- Welcome, everyone, to Wednesday Nite @ the Lab. I'm Tom Zinnen. I work at the UW-Madison Biotechnology Center. I also work for the Division of Extension and Wisconsin 4-H, and on behalf of those folks and our other co-organizers, PBS Wisconsin, the Wisconsin Alumni Association, and the Science Alliance of UW-Madison, thanks again for coming to Wednesday Nite @ the Lab. We do this every Wednesday night via Zoom, 50 times a year. Tonight, it's my pleasure to introduce to you Nathaniel Chin. He's a physician and member of the faculty here at UW-Madison. He was born in Watertown, Wisconsin and went to high school there and came to UW-Madison to get his undergraduate degree in medical microbiology and immunology. He stayed to go through medical school here, and then he went to the University of California San Diego Medical School to get his internship and residency. In 2015, he returned to Madison on a fellowship, and now he's the director of the Wisconsin Alzheimer's Research Center. 

 Please join me as Nathaniel Chin speaks to us about six ways to reduce your risk of Alzheimer's. - Thank you for that introduction, Tom. I'm very happy to be here and be able to share with you some of the great work that we're doing on the front of Alzheimer's disease research. Really, my objectives for today are to share with you how we define brain buffer in the context of cognition and getting older. And then I'd like to introduce the six brain health pillars that our Alzheimer's disease research program is focusing on for the time being, and then highlight the research that does support those brain health pillars. So to start, I'd like to go over some of the basics of our brain, in particular the cells that make up our brain, and so the figure here that you see is from the National Institute of Health, and so what we see is this yellow structure, and that is a really important cell called the neuron, or the brain cell. And then we also have two other cells, which I'll talk about in just a second. But focusing on that yellow one, the neuron, you see on the left side of this figure kind of the bulk of it, and that is the main body of the neuron. But coming out from that are projections, these little finger-like things that we call dendrites. And that's a really important part of the neuron. 

 That's what receives signals from other aspects or other neurons when they are communicating. And then you see to the center and the right of that yellow figure is the axon. So that is the other really important part of the neuron. And that's what conveys the message of this particular brain cell. So it goes down that one long tube, and then it's conveyed to the other neurons. And so with that neuron are two other cells, and the red one is called an astrocyte. That is connected to blood vessels and to the neuron. That's what helps give the neuron the nutrients it needs, the blood, the oxygen. The blue structure is another cell called the oligodendrocyte cell. That's what puts a very protective sheet, or lining, over that axon, so you can tell the axon's important, because there's a cell dedicated to keeping it healthy. 

 That improves effectiveness and efficiency of conveying a message. And so in short, though, a neuron has many different ways of receiving a signal and just one way of conveying it. Now this picture here shows a synapse. That is where all of the connection and communication happens. So in the center of the picture, you see that main neuron body with all those dendrites, and then you see two other axons, so two other neurons, one in the upper left and one in the upper right. And so they're communicating with that center one, and all those little red tiny dots, that is where communication occurs. Those are chemical signals that are being shared from the axon to the dendrite. All of this is meant to show you that this is a really complicated process, but it's really important, because this is how our brain cells are able to communicate with each other. So then when I say cognition, and I'll say that throughout this talk, what I'm referring to is the brain's ability to perform, to function. And so cognition would include memory, but it would also include thinking ability, attention, language, your visual abilities. 

 So the brain has many different functions. And so cognition kind of summarizes all of them. So what you see here is a picture of a brain. And that brain in particular has this front part, the green part, which is the prefrontal cortex. It's what makes humans so advanced and so capable. This is where we're able to problem-solve, to reason, to have insight, but the structure I want you to pay attention to is right in the middle of the brain. It's blue, and it's called the hippocampus. That is where we store our short-term memories, the things that have just happened to us. Now that hippocampus is a really important structure when we think of Alzheimer's disease because it does get smaller, but how it works in a normal individual who's not having memory symptoms is that those memories that are there are then shared to the rest of the brain. And so you see at the top of it, that's where we use neocortex. 

 That's just the rest of the brain and the different parts of the entire brain, which are where our other neurons are that help us learn and have those memories. So again, this figure here showing you that synapse, so two brain cells connected, or sharing information, occurring at the synapse. But when we think about how our cognition works, it's not just one neuron. It's not just one synapse. It's a whole sequence, a whole network of them, which is why we call them neural networks. And this picture here, that I just brought up, the different colors represent different neural networks. And all of those networks are where those longer memories are stored, or how we communicate from one part of the brain to the other, how we pay attention. So brain cells are really critical, but how they interact with each other and the networks of those brain cells really are how our cognition works. So I want to keep that in mind when we talk about getting older, because we know that our thinking ability, our cognition does change as we get older. And so this figure here, on the horizontal access, is your age, so you are getting older as you go from left to right. 

 And on the vertical access is cognitive function or ability, and so you're losing some of that ability as you go from top down. So what we see here is that it's not a straight line. Unfortunately, we're not the same as we were when we were in our 20s. We also see that it's not an upward line. So it's a slight downward line, meaning that we do have some changes, some declines, as we get older. So in normal aging, we know that roughly at about the age of 30, things start to change for us. We start to notice some of the declines in some of our abilities, not every ability, and it is different for individuals, based on how they're living. But around 60 to 65, there's this inflection point where most, if not all of us, will notice some difference, no matter how we live. At this point, there are going to be some symptoms. This does make sense, because at the age of 50, we lose roughly 1% of our muscle mass each year. 

 It makes sense that our brain would be included in that concept of changing, as we're getting older. Now the most likely things to decline are what we call episodic memory or that short-term memory, the things that are just happening to us, as well as processing speed. The things that are least likely to decline are our speech, our language processing, and that procedural memory, the things that we do on a routine basis. Now there are some things that do get better over time. One, I would say wisdom, but then, two, our vocabulary knowledge. As we are learning, we are gaining that knowledge. And it does continue to go up. Something we should keep in mind is that the definition of normal also changes as we get older. An example would be, one of our memory tests is providing someone with 15 words and asking them to remember them 30 minutes later. Now a 70-year-old who remembers eight of those words, that is considered normal. 

 But if you're a 30-year-old and you remember 8 of those 15 words, that would be a bit more concerning, and we might call that person having borderline changes that are not typically normal. Now some other symptoms of normal aging include that slower rate of learning. We're less efficient than we were when we were younger. We may need more repetition in order to learn. The key thing being here, we are still learning. Now our slower processing speed may affect us as well as our reaction times. We might just be slower and more sluggish in that way. Now there's also an increased difficulty with free recall. This is one of the most frustrating things for people as they get older. This means that in the middle of a conversation, It's harder for you to find that fact that you want to share, or that word, and so we might need more cues or more contexts in order to find that specific fact that we're looking for. 

 There's also more word finding and more name finding. Now these are very common symptoms, but they're also one of the least sensitive as far as identifying true disease. They still are bothersome, and people notice them more and more as they get older. Lastly, we talk about cognitive flexibility, which is our ability to handle distractions. And we know that as we get older, we simply have less of that flexibility. We're more likely to be distracted. It doesn't mean we can't focus. It just means it takes more of us to be able to do that. So why our brain changes over time. And, well, first of all, we notice shrinkage. 

 So the medical term, or the scientific term, is atrophy. We just know that our brain gets smaller over time and that this is considered normal. So the figure in the middle and at the top is two normal, healthy brains. The one on the left represents a 30-year-old for instance, and the one on the right represents that 70-year-old. And so both are healthy individuals, but we see that the brain of the 70-year-old is simply smaller. Part of that is because brain cells themselves are dying, the neurons, but also we know that the connections between those brain cells, those synapses, they are also shrinking in density, or in the total amount of them. And so those things together do lead to that atrophy or that shrinkage. Now the figure to the right represents or shows that neuron that we've already looked at, but it's connected to another neuron through that synapse. So synapses can increase and decrease in amount, and that decrease leads to some of that shrinkage. Now the figure in the middle at the bottom, that is to show you that the blood vessels are absolutely critical in our brain. 

 They're already really small in order to be in the brain, but we know that with time, they do get narrower. They do get smaller. And that shrinkage in the blood vessel does lead to some of the brain cell death, and that leads to some of those synapses decreasing in density. So Alzheimer's disease is an abnormal deviation from getting older. So here's that figure that I showed you before. Again, you're getting older as you go left to right. And your cognitive ability is going down as you go from top to bottom. So we see with normal aging, yes, there's that mild decline. We know that for individuals who develop Alzheimer's disease, over decades, they're developing those proteins, the abnormal changes in the brain, even before they develop symptoms. So over time, the proteins are increasing in amount. 

 They reach a tipping point, and eventually that person deviates from that normal aging scale or line, and that's this red line, so this is an abnormal case. A person will eventually present to a clinician and be diagnosed, and they'll be diagnosed with mild cognitive impairment if they don't have any day-to-day functional changes, but eventually those symptoms get worse, and they do experience those changes in day-to-day activities, and so then they're diagnosed with dementia due to Alzheimer's disease. And it all starts with the buildup of these proteins, this figure on the right, the amyloid plaques, which are sticky proteins that develop outside of brain cells, and the neurofibrillary tangles, these are proteins that develop inside of the brain cell, eventually leading to that brain cell death or accelerated death in brain cells. Now we can detect the pathology, these brain cell changes, without an autopsy. Prior to advanced technology, we relied on people passing away and then looking at their brains on autopsy. But that wasn't good for people. It's not helpful for living people. And so what we needed was the ability to identify amyloid and tau in living people, and through the use of lumbar punctures and spinal fluid as well as PET scans, we can do that. So this picture here in the middle is just a representation of a generic or non-identified 70-year-old person who's a research participant giving his or her time to us so that we can study this disease. And the picture on the left is of an MRI, so looking at the structure of the brain. 

 But the one in the middle, this is an amyloid PET scan. So this scan attaches to those amyloid proteins and lights up on a screen. And what we see here is that red color, the yellow color, that identifies that protein. So this individual has amyloid in his or her brain. The figure on the right is of a tau PET scan, looking for those neurofibrillary tangles. It's the same concept where the dye or the tracer attaches to those tau proteins and then lights up on the PET scan. And so this person has both amyloid protein and tau protein in his or her brain. And that is how we would define Alzheimer's disease. But we know through many different autopsy studies that people who die and donate their brains to science, they will not have any symptoms. There'll be no memory complaints or thinking complaints, but on the autopsy, on the microscopic slides, there will be lots of Alzheimer's disease pathology. 

 These studies have gone back all the way to 1986 when the Nun Study happened, and were repeated in the 1990s and early 2000s. We would see people who had no complaints, no clinical diagnosis of Alzheimer's disease, but yet their brain on autopsy showed lots of evidence of it, and that disconnect is really important. But the big study that I want to go over again is the Nun Study. It started in Minnesota in 1986. It spread throughout the rest of the country. And what we did, or what they did, is they looked at nuns, sisters, who donated their time, their energy, their journaling, and then eventually their brains to science. There are 678 of them. Many of them were here in the Midwest, in Wisconsin, Chicago, Minnesota, Indiana. And what we found was that we were able to correlate, to associate people who were living a certain type of lifestyle, had certain behaviors, with this phenomenon of not having symptoms, despite whatever was seen on the autopsy. So I have a picture here of nuns playing soccer and card games. 

 People who are physically active, people who are cognitively active tended to not have the symptoms of Alzheimer's disease. This was a really critical finding, because it led to the concept of a cognitive buffer. And what I mean by buffer is about to be explained in the next few slides. I have in the upper right-hand corner that picture of Alzheimer's disease and the development of Alzheimer's disease. But the figure in the middle, that's supposed to represent that change of Alzheimer's. So again, on the horizontal axis is age. You're getting older as you go to the right. And then on the vertical axis is your cognitive ability. You're losing that ability as you go from top down. A new addition to this slide, or this figure, is this dotted horizontal line, which we have labeled abnormality threshold. 

 What this really means for our purposes is once you cross that line and you're beneath that line, you have a clinical diagnosis of dementia. So the two colored curves here, the red one and the blue one, these are different scenarios for a single individual. So starting with the red curve, this individual happens to have what we call low resilience or a low buffer. It simply means that they don't have some of the protective factors that would be buffering against those proteins of Alzheimer's disease. So we know that that curve really shows more of a decline, a more rapid decline, over time. And they cross that abnormality threshold earlier, at a younger age, in developing dementia. Now the same individual, if they had higher resilience, more of these behaviors that are protective or reduce their risk of Alzheimer's disease, their curve looks different. That slope is different, meaning the changes are happening at a slower pace. And so eventually, they're diagnosed with dementia, but it's years later. And so that buffer has allowed them that time between, potentially years, of not having the functional changes that can happen in Alzheimer's disease. 

 So think of cognitive buffer as that resilience, a way of coping and fighting back against things we may not be able to change. It's a complicated topic, but it's really important, which is why I want to use another analogy. And so that's the rain. And so weather, rain in particular, like aging, is something we cannot control, but it may not be something that we want in particular. So my example here, it's raining outside, and you need to get to work. Well, you can't control the rain, and you don't want to get wet before you get to work. Similarly, we don't really want to get older, but if we're going to get older, we don't want to have the memory changes. We don't want to be diagnosed with dementia. So what do we do about that? Well, when it comes to the weather, we do have certain tools, first one being an umbrella. So we may not stop the rain from falling, but we don't have to get wet. 

 We have that umbrella to protect us. But the weather, like getting older, is not straightforward, and it can get complicated, and there are a lot of different variables. And so in some situations, the rain doesn't come from directly above us. It can come from the side. And so therefore, an umbrella might not be enough. It might not be enough of a buffer to protect us in that way, to keep us dry. So what do we do? Well, fortunately for us, we have raincoats, so another buffer against getting wet, against something that we can't control, such as the rain. So with this in mind, think of what other cognitive buffering mechanisms that we could have, different things that we, as a human species, can do to help us buffer against getting older and developing Alzheimer's disease. So the first one is epigenetics. This in and of itself is a completely different topic. 

 So briefly, epigenetics is the scientific knowledge and discovery that we are not just our genes, that we have some control over how our genes are expressed and how they're modified and how they're manifested in our bodies. So we can't control our DNA. That comes from our parents. But how genes are organized and how we, what we call transcribe, how we create things from our genes can potentially be modified. And the figure here shows you that there's certain proteins that can be increased or decreased. And all of this affects what really matters to us, what becomes of our DNA, and some of this is modifiable, which is why epigenetics is a very powerful field and a powerful motivator for many people to live a certain way. Another mechanism is neurogenesis, the growth of new brain cells. For a long time, scientists felt that the brain cell total that you had when you were at a certain age was it. You cannot create more brain cells, and every time you lost a brain cell, that was it. But we know now, through better science or more science, that that's not the case, that we can continue to grow brain cells into our adult life, and certain things can increase that growth. 

 The figure here that I show you at the bottom, is simply brain cells that are growing and sprouting, showing new axons and new connections, but it also speaks to synaptogenesis, so synapse being those connections where we can actually grow more connections between the brain cells that we still have, those neurons. And again, some of that is modifiable through our own lifestyle. So one other thought when it comes to cognitive buffer is brain health, making sure our brains are as strong as possible so that they can buffer against whatever changes happen to them. And so the brain, while a very special organ, is not in and of itself isolated. So we have to think of the whole body. The brain is very much dependent on the health of the rest of the body, so that means maintenance, that means taking care of our bodies and our brains. It means optimizing our health. It means really addressing our chronic conditions. And so the figure here that I just pulled up was many of the common chronic conditions. There are lots of them, but the ones in particular that you see here, high blood pressure, having a heart attack or heart disease, having a stroke, having sleep issues like sleep apnea, cholesterol issues, diabetes, these conditions do impact our brain, even though we think of them below the neck. 

 And so we need to do more than just treat them with medications. We need to optimize them. We need to manage them the best way possible, which can often be a combination of medications and lifestyle behaviors. Now this matters a lot, because many risk factors for dementia are modifiable. And there was a study that was done in 2014 that looked at all the prior studies and all the different risk factors that are modifiable, and they classified them and they ranked them based on the evidence. And what I have here for us is really nine of the key ones. And so, as you see in the top left, depression being a major risk factor for the development of dementia. The RR represents relative risk, so just risk to those without it compared to those with it, and so don't worry about the 1 part of it. The 0. 85 represents an 85% increased risk of dementia by having depression. 

 It then goes to hypertension, high blood pressure, 61% increased risk, obesity, 60%, smoking, 59%, cholesterol, 54%, all the way to inflammation, physical inactivity, kidney dysfunction. Number 10 is heart disease at 36% increased risk. The key thing to this is that we may not be able to have a treatment yet for Alzheimer's disease, but we do have treatments and strategies to truly address these other modifiable conditions. So this has garnered a lot of support. And in 2017, the Lancet Commission went and explored what should we be doing to modify this risk of preventing or intervening on dementia? And they came together with a very elegant picture here that you see of a life course, the different things that happen to us from birth until death, some of them modifiable, some of them them not, and I'll highlight some of the key areas here. So I'll blow up that picture. So this one in the middle, early life, well, we can't control our genetics, just like I said. That APOE4 is a genetic risk factor, not a guarantee, but a risk factor, and we can't necessarily control, or we don't control that gene. But we can control how it interacts with the rest of our body, through epigenetics. Less education, again, something we may not have control of, but an important social determinant of health. 

 I think of education as something that is ongoing throughout life. So that is potentially modifiable later on. And then midlife, so this is the middle to the bottom right. Midlife risk factors, so hearing loss, untreated hearing loss, high blood pressure, obesity, those are modifiable, and as you can see in the circles, do increase risk in and of themselves, with those factors. So looking closer, towards the end, later life, things like smoking, depression, physical inactivity, social isolation, diabetes, all of those independently have an increased risk, anywhere from 5% to 1%, but they are potentially modifiable, or they are modifiable. Now all of them together compose 35% potentially modifiable risk factors. So when we think of dementia, it's not something that's guaranteed, based on your age or your genes. 35% of those contributing factors, we have some control over. 65% we may not. But more time is needed to really explore those as well. 

 The conclusion from this panel of experts was that there are three main mechanisms that we should be utilizing to address risk reduction for Alzheimer's disease and dementia. The first one is what we're talking about now, increasing your brain buffer. They talk about this through preserving your hearing, education, cognitive training, being socially engaged, addressing some of those chronic conditions like depression, and then exercise. The second one is reducing external brain damage. So this would be things like addressing obesity and smoking, treatment of diabetes, hypertension, certain types of cholesterol abnormalities. The third one is reducing internal brain damage, so these would be things, or treatments, like exercise, a certain type of diet. Really, it's talking about inflammation in particular. This has obviously spread throughout the rest of the world, this type of knowledge and this type of action. And so the World Health Organization just recently came out with their own list and their own guidelines of what we should do to reduce our risk for any form of cognitive change and dementia. But as you can see from the list below, they're the same ones that we've been talking about. 

 Physical activity, smoking, management of chronic conditions. So there's a lot of overlap here, which really represents the strength of the knowledge that we have so far, based on our research. So how do we do this? Well, our Alzheimer's disease research program, which really consists of the Alzheimer's Disease Research Center, the Wisconsin Registry for Alzheimer's Prevention study, WRAP study, as well as the Wisconsin Alzheimer's Institute, WAI. We speak to the six pillars of brain health, physical activity, the foods that we eat, sleep, cognitive activity, social activity, and stress-reducing activity. I intentionally use the word activity so that people know this does take effort and work. This is not something that we can simply take a pill, and it goes away. It does involve us 100%. So the brief summary and overview of all of these can be found with this figure. When it comes to physical activity, I'm speaking about 150 to 300 minutes per week of aerobic activity, getting your heart rate up. This is the CDC recommendation. 

 150 minutes is great, doing more, even better, but doing something consistently. When it comes to food, this is a more debated subject, but most, if not all people would agree that the Mediterranean diet holds the most promise, at least the most research and evidence to support it. We happen to have a slight modification to that diet, and it's called the MIND diet, or Mediterranean-DASH Intervention to Reduce Neurodegenerative Delay, or Decline, and so that diet, I'll speak to in just a minute. Sleep, restorative sleep is really critical, so good quality sleep, roughly seven to nine hours each night. Cognitive activity or engagement, something that's daily so that you do it routinely and something that's challenging, because it goes back to those neural networks. You need to challenge those networks and form new networks, so that's learning something new, that's pushing your brain a little bit more than what it already knows. Social activity, enjoying time with your friends, your family, the people that you care about. And then stress-reducing activity, something that's daily or fairly routine that helps you unwind and relax. So some of the evidence that supports these six brain health pillars, this first one comes from one of our own researchers at UW, Dr. Ozioma Okonkwo and his team, and this publication was in 2014, really looking at cardiorespiratory fitness and its impact on our brain. 

 And so when I say cardiorespiratory fitness, I'm talking about heart, lungs, and overall health of our blood vessels. And so the figure on the left shows a picture of a brain, but that little graph next to it's really critical. So on the horizontal axis of that is your cardiorespiratory fitness, so you are more fit as you go left to right. And then on the vertical axis is hippocampal volume, hippocampal meaning that brain center within our brain that has our short-term memories. So as you are going left to right, as far as your fitness, you notice that there's an upward trajectory, meaning that more fit people tend to have bigger brains. This has been found in many other studies as well, but it was found in Dr. Okonkwo's lab too. The figure on the right is of an amyloid PET scan, so amyloid being that protein, the initial protein of Alzheimer's disease. So the graph shows you fitness. So again, you're more fit as you go left to right. 

 But now it's amyloid burden, meaning as you go from top down, you're having less amyloid. And so you see that the more fit you are, the less amyloid you have in your brain. This was not an intervention study, meaning one did not cause the other. They were associations, meaning they just tended to find this relationship. It leads to an intervention study, but this was the beginning with this particular one. So the intervention study was just recently finished and published on, so this comes from the doctor, Dr. Okonkwo's lab. This comes from Max Gaitan, one of his lead researchers. And so what they did was they separated and controlled for two different groups of people. The control group of individuals, they had doing what's called usual activity. 

 And then the intervention group was under what's called the aerobic exercise activity. So these were late middle-aged participants from our research center who were willing to do at least three times a week of some form of training over a six-month period. And you see in the graph to the left, if you're in the usual activity group, which primarily consisted of walking, they continued to do the same sort of activity during the six-month period. But if you were in that exercise intervention group, you ended up working with a trainer, and you were typically on a treadmill. And you're increasing your intensity over time from 50% of your maximum heart rate all the way up to 80%, and increasing the duration of each exercise activity from 20 minutes, roughly, to 50 minutes, so it's truly a workout for these individuals. And what they found is really compelling. So the figure on the left really speaks to cardiorespiratory fitness in just the type of activities that they were doing. So the bar, the darker bar on the right side shows enhanced physical activity. So this was the exercise group. So the more you exercised, the greater your cardiorespiratory fitness. 

 This makes sense to us. The figure on the right, though, shows cardiorespiratory fitness, our exercise group, and then performance on two particular types of cognitive testing. So the one on the left, which we've labeled CVLT Total, that's a different type of memory test. And you see that there's a dark gray bar that goes up and then a lighter bar that goes downward. Well, people who had more fitness or were exercising more performed better. So it was going upward, indicating that they were remembering more, so they improved performance on that memory test. Now the figure, the part on the right of that figure is really showing processing speed, or problem-solving speed. So in this regard, you want to be faster, so you want, the desired goal is to have your bar going downward. And so what we see is those who exercised more, they had the bar that went downward, the darker bar, and that meant that they were performing faster on that executive function or that processing speed. And those in the usual activity, they performed a bit slower, which is why it's upwards. 

 So then, this is a really important finding. And so the figure on the left is of an FDG, or a glucose PET scan, and a glucose PET scan, what happens is a tracer is injected into the body and it attaches to brain cells, or it is utilized by brain cells, and so it represents blood flow and metabolic activity of the brain. And so the more blood flow and the greater activity, that usually means that your brain is healthier. It's more active, it's more avid. And so what we see is that when a person is healthier, there's more color. There's more of the red and yellow in the PET scan. And so the top part of this figure is the usual activity group. So these were the individuals that were walking, and you see they have healthy brains. Part of their brain has that red part. And so that indicates a part that's more active and has more blood flow, but there's more yellow and green to it. 

 And then for the bottom part of this figure is the aerobic exercise group. And what we see is more red, more yellow throughout the brain, which would indicate greater blood flow, greater metabolic activity, and just healthier brains overall. So the graph to the right represents the same thing, meaning as you're going from left to right, you have improved cardiorespiratory fitness. And then on the vertical, if you're going from bottom up, you have more of that metabolic activity. So we see this relationship, the more you're exercising, the greater the health of your brain. There are other health benefits of exercise, though. There's improvement in depressive symptoms, anxiety and stress, a reduction in blood pressure. It can help with weight management and appetite control, and it can help improve sleep, all factors that are also important in addressing brain health. Now that MIND diet is really critical. So there are studies that are coming from Rush University, our colleagues down in Chicago, that are really looking at the MIND diet and the risk of Alzheimer's disease. 

 And so using food frequency questionnaires, which is that figure to the left, they were able to figure out who was following the diet the most, the middle, and the least. And then they were doing similar testing that we do at our own center on cognitive abilities and performance and eventual diagnoses of dementia. So what they found is that individuals who were in that middle group, following it right in the middle of the diet, they had a 35% reduced risk of developing Alzheimer's disease. If you follow the diet the most, if you're in that particular tertile, you had a reduced risk of Alzheimer's disease by 53%, which is quite similar to the Mediterranean diet. The Mediterranean diet's a bit harder to follow. There are more restrictions. And so this diet, while more relaxed, more feasible, still offered quite a significant benefit. Statistically, they were able to compare people's brains and their size and their performance and conclude that the people who followed the diet the most had a brain that was younger by seven years, compared to people who didn't follow the diet as much. And the diet really still is very tasty and delightful and delicious, and so it's fruits, vegetables, lean meats, salmon, healthy fats. And the more a person follows some of that diet, the better. 

 You don't have to follow it completely. Other health benefits of the Mediterranean diet include lower markers of inflammation, reduced rates of heart disease, reduced rates of diabetes. It too can help with weight loss. And there are some studies that associate it with a longer lifespan. Now sleep, sleep is a really important thing to the human person, and we all know it, because we feel it if we don't get good sleep. And so in a study that was done here at Madison, in our Wisconsin Registry for Alzheimer's Prevention, we examined participant responses to sleep questionnaires, asking them about their quality of sleep, asking them about sleep symptoms. And we had 101 participants. And we also happened to have those biomarkers of amyloid and tau findings from our PET scans, as well as our spinal taps on those particular individuals. And then we looked for a relationship. And what we found was that those who reported poor sleep actually had changes in their brain indicative of Alzheimer's, the amyloid and the tau. 

 So in particular, those who reported less adequate sleep, more sleep problems, and increased daytime sleepiness tended to have more of the amyloid and tau proteins in their brain. Now again, this does not mean that one caused the other. This was not a study to prove that poor sleep caused those changes in the brain, but rather just an observation that those who had those sleep symptoms tended to have those proteins in the brain. So there are other health benefits of sleep: improvement in mood and stress, help with blood pressure, heart disease, weight management. It can reduce-- or help with your immune function by reducing inflammation. And it can help with learning and memory. In fact, many in the scientific field believe that it is through sleep that we're able to develop our memories, that we're able to solidify our memories and keep them in our brains, as well as clear out that amyloid protein. So sleep is a really critical part of the actual process of memory as well as of Alzheimer's disease. The figure on the right just highlights some of the other key things when it comes to sleep. It can help with our energy levels, our concentration, our decision-making, memory, ability to manage stress, as well as just our overall physical health. 

 Now cognitive engagement is another key part or another pillar for us. We have science that shows that it keeps our brains healthy, in particular from 801 Catholic nuns, priests, and brothers who were observed between 1994 and 2001. 111 of those participants developed dementia. And what they found was, by comparing different groups, participants who engaged in more frequent cognitive activities had a 33% reduced risk of developing dementia, compared to those who did not engage in as many activities. Our own study at WRAP, Dr. Jonaitis in 2013, looked at 762 WRAP participants. And those that reported on questionnaires playing more games like checkers, crosswords, or other puzzles, tended to have higher scores on memory tests than those that did not. Now often linked with cognitive engagement is social engagement. Often, those two come together. And what we find overall is that more social engagement is associated with better cognitive function over time. 

 There's a study from 2001 that looked at over 1,000 people in their 70s and followed them for 7 1/2 years. Those that reported more emotional support had higher cognitive function at baseline and slower cognitive decline over time. In 2008, in a very large study of 16,638 adults 60 and over, they looked at marital status and volunteer activities and contact with family and friends. And what they found was that people who had the highest amount of social engagement had nearly half the rate of memory decline. It reduced that decline by 50%. Now there are some intervention studies where you have more control over the study, and you're really looking at a particular factor. And in 2011, in Finland, in an adult daycare, 235 adults were studied. 117 received the intervention, which was really going out to a writing exercise, a physical exercise, or an art sort of activity, and then getting together and talking about it. That was compared to 118 people who engaged in just the usual activities at the adult daycare. And what they found was that those that were in the intervention group, the physical or mental activity plus the social outing had improved scores versus the control group. 

 Now stress, it's not always good for us. So think of stress as a fight-or-flight response. And in general, it is meant to be protective. If you were to see a lion, and while this lion is not very scary, in general, if you were to see a lion, it's meant to increase stress so that we behave appropriately, which I believe means running away. The same is true for a cold. The cold generates stress so that we can fight that cold. It also can provide motivation for us so that we can meet our daily challenges or achieve our goals by providing that healthy level of stress. But duration matters. And so those who are under chronic stress, that have no set end point, whether it's every day or intermittent throughout the week, that is not healthy stress. That's not designed to have a purpose for us. 

 And so that can cause unintended changes in the body, in particular, increases in cortisol and adrenaline. And cortisol in particular affects our body in multiple ways. It increases inflammation. It disrupts our metabolic system. It changes the flexibility of our blood vessel walls. And all these things can lead to increased blood pressure, heart disease, digestive issues, high blood sugar, can affect our thinking, as well as our mood. So studies that have been done in the past few years have really shown a connection between stress and our brain and its function. So this comes from 2018. This is a study at Harvard showing that circulating cortisol, that hormone that is a result of stress, does impact cognition as well as the structure of the brain. They found that higher cortisol levels were associated with worse memory, that people had lower total brain sizes, in particular, the front and the back, that this was more evident in women, and had nothing to do with genetics. 

 Our own center has shown that there is a relationship between lifetime stress events and in cognitive performance. So we looked at not stressed by a hormone, but just the number of reported life experiences that were stressful and then compared them to performance on certain cognitive tests. So in this regard, it was speed and flexibility, so the front part of our brain that helps us problem-solve and process information. And we found that the more lifetime stressful experiences you had, the worse you did on those tests. So that's why it's a downward slope, because you're performing at a worse rate. And this is important because stress is not fairly distributed across all populations. And when we think about the social determinants of health and the disparities in healthcare and health access, this is an important piece of evidence. And so there's a recent publication by one of my colleagues, Dr. Megan Zuelsdorff, that talks about stressful life events and its impact on racial disparities in a person's ability to think and perform on those cognitive tests. Even the perception of stress can affect our brain function. 

 So this is a study from 2014 where they didn't measure the circulating hormone or ask a questionnaire about stressful events. They simply asked about perceived stress, how they were feeling their stress level was, and what they found was an association, a relationship between perceived stress and lower initial cognitive testing scores, faster rates of cognitive decline over time, and that this was present in both white participants and Black participants that were over the age of 65. It also showed a 30% increased risk for developing mild cognitive impairment. And that was supported by another study done just two years later in 2016. I think this is a really important finding, because it shows the power of our brain in just the perception of something and how it can impact our testing abilities and our ongoing testing performance, which comes to a topic of repetitive negative thinking and its relationship to Alzheimer's disease. So repetitive negative thinking is a measurable process, a cognitive process that really covers future issues, or future thoughts and past thoughts. Future thoughts are worrying about things that have yet to happen, and past thoughts are rumination about the things that have already happened. So it describes the process rather than the time that's spent in doing it or the content of what you're thinking about. And so a recent study that was published just in 2020 looked at the power of thoughts. There are 292 people over the age of 55 that were in good physical health, cognitive health. 

 They had one parent or at least two siblings that had Alzheimer's disease. And they asked these individuals to fill out questionnaires, a lot of questionnaires, over a two-year period. They asked about repetitive negative thinking, anxiety, depression, and then cognitive ability. So they tested these individuals at a year, and then in the future. Some of them also had PET imaging, so those brain scans looking for amyloid and tau. And what they found was that those who had higher repetitive negative thinking patterns experienced more cognitive decline over a four-year period. They were more likely to have decline in memory and more likely to have amyloid and tau on those PET scans. Depression and anxiety are also associated with cognitive decline, but they're not associated with those proteins, which means there is something separate and important about our thinking process, this repetitive negative thinking. And so it might actually be a mechanism of Alzheimer's disease risk in people with depression or anxiety. So then the question comes, how do I begin with this information? So when it comes to physical activity, I would limit sitting on the couch and watching television. 

 It's reducing your sedentary behavior. Getting up and moving is a really good thing for people. There is a common expression that sitting is the new smoking. And really, that comes from the fact that being sedentary is not healthy, and so anything we can do to be more mobile is better for us. So I would say assess where you are with your own fitness and be realistic in your goals. You do not need to be running a marathon tomorrow. Pick an activity that you enjoy and consider a variety of activities that just increase your heart rate, something that will be more sustainable and enjoyable for you. Gradually increase that duration and that intensity over time. Diet is a really hard one. So often here, I list just things that we can do to reduce unhealthy diets, so limiting fast food, highly processed food, desserts, really not drinking sugary beverages or soda, trying not to stress eat, which has been a very difficult thing for us during this pandemic, trying to eat more healthy foods like salads and vegetables. 

 When it comes to sleep, avoid watching TV, iPads, phones, right before bed. It's the blue light that really tricks our brain into thinking it's still daylight. Avoid drinking alcohol after dinner. It may help you fall asleep, but it disrupts your sleep cycles, and it doesn't allow you to get the restorative sleep that you need. Keep your environment ideal for good, proper sleep. So that's keeping it cool and dark. Wake up around the same time every morning. It may be hard to do, but that kind of routine is good for your body, and it helps keep you consistent. When it comes to cognitive activity, do something every day and just make it a part of your routine. That way, you're more likely to do it. 

 Try something that is enjoyable but challenging. So consider learning a new hobby, if you're interested. Try to get others involved, because often, when it's social, it helps you keep yourself accountable, and it's something you can share with another individual. And some examples would be reading and puzzles, card games, learning a new musical instrument, something that you enjoy, something that helps you learn. When it comes to social activity, which is difficult during times when you're more isolated, talking to someone is really important, whether that's over the phone, virtually, outside, if you happen to be. . . If this is during a pandemic, socially distancing yourself. But virtual support groups are very common these days and very popular, and a good way for you to reach out to other people who might be in a similar situation to yourself. When it comes to stress-reducing activities, don't eat or drink your feelings, acknowledge your stress, address your stress, be kind to yourself, avoid some of that negative self-talk. 

 Having a daily intentional activity that helps you unwind is helpful. And whether you establish that at the beginning of the day or the end of the day, pick some time and plan to do it then. Some examples, mindfulness has a lot of evidence to be helpful, as has art therapy, music therapy, pet therapy, even a grateful journal, where you're able to write down how you're feeling and the things that you're appreciative of. And it's not just one. It's a combination of these activities. And so a study that was recently done looked at the combination of healthy lifestyle behaviors and risk for Alzheimer's disease. So each participant was given a score based on five certain behaviors, and you can see them here, not smoking, physical activity, light to moderate alcohol use, following that diet, the MIND diet, and then engagement in late-life cognitive activity. And so what they did was they compared those individuals that developed Alzheimer's disease to healthy controls and then they compared people who followed one or zero of those behaviors to those that followed more. And if you've had two or three of those healthy behaviors, you had a 37% lower risk of Alzheimer's disease. If you had four to five of those behaviors, it was a 60% lower risk of Alzheimer's disease. 

 Really, this is showing that the combination of behaviors can be quite helpful and potentially synergistic in reducing that risk. So I'd like to end with a couple of concepts that I've learned through reading other books. And this comes from Mark Manson, who's an author, and he came up with the "Do Something" principle, which really speaks to the difficulty that many of us face in having a new behavior, in having a new habit. Oftentimes, we're waiting for that inspiration or that reason to do it. And his argument is if that happens, act first, start with action, and through action, and routine action, you can potentially form that inspiration and then that would form your motivation. And then you will actually be reinforced in having that action. I think this is a helpful philosophy for those of us that are struggling to pick up a new healthy behavior, one of the brain pillars, for instance. One thing I would add to this concept is awareness. I think it's really important for us to be aware and purposeful of what we're doing and why we're doing something. Awareness increases our knowledge and our understanding. 

 And it is through that, that potentially we act or we find our inspiration and our motivation. So hopefully, something like this or the learning that you're doing about health will provide that awareness and that knowledge and understanding so that you do act. The other concept comes from another author, James Clear, who talked about certain techniques to make a habit more automatic. And so in creating brain healthy habits, I wanted us to think about this. It happens through practice. So through daily routine practice, that's how we form a habit. Focusing on one habit at a time, not overwhelming ourselves by doing eight different things, but instead dedicating time to one thing. And then utilize implementation intention, which is a concept about creating a very specific plan, addressing when you're gonna do something, where you're gonna do it when you do it, and then how you're going to do it. I would also say habits are not easy to form, and it takes time. And so the average is roughly 66 days, and that comes from a researcher at the University of London. 

 And they found that the range can be anywhere from 18 days to over 250 days. So give yourself time and space to do this, be kind to yourself, be patient with yourself, and remind yourself of the purpose. Hopefully, it's for good reasons, and that reinforces your desire to pick up any of these brain-healthy habits or these health pillars. For those that are interested in learning more about the science behind what I've described or the other science that is happening in the Alzheimer's disease field, you can always go to my podcast "Dementia Matters," which can be found in multiple sources, whether it's our ADRC website or by Googling it. And with that, I'd like to thank you, and I appreciate your time and your dedication to learning more about brain health and health pillars. I'd like to end with a thought that so often we feel powerless in our health and in getting older. And hopefully, today, as you watched this presentation, you see that there is more power than we thought. Our brains are unbelievable organisms that represent our ability to have more control in how we age and how we live. And so I thank you for your time, and I hope that you are able to take something from this afterwards and that you improve your own health and quality of life.