would take a lifetime if not several lifetimes. So we do use computers, which is essentially like taking really large puzzles, like a bunch, a bunch of puzzles from all over the place, and trying to piece them together. And oftentimes you don't even have all of the puzzle pieces, you only have parts of the puzzle pieces. Then, when you put them all together, you try to see what that puzzle was looking like, what was the story that puzzle was telling you, and then you communicate that with others.

Dr. Biology: 16:28

It's interesting you mentioned puzzles, because at Christmas I play this little trick on my kids and I've done it for many, many years. Basically,  it's with a box of Cracker Jacks. I remove all the Cracker Jacks and, just so you know, I save them so they can have them later, and then I replace those Cracker Jacks with something else in the box that sounds a lot like it would be Cracker Jacks, but it's not. So, one year I actually got a bunch of 100-piece puzzles and what I did is I scrambled them all up and I put them all in the different boxes and it's become quite a favorite for the kids. What I didn't know is maybe I was creating future bioinformatic scientists. So, in this space, if we're talking about data, how much are we talking about? I mean, is there any way to get a visualization of how much information we're having to process?

Kimberly: 17:29

Absolutely so. If you think about your cell phone or your laptop and how many pictures you have stored on there, I'm sure of your friends and family and it's probably happened to everyone where it's like, oh, you've ran out of storage, which is quite surprising, especially in today's technology where you can have almost a terabyte of data on a cell phone, like that's a lot of data that you can have storing tons and tons of photos. The kind of data that we're working with won't even fit on a standard laptop or a cell phone, and that's just for like one project. So, you need what's called high performance computing for like one project. So, you need what's called high performance computing. So, it's essentially stacks of laptops and you use all of those laptops to process and analyze the data.

Dr. Biology: 18:17

Right, a bunch of computers all working together Got it. And then, when we're talking about looking for data and what might be missing, what would you be asking for to make it a little bit more effective?

Kimberly: 18:32

Yeah, so there's very different types of data. Data that I often work with is pathological data. So, what was their pathology scores? So, when they actually looked at the brains, how many amyloids did they have, how many neurofibular tangles did they have, or how many Lewy bodies did they have? So that's one type of data, is their pathology score. Another type of data is sequencing data. That could be information like what kind of variants did they have that could give them a greater risk of having Alzheimer's disease or Lewy body disease, or what genes are on and off, called gene expression, and that assumes all the cell types together. You can also look at individual cells. That’s a different type of data as well.

Kimberly: 19:22

And one thing that we really haven't talked about was their clinical data. What did the clinicians or the neurologists that they met with say that they had? Did they say that they had Alzheimer's disease? Because it's really hard to distinguish between Alzheimer's disease and Lewy body disease and Parkinson's disease. And why is it so challenging to tell if someone has one disease versus the other is because they often overlap in their symptoms, such as cognitive impairment or motor dysfunction, and it's really important to properly diagnose, because the treatments available to them could have adverse reactions if they're not given the right treatment for the right disease that they have.

Dr. Biology: 20:08

Right, and also what their history was.

Kimberly: 20:12

Right, absolutely so. If they were a female, did they have children during their lifetime? Because we know that pregnancy can cause changes in a female's brain hormones. Menopause how did that impact the brain? What age were they when this happened? That's often something that isn't included in the clinical notes, and it's something that I would like to see be included in future data collection.

Dr. Biology: 20:40

What do you see, from your perspective, as the future for treatment of dementia?

Kimberly: 20:50

Well, I recently went to a conference and one of the big talking points at the conference was early detection, because that's so important. Just as you shared, you didn't even know that your mother had the early signs of Alzheimer's disease. So, at the conference they were talking a lot about how can we better understand what's happening at the population scale. If we're only looking at post-death individuals. We're really missing an opportunity to understand what happened before then. So, one of the big things was like wearables, like smartwatches and being able to monitor movement and rigidity that is common in Parkinson's disease. How are people walking that shuffle to really kind of understand the early signs, to give them the treatment that they need, to kind of slowdown that progression?

Dr. Biology: 21:48

Oh, interesting. So,  the wearables other than you know, right now I'm wearing one that will do my heart rate and things like that. But if we have something that's incorporated that starts to detect that I'm doing some kind of behavior, that could, doesn't mean it is, but could be a pre-dementia mode or early dementia or early Parkinson's 

Kimberly: 22:12

Yep. 

Dr. Biology: 22:13 

All right. So how long have you been at the Mayo Clinic now?

Kimberly: 22:17

Three years.

Dr. Biology: 22:18

What's your favorite part of this research? What really gets you excited every day?

Kimberly: 22:24

What really gets you excited every day? What really gets me excited every day is to help enhance health research to help everybody, and that includes males and females, people of diverse backgrounds. It's something I'm extremely passionate about is making health information available to everyone, and that includes the data that we analyze and process has to be a good representation of the population. 

Dr. Biology: 22:52

Okay, so sex differences.

Kimberly: 22:56

Yes. So that's something I'm very interested in is understanding sex differences in these diseases. So,  females are more likely to have Alzheimer's disease and males are more likely to have Parkinson's disease, and Lewy body disease tends to be somewhere kind of in between the two. And what I would like to know, is there certain molecular mechanisms that differ between males and females to why they would be more likely to have one disease over the other, so that we can create better treatments to help treat both men and women?

Dr. Biology: 23:33

Right, this personalized medicine, something a little more targeted. It's not one size fits all.

Kimberly: 23:39

No, exactly, it's not one size fits all, and before we can even begin to talk about personalized medicine, I think we need to include half of the population, which includes females because most research in the past has been primarily focused on white males.  

Dr. Biology: 23:54

Really? 

Kimberly: 23:55

Yeah.

Dr. Biology: 23:56

Well, Kimberly on, Ask A Biologist. None of my scientists get to leave without answering three questions. It's the same three questions, so you ready. It's the same three questions, so you're ready. 

Kimberly: 24:06

Let's go 

Dr. Biology: 24:07

All right. The first one is when did you first know you wanted to be a scientist?

Kimberly: 24:13

Immediately 

Dr. Biology: 24:15

immediately at birth 

Kimberly: 24:17

Yes, ever since I could remember, I think evolution is the greatest show on earth and I just wanted to be part of understanding it. Obviously, I love puzzles and it just seems like the biggest puzzle to be a part of and I just really greatly enjoy it.

Dr. Biology: 24:39

That's interesting. You love puzzles. Do you really love puzzles? Do you do a lot with crossword puzzles and other kinds of puzzles?

Kimberly: 24:45

Not crossword puzzles, more of the cardboard puzzles.

Dr. Biology: 24:49

Jigsaw puzzles. Jigsaw puzzles. Yeah, yeah, okay.

Kimberly: 24:52

Jigsaw puzzles. My favorite part of my job is the coding aspect of it, because computers are really good about telling you if something didn't work or not, because they're very sensitive to it. So, if you didn't code it exactly the way that you want it to, it's not going to give you the answer that you were looking for. So,  it's very precise and I just really like that meticulous organization of it.

Dr. Biology: 25:17

Okay. When did you start with bioinformatics? Because I bet that wasn't right at the beginning. I mean, you like puzzles, but you didn't necessarily know about bioinformatics.

Kimberly: 25:26

No. So I got my undergraduate degree here at ASU in the School of Life Sciences and that was in biology, and then afterwards I worked as a chemist and I didn't really quite enjoy it, it wasn't for me. And then I got a position as a research tech in Melissa Wilson's lab at ASU and her lab specializes in bioinformatics and I fell in love with it.

Dr. Biology: 25:53

Ah, ok, so you got turned on to bioinformatics when you were in college, 

Kimberly: 25:58

Yep. 

Dr. Biology: 25:59

Well, now I'm going to take it all away. I'm not going to let you use your computers, I'm not going to let you teach. I want to see what you might want to do, if you could do anything.

Kimberly: 26:11

Movie director. Movie director yes.

Dr. Biology: 26:15

Yeah, yeah, because you've got to pull together a lot of pieces to tell the story.

Kimberly: 26:20

Yeah, storytelling.

Dr. Biology: 26:21

Oh, I like that Movie director.

Kimberly: 26:24

I love to storytell.

Dr. Biology: 26:25

Okay.

Kimberly: 26:26

Bioinformatics is one aspect of storytelling.

Dr. Biology: 26:31

Do you have any particular movies? You like the types of movies.

Kimberly: 26:35

Oh, I enjoy all movies. My favorite right now is Dune, part Two.

Dr. Biology: 26:38

Hey, you said you're a storyteller. Do you do any writing?

Kimberly: 26:43

Well, I write papers for the projects that I work on for my job. That is most of the writing that I do, but I do enjoy writing poems every now and then.

Dr. Biology: 26:53

Oh, I should have had you bring a poem. All right, the last question what advice would you have for a future young scientist, or someone that's maybe not even in the sciences but always loves science? What's your advice for them?

Kimberly: 27:10

To keep going and to not be discouraged. So, growing up my parents didn't go to college. They cleaned houses for a living and going to school, especially for a PhD, kind of seemed out of the cards. But I just had the mentality of I'm just going to try, I'm just going to keep going until I can't keep going. And I'm still going and I plan to keep going.

Dr. Biology: 27:38

As a graduate student. If you're talking to another graduate student, what advice do you have for them?

Kimberly: 27:43

It's a marathon, not a race.

Dr. Biology: 27:47

[Laughter] It's a marathon, not a race.

Kimberly: 27:50

One of the other aspects that I really enjoyed about graduate school was the other graduate students here at ASU, and particularly the School of Life Sciences, is such a great community of individuals.

Dr. Biology: 28:02

And it's a big community, right, Because we have a lot of graduate students here. So, is that an advantage you think?

Kimberly: 28:10

I think so. Yes, absolutely so. There's many graduate students, but then you're in your own particular program. So, I was in the evolutionary biology program and in my cohort so the individuals that all started at the same time that I started graduate school there was five of us in our cohort.

Dr. Biology: 28:28

When you graduated, were you thinking you were going to be doing work on dementia, the many forms of dementia?

Kimberly: 28:36

No, so I didn't know much about neuroscience or even neuroanatomy before graduation. My PhD is in evolutionary biology and I got a position at Mayo Clinic in the neuroscience department and I was just extremely excited because I think the brain is a crazy puzzle that I had to be a part of. So, I was really excited to be part of that, but I also had to learn a lot in my first couple of years as well.

Dr. Biology: 29:03

Right, so you get your doctorate, your PhD. You're not done learning.

Kimberly: 29:09

No, learning is a lifetime.

Dr. Biology: 29:10

Well said. [laughter] Well, Kimberly. With that, I'd like to thank you for being on Ask A Biologist.

Kimberly: 29:18

Thank you so much for having me.

Dr. Biology: 29:20

You have been listening to Ask a Biologist. My guest has been Kimberly Olney, a bioinformatics scientist and one of our alumna in the School of Life Sciences, who's now working at the Mayo Clinic in Scottsdale, Arizona, studying two forms of dementia Alzheimer's and Lewy body dementia. Now I suspect, and I hope, that you would like to learn more about the things we talked about today. For that reason, we've put quite a few links in our show notes and I'm hoping that you'll take some time out to check those out.

Dr. Biology: 29:06

The Ask A Biologist podcast is produced on the campus of Arizona State University and is recorded in the Grassroots Studio housed in the School of Life Sciences, which is an academic unit of the College of Liberal Arts and Sciences. 

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