University Place Wednesday Nite @ the Lab Sterling Johnson, "Brain Changes Associated with Risk for Alzheimer's Disease" 8/4/2010  UP 464   cc >> Thank you for joining me for Wednesday Nite at the Lab at the UW Madison Biotechnology Center. Tonight we welcome Dr. Sterling Johnson of the Department of Medicine. Dr. Johnson is a neuropsychologist who received his PhD from Brigham Young University and has research interests in brain function and clinical disorders. His current projects focus on the neurobiological and psychological processes that affect memory, early detection of Alzheimer's disease, imaging markers of Alzheimer's disease progression, brain changes in normal aging, the effect of intervention on the brain and aging and Alzheimer's disease. I don't think he's going to cover all that today or in this seminar. (laughter) His lab has funding from several sources including the National Institute on Aging, the US Department of Veterans Affairs and the State of Wisconsin. So please join me in welcoming Dr. Sterling Johnson to Wednesday Nite at the Lab. (applause) >> Thanks. Thank you, Nadia. It's good to be here. 

And thank all of you for coming tonight when it's such a lovely night out there. I'll be talking tonight about brain changes that are associated with risk for Alzheimer's disease. And before I go to the next slide, I just wanted to point out the institutions here that I'm a part of. This first one here is the Wisconsin Alzheimer's Disease Research Center. This is a newly funded center, I guess it's been about a year now, and we are a group of investigators looking at clinical trials, we're looking at research in early detection, we're looking at basic science of Alzheimer's disease. So this is a major development and it's funding from the NIA, the National Institutes of Aging. I'm also part of the Wisconsin Alzheimer's Institute. This is the partnering organization for the ADRC or the Alzheimer's Disease Research Center. The Alzheimer's Institute is more about teaching and outreach and training of clinicians and outreach to the public. So this is, I'm fulfilling part of the role of the Wisconsin Alzheimer's Institute tonight. 

The other organization is the Geriatric Research Education Clinical Center, we call it the GRECC, and that's in the Madison VA hospital and that's where my office is. So I just wanted to point those organizations out. They are really instrumental in helping me do what I do. So tonight I'll be talking about Alzheimer's disease, and first thing I'd like to do is kind of frame the problem for you, why this is important for us to talk about. And then I want to talk about the clinical features of Alzheimer's disease. Give you an idea of what the clinicians might look for when they're evaluating a person for possible Alzheimer's disease. And then I want to tell you about some of our research, and that's the exciting part for me of our talk because I think it's really important that we identify this disease as early as we can in order for people to get into treatments before the brain undergoes extensive neurodegenerative change. And I think that's key, and I'll explain more about that later. So why is Alzheimer's disease important for you to know about? It's important because right now 5.3 million of us in the US have Alzheimer's disease. It's the sixth leading cause of death. 

There's a new case diagnosed every 70 seconds. And this is a staggering number. There's $148 billion spent annually in costs associated with this disease. This is medical costs as well as costs to the care givers and to the communities for dealing with this disease. And we'll start this off with another depressing point. 78 million baby boomers start turning 65 in just a few more months. That's according to the definition of what a baby boomer is, the age range moves into old age territory starting in 2011. So another interesting thing here is that medicine has a good handle, or at least a better handle than it did, on major diseases like heart disease, breast cancer, prostate cancer, and stroke. And if you look here at the last column for these different disorders, you see that there's a negative percent change here. That means the deaths due to this disorder are decreasing. 

Heart disease is down 11%. Breast cancer is about even. Prostate cancer is down 14%. Stroke is down 18%. Alzheimer's disease is up 47%. This is due to a number of things. One being the population is aging. Number two, the medical community is more tuned into this. And three you are more tuned into this. That's evidence by you being here tonight to learn about this. 

The public is more educated than it used to be about this disorder and that helps. It helps to go to your clinician and ask questions and determine if this applies to you or to a loved one. I don't know if you can read this or not, but this is just about Alzheimer's in Wisconsin. In our state in 2000 there were 100,000 people with Alzheimer's disease. In 2010 we have about 110,000 people with Alzheimer's disease. And it's expected to climb just as it is throughout the country. Why is this important to try and intervene earlier? Well, if we could delay the onset of Alzheimer's by 10 years that would translate into 3.5 million cases instead of the predicted 14 million cases over the next 50 years. And even just a two year delay, a postponement of symptom onset would result in two million fewer cases over the next 50 years. And that's substantial. And it's going to save the country billions of dollars, not just millions but billions, if we can even just postpone this disease. 

And one of the reasons for that is one of the major expenditures is in nursing home care. And if we can keep individuals out of a nursing home, keep them functional, we save the state and the country money that could be spent elsewhere. >> Why is this delay because the people die of something else instead of Alzheimer's? >> Possibly they die of something else or stay healthy for longer. And either way if we can avoid the chronic long-term healthcare burden then that's economically important. >> But then they die of something else. >> Possibly, possibly. That's very true. >> Repeat the question please. >> He had a question of why is this delay important or what happens during the delay? And I said they might die of something else or they might stay healthy for longer. Well, let's talk about now about dementia. 

Dementia is the overall syndrome that Alzheimer's disease is a part of. Dementia is a behavioral syndrome, and it's got several symptoms associated with it. And the important distinguishing feature between the terminology here of saying someone has dementia versus saying someone has Alzheimer's disease is that dementia is an overall category, and Alzheimer's disease is one possible cause of dementia. So dementia is defined as the loss of cognitive ability that interferes with your daily life, it represents a change from how you used to be, and you have deficits in at least two different cognitive areas like memory, language, visual spatial ability. There's a term called agnosia which is inability to have knowledge of something. There's a term called apraxia which is poor coordination and the like. So there's different kinds of deficits that can occur. Importantly this diagnosis of dementia is through a clinical work up by your physician and possibly a psychologist to help measure your memory function. So what about Alzheimer's disease? It is form of dementia, as I said, and the main feature, especially early in the disease, is a deficit in memory. What do I mean by memory? Well, I use the term episodic memory here. 

And that means memory for a particular episode in your past, whether it's an object or a person or an event. Something that has a context in time and space is an episode. And so that's where the memory deficit is. It's bringing that information back into conscious awareness. There's a problem there. There's also a deficit in at least one other cognitive area. And activities of daily living, again your ability to function in the world is affected. And other possible causes of Alzheimer's disease have to be excluded. And this is important to mention here that there's really no blood test type of a measurement for Alzheimer's disease. There's nothing that you can just go and get a test for and you have the diagnosis. 

It's through an extensive clinical work-up usually involving several hours and possibly several tests including imaging tests and lab tests and cognitive measurement and so forth. And this is a list of other forms of dementia or other causes of dementia that your physician might be tuned into when evaluating your or your loved one for dementia. So Alzheimer's disease, mild cognitive impairment, Lewy body disease is another common form of dementia. Vascular dementia, which is multiple strokes. One called frontal temporal dementia and so forth. If look here further down on the list, depression is something that we consider because that's an important symptom that's treatable, and it often mimics dementia, and once the depression is treated, memory function improves and activities of daily living improve. And there's other things on the list that are treatable including medications that might be causing memory trouble. And all of these things are important to bring to your clinician or your loved one to a clinician if you have a question about this. Well, the evaluation involves taking a history. This is often the most important part of the diagnosis is understanding how the symptoms have evolved. 

Whether there's an abrupt onset or a gradual onset, these are important features for the clinician to understand. A neurologic exam, a chemistry panel, different lab tests, B12 test, thyroid test, a CAT scan or an MRI scan is usually done, and depending on the history there's a bunch of other labs that might be done to help make the diagnosis. As I said before, episodic memory is the most important feature, the cardinal feature, at least early on. Misplacing objects, getting lost, repeating questions, forgetting familiar names and places. Those are important early symptoms. I know what you're thinking. We all do this. (laughter) I do it several times a day it seems like. And so we have to distinguish between those common memory failures that we all exhibit between the more severe forms of memory loss. And sometimes that's hard to do, and you should, again, go to your physician if there's any questions about that for one of your loved ones. 

Language impairment is important. Problems in word finding, naming semantic and metaphorical errors. And you make those errors too. You'll hear me make some language errors tonight as I speak to you probably. Visual spatial impairment. That means things like having trouble putting a key into a key hole or spilling things when you're pouring out some liquid into a cup. Driving accidents are very common, and that usually involves visual spatial abilities as well as attention abilities. Later on in the disease there's, of course, other symptoms that occur. Incontinence, loss of mobility, difficulty swallowing, and often that's one of the causes of death in Alzheimer's disease is the aspiration pneumonia due to swallowing problems. Let's focus now on the early symptoms of the disease, and I want to bring us back to memory since that's the most common symptom. 

And I've got bolded here this idea of episodic memory, and again that's your memory for events that have occurred previously. Like what you had for breakfast or what you did earlier today or what happened yesterday, what happened at the holidays last year and so on. Working memory, just to orient you to some of this terminology and then we'll get back into some of the research here, working memory is your ability to remember things for just a few seconds or maybe up to 30 seconds or a minute. Remembering a phone number, remembering a name, remembering what somebody says long enough to take notes, that's working memory. And working memory and episodic memory both involve either keeping something in conscious awareness or bringing something back into conscious awareness. And that's important because that ability is compromised in Alzheimer's disease. Semantic memory is your ability to, semantic memory is your fund of general knowledge. So a phone number, initially when you hear it you write it down based on your working memory ability. But after you've used that phone number dozens or hundreds of times, it's just part of your general knowledge and you no longer have to recall a particular context for when you learned that phone number, it's just something that you know. Classical conditioning and procedural memory are very important but they don't necessarily involve consciousness, and that's an important distinction here. 

And it's important to actually not have consciousness probably for procedural memory. When you're driving you don't really want to take the time to remember every single detail. You need to have that sort of automatic ability. The same thing for any kind of skilled motor function. Like musicians, if they had to think about every note they were going to play, they might not get to the song that they were trying to play for you. And the same for athletes and so on. So procedural memory is very important, but it's not affected in Alzheimer's disease. So if you think about what you may have heard regarding the brain and its capacity, it does have a remarkable capacity to remember things, but it's not a computer. We often refer to that kind of metaphor for the brain but it really isn't a computer. When you bring things back into consciousness, it's a reconstruction of what happened before. 

And that reconstruction is biased by your own schemas that you have about life and your belief system and so forth. Other things that affect your reconstruction is how well you encoded that information in the first place. And I'll talk to you about the anatomy of the brain that's involved in encoding that's bringing things into memory. But here I just want to focus on some of the factors that have influenced memory. One is how well you're paying attention. Of course that's common. That's obvious. Mnemonics or memory tricks are important ways to get things into memory and organize information. The affect --, what I mean there is how emotionally important is this for you. What's the relevance of this information to you? We don't remember things typically that aren't important to us. 

Obviously your mood, and some of us just have more of a talent for remembering things than other people, and I wish I was one of those people who had more talent at that. But I have to write things down myself. So getting things back into consciousness is influenced by a number of things in this box over here. How much you use the information. The relevance of that information again is important. Your own history and your own biases influence how things are recalled as well as how they're encoded. And of course time. The longer something, the further back in time that event occurred, the more difficult it will to be bring an accurate recollection of it back into awareness. And again individual differences play an important role here. Well, that's kind of a tangent on memory function, and now I want to get back to Alzheimer's disease and some of the brain changes that occur, and I want to get into some of the research that we're doing looking at early detection and early brain changes. 

And so we're thinking of Alzheimer's disease as a chronic disease, and you might be familiar with the cancer model for chronic disease where you have a preclinical phase and you have maybe some promoting things and maybe an initiation factor that occurs early in life, and then eventually the clinical symptoms occur and the cancer is formed and so forth. Alzheimer's disease is similar. There's a period of normal function, and then there's a continuum here that goes on to progressive disease. This area here in the gray zone between normal and Alzheimer's disease is called MCI or mild cognitive impairment. And sometimes mild cognitive impairment is benign, and the person's memory can be treated or goes back to normal for whatever reason. And sometimes, in about 15% of the cases, it progresses further into Alzheimer's disease. That's 15% per year convert to Alzheimer's disease. So after five years there would be roughly 45% of people with MCI convert to Alzheimer's disease. So it's important. What we're trying to do is not only look at brain changes that occur in MCI that would predict who would develop Alzheimer's, but we want to look even further back when function is still very much normal and when maybe the age, the chronological age is in their 40s and 50s, we want to know if that individual is going to develop Alzheimer's disease because it's that individual whose brain is still healthy, their hippocampus, the part of the brain that's important for making memories, is still intact and that's when interventions are likely to be most effective. 

Well I introduced this concept to you of mild cognitive impairment. It involves subjective memory, complaints, memory symptoms, some objective evidence of memory loss. If you go to your doctor and they do a memory test with you, it might be impaired. But otherwise function is generally intact. And there's no evidence of functional decline. And, as I said before, 10% to 15% convert to Alzheimer's disease each year. And thus, this could be a prodromal syndrome of Alzheimer's that's important to key in on. Now I want to move in to the organ that's affected in this disease, the brain. And first let's familiarize ourself with the brain. This structure in red here is the hippocampus. 

The hippocampus is important for making new memories or encoding new information into memory. And it's deep in the temporal lobes of the brain on each side, and it's one of the structures that are affected very early in Alzheimer's disease. If you think about the brain, it weighs about three pounds. It's the size of a medium cauliflower. There's about 100 billion neurons in the brain. And if you think of the connections between those neurons, there's about a hundred trillion connections. So this is remarkable because the brain has a lot of capacity to rewire itself and get around some pathology. And this is what makes this disease so difficult to study, actually, is that the brain is so good at rewiring itself and accommodating injury as it occurs. But there gets to be a point where the degeneration is too extensive, and that's exactly when the symptoms begin. It's when you reach some critical threshold of neuronal loss that the symptoms begin. 

From a large perspective, this is a normal brain over here on the left, and here's an Alzheimer's brain here on the right. And you see the gyri, which are kind of these bumps here, part of the gray matter that folds on itself, these are atrophic, meaning that they've lost neurons, and these fissures and what are called sulci that are between the gyruses are enlarged and that also reflects atrophy. What causes this is amyloid plaques and neurofibrillary tangles. Those are the two major pathology features of this disease. The amyloid plaques occur in between the neurons, and the neurofibrillary tangles occur inside of a neuron. And both of these things are important. Turns out that the neurofibrillary tangles occur mostly in the hippocampus. That's where they occur first at least. And then they spread out from there. And the amyloid plaques are more in the cortex in the outside surface of the brain. 

This is what an amyloid plaque would look like under a microscope. This area right in here is the plaque. And this is what a neurofibrillary tangle would look like. It's inside of a neuron. And that's it. So what do those things cause? They cause neurons to die. And that results in atrophy that we can see with something like an MRI scan. So here's a healthy individual, and I'm showing you the hippocampus. It's right here in this circle, in this area right here. The hippocampus in this normal brain is very healthy. 

And as we move to this MCI subject, here's the hippocampus in the MCI subject. It's lost some of the volume that it had in the normal brain, both on the left side and the right side. And here's a patient with Alzheimer's disease. And here the hippocampus has lost maybe 70% of the volume that should be there. And that explains the symptomology or the memory loss that occurs. This is a view of the underneath side of the brain. Here's the brain stem area and here's the underneath side of the temporal lobes, here on either side. And if you dissect this first gyrus away, you get the hippocampus. And that's shown here on the right side. And this is oriented in a view that tells you why the hippocampus has this name. 

It looks like a sea horse, and that's the Greek name for sea horse, hippocampus. >> Excuse me. >> Yes. >> The hippocampus, are they two separate individually functioning objects or do they function in tandem? >> The question is does the hippocampus, there's two of them and do they function together or do they function separately? And that's a great question. They mostly function together, but the left hippocampus is probably more associated with encoding verbal information because the left side of the brain is our language side. It's not completely cut and dried like that but there is some specialization, but in general they work in tandem. Well, most of what I'm going to talk about is in the gray matter or the cortex of the brain. This is the area that's on the outside of the brain. The gray matter is these, that's where the cell body is, and it's right around the edges of the brain. In the middle though is the white matter. 

And the main theory of Alzheimer's for years has been this is a gray matter disease, the neurons lose volume and it happens in the cortex. But there's growing evidence that the white matter might be affected in a primary way. And we have investigators here at the UW who are looking at this and are finding white matter deficits very early on, even in the presymptomatic phase of the disease. And this is going along with other research. I'm not going to go into detail on this story because it's still evolving, but it's not just a gray matter disease even though most of what I'm going to be talking about is gray matter. How do we measure function in an Alzheimer's disease brain? One way is with a PET scan. PET scan stands for positron emission tomography, and you give a very small amount of radioactive sugar actually. You inject it into the arm, it goes into the brain, the brain is the main consumer in the body of sugar, of glucose, and we can tell how well the brain is functioning by how well the brain is metabolizing sugar. And these areas in purple or dark blue here are areas where the brain is not functioning properly in Alzheimer's disease. It's hypometabolic, meaning that metabolism has gone down, it's decreased in these areas. 

And I want you to pay attention to these because these areas are going to come up later, there won't be a quiz, but I'll show you that this area shows up again and again even in people with risk for Alzheimer's. And one important area is here in the middle surface of the brain right along the midline just above the brain stem as you go up in the back of the brain. This area is called the posterior cingulate. It's right here and this area is very important when you bring memory back into your conscious awareness, you're using that part of your brain. And it just so happens that this area is hypometabolic in Alzheimer's disease. >> What does that mean? >> That means that that area of the brain is not functioning very well in Alzheimer's disease, and that might explain the symptom, one of the reasons why there's memory loss in Alzheimer's disease. So here's what a normal healthy adult looks like. One of our research subjects who had an MRI scan and a PET scan. If you look at their hippocampus, it's in the normal range. And this is their PET scan. 

And there's a nice ribbon around the cortex, and that means that the cortex is consuming sugar as it should in the normal way. And here's a patient with Alzheimer's disease, and if you look here at the hippocampus underneath my cursor here, there's mostly just the water-filled space or the cerebral spinal fluid-filled space. It's just fluid where there used to be tissue. And if you look at the PET scan there should be a nice ribbon, the ribbon here is much thinner, the red part, and it actually doesn't exist down here in the temporal lobe near where the hippocampus is. So these are some of the diagnostic things that are important for Alzheimer's disease. Well, I want to get now to early detection of this disease and talk about some of the research that we're doing here at the university. I just showed you a PET scan and showed you that in Alzheimer's disease there are certain areas that are not functioning normally and it's called hypometabolism. But if you look at individuals who have risk factors for Alzheimer's disease, they also show hypometabolism or decreased  metabolism in the same areas as patients. And this picture is of a study that really changed my world as a researcher. I came across this shortly after it was published about 14 years ago. 

And what this, the important thing here is that this studied 55-year-olds, 56-year-olds who had a certain genetic profile. And they found that these individuals who were cognitively normal had the same brain changes as the patient with Alzheimer's disease. And this suggested that even cognitively normal individuals might be showing some brain signature of this disease despite normal cognition. And this goes back to that idea I mentioned previously that the brain has to lose a certain amount of neurons before the symptoms do appear. So it may be that we can actually look at the brain with some kind of imaging technique or other technique and identify the disease before any kind of cognitive symptoms emerge. And that's the approach that we are taking here. One of the major themes of our Alzheimer's disease research center is to look at early markers, early imaging and spinal fluid markers of the disease. We have a registry called the Wisconsin Registry for Alzheimer's Prevention. We call it the WRAP study. And this registry is useful for helping us to understand the natural history of preclinical Alzheimer's disease. 

Well, what are the risk factors that we might look for? If we think that the brain is changing early but we don't really have any kind of handle to grab on to here, there's no cognitive symptoms, what do we do? We look for the risk factors. We look for age. Age is the most important risk factor. This APOE gene is a very strong risk factor. And it turns out that if someone has the E4 allele of APOE, that they have a much higher incidence of Alzheimer's disease. So APOE, let me say a little bit more about this, APOE comes in basically three different flavors, or three different alleles. You inherit one from your mother and one from your father. It's E2, E3, or E4. E2 is usually considered beneficial, protective. E3 confers neutral risk. 

It's neither helpful or hurtful. E4 is considered the bad form of this gene. And you can have different combinations. You can be an E3/E4, getting and E3 from one of your parents, an E4 from the other, and you might be at higher risk. If you get an E4 from both parents, you have 50% or 60% chance of developing the disease later in your life. Family history is also an important feature, and it's been shown recently that this factor of family history explains unique variance that's not accountable by APOE. There's some unique information there. So there's probably some other gene or some lifestyle or environmental factor that's reflected in this family history idea. Gender is an important risk factor. Women have AD twice as often as men. 

Lifestyle and diet are also important. We found a new gene in collaboration with Duke University. It's called TOMM40 and if there's time, I'll show you some results of that. We've been studying this registry, the Wisconsin Registry for AD Prevention. Yes, question? >> Can you expand a little bit on the lifestyle and diet aspect? >> Yeah, I can. I'll say just a little bit now and then we can talk more about it in the question component later. It's thought that if you can maintain, what's good for your heart is good for your brain. So if you maintain good cholesterol, good blood pressure, then your brain is at lower risk for developing AD pathology. Also there's research on the diets that people eat. We know that diet restriction is helpful in reducing amyloid in other animals. 

It might be helpful in humans. The Mediterranean diet has been shown to influence symptoms in Alzheimer's disease and is healthy. So things like that are good for the brain. So we're studying this registry. There's about 1400 people in this. They undergo testing, they undergo genotyping, and they donate, generously, some blood and their DNA. They're from all around Wisconsin. Right now their mean age is 59. Most are under 61. 16 years of education. 

93% are non-Hispanic white. And the idea here is to test them at baseline at this first wave and then four years later at their second wave. And then after that they get tested every two years with cognitive measurement tools so that we can measure memory function and other things. I'm just going to keep going because I want to talk about our research. And that point I've already made so I'm going to keep going here. I want to talk about our first study that we did with the WRAP sample. We asked individuals in WRAP, among these 1400, to have a brain scan where we could measure their memory function. And what we did is we asked them to memorize a small set of items, and then in the scanner during a functional MRI scan we showed them those same items mixed in with new items. And the idea here is that the hippocampus should be more responsive to things that it hasn't yet grabbed into memory or encoded. And so it ought to be more responsive to novel objects. 

And that's indeed what we found is that the hippocampus was really quite responsive to novel objects versus the ones that the hippocampus had already learned. But importantly, I can show you here, here's the hippocampal response in people who don't have a family history of Alzheimer's disease. The people who did have a family history of Alzheimer's had much less brain activity during this functional MRI memory test. And we published that and the thought was that this was probably suggestive that this disease is, in fact, beginning in our 50s, maybe earlier, and that the hippocampus, this important structure for memory, is involved early on. We did another kind of test in a different study asking people to appraise their own traits and abilities. And this kind of reflective task also activates the hippocampus and related structures. And we found a family history effect there. And by the way we didn't find an APOE effect in these studies. We are also looking at, as I said, white matter changes, I mentioned this earlier, and we're finding family history effects there. And this was, in the context, we're also finding that maternal family history has a greater effect than having a father with the disease. 

We started publishing this and it was initially met with mixed reviews or mixed acceptance, I guess we should say, because APOE has been the dogma, that's been the -- for so long that this is what the most important risk factor is and everything else can be explained by this. But when people actually look at family history and APOE side by side in the same analysis, family history accounts for something unique that's not explained by APOE. And so we were starting to find this, and here's some of our studies here, and now there's a whole bunch of studies that have found the same thing, including some studies that are much bigger than ours like the Framingham study and the Rotterdam population health study. So this was really a finding that's taken hold, and I think we're now tuned into the idea that there's something more than APOE that's an important risk factor for Alzheimer's. We were in Hawaii a few weeks ago, our lab was, and while we were there there was some news about one of the findings we had, it's called TOMM40, and that's a new gene. And I just want to briefly go over that with you. TOMM40 is a gene that sits next to APOE. And what it is it's an area of the, it's a gene that actually repeats. And so it's called a poly-T repeat polymorphism. And you can have this protein that repeats a few times, and that would be a short repeat, you can have it repeat several times, and that's long, or you can have it repeat an awful long for several repeats and that's very long. 

And so the way this is categorized, the very longs it's more than 30 repeats, 30 of these proteins lined up, or amino acids lined up. Long is 20, between 20 and 30. And short is below 20. And again, this is a polymorphism, a gene structure that sits right next to APOE, and, in fact, it's pretty tightly linked with APOE. At least part of it is. And this is kind of complex, but the long variant of TOMM40 is explains the same thing that APOE4 does. But interestingly, the very long alleles and the short alleles, they mainly occur in people who we thought were at neutral risk for Alzheimer's disease. And one of the problems with APOE has been that half the people with Alzheimer's actually don't have APOE4, they have APOE3 or something else. And this gene might explain it. And this is why. 

Because among these APOE3 individuals, half of them have the short version of TOMM40 and the other half have the very long version of it. And when you look at the E3s, again this is the neutral category, the neutral risk for Alzheimer's, there's three scenarios. You can either be homozygous for this short polymorphism of the gene, and 25% are short-short. You can be heterozygous, short-very long, and about 50% are. And the other 25% are homozygous for the very long polymorphism of this gene. And so the finding that we presented a few weeks ago was what about this bimodal distribution in this TOMM40 gene where some of these APOE3 individuals are low risk and some are high risk. And the natural hypothesis is that maybe there's a group of E3s that actually have greater risk. And so we did a study to look at that, and we found that this group of people who were at low risk were doing better on tests of memory, and again these were people in their 50s. And we also found that their gray matter in this important structure, this posterior cingulate region of the brain, was actually, it had better brain volume in the people with the low risk version of this new TOMM40 gene. This is really helpful information. 

This has to be replicated, it's not really clinically useful yet, but if this holds up, this says to us that this group of Alzheimer patients who APOE really didn't predict would get the disease, we now might have some genetic marker that would predict whether they're going to get the disease or not. And we've also shown that the people with this very long-very long type of the TOMM40 gene have a greater decline in brain volume with age. And this is important because Alzheimer's disease is an age related disease. So this was very exciting. It generated a lot of interest at the Alzheimer's disease international conference held in Hawaii a few weeks ago. And we were delighted to present that. But again this is brand new and it's going to require replications. This has no clinical value at this point, but it's very promising. That region that we found our effect in, I've already told you about this, that that region is very important for recalling memory, it's important for metacognition and regulating your behavior, and importantly it's part of the neuropathology of the disease. It's hypometabolic in people with Alzheimer's and in people at risk. 

And it's also an area that receives a great deal of amyloid burden. And amyloid is the major, one of these major pathological features of Alzheimer's disease. So it's a plausible result and we're excited about it. Well, let me just make some concluding comments here, and then open it up for more questions from you. APOE was thought to be the major risk factor, the major genetic risk factor, it may not be. And in fact there's probably a group of people who we used to consider neutral risk, who may not be, who may be at actually higher risk for the disease. And so this might be a useful way to inform prevention trials and clinical trials for Alzheimer's disease. In our lab, we have NIH funding and VA funding to do longitudinal studies, and we're continuing to image individuals in the WRAP population as well as other people who have Alzheimer's disease or mild cognitive impairment. We're trying to determine what the presymptomatic rate of change is in the brain. And so we're evaluating people longitudinally with the cerebral MRI and PET scans. 

We want to predict who will get AD using some technology that was partially developed at UW. One is called arterial spin labeling. It's a way to look at brain function without using a radioactive PET scan. We're also looking at amyloid scans. This is a PET scan but it's our only way of looking at amyloid in the brain in a living individual. And we're also looking at white matter and gray matter structural atrophy. And this is an exciting type of scan. This is an amyloid scan, and we're one of maybe a couple of dozen centers around the country that can do this. This is a case with AD, if you look at the MRIs, a case with AD and a MCI case. And there's really not an awful lot on the MRI that distinguishes these two patients, but if you look at their PET scan, their amyloid scan, the AD patient has a lot of amyloid, this red area, in the posterior cingulate and related cortex. 

This MCI patient has a little bit of amyloid but not much yet. And here's a control subject who doesn't have any amyloid in their brain, at least not yet. This is actually me. (laughter) So hopefully that will stay there for a while. So just to conclude our talk for tonight, you should appreciate by now that family history might be explaining something unique that the major genetic risk factor APOE doesn't explain. And now we think we might have something that helps us understand another genetic feature of Alzheimer's disease in this TOMM40 effect. Our studies are mainly group studies at this point. The WRAP sample that we're studying is still too young. We don't have any end points. We don't have people who have developed Alzheimer's disease. 

There's a few but most are still very much cognitively normal. And we will continue to follow this group of individuals, and some of them will convert to MCI and AD over the course of the study, and as we look at the data and the evolution of their symptoms, our hope is that using our imaging technology and measurement protocol that we'll be able to predict, or at least postdict, who developed the disease and then apply those algorithms to new individuals. And that's important. That's really where we are in the field. We need to develop these predictors because drugs just are not working when the patient, when the brain has already exhibited a state of failure. When it's already in a neurodegenerative state sufficient to cause dementia. That's really too far to help in a way that's going to cure the disease. We can help alleviate symptoms, but by then the brain has undergone extensive change. So our goal is really to study these people who have risk, to define the predisease course, and then design treatment trials to determine whether new drugs that come along will work in this kind of population. I want to acknowledge all the people that have helped with these studies. 

This is something that can't be done in any one small lab. This requires the effort from radiology and medical physicists and statisticians and cognitive psychologists and computer scientists and a great many people to do the work. And so I'd like to acknowledge all of our collaborators and the people in the lab who really do this work. And also our funding sources, the National Institute of Aging, the VA, and also the State of Wisconsin. And here's some contact information for me. And I want to thank you for attending tonight, and I'll answer any questions you have. (applause)