 I'd like to begin our conversation today on November 25th, 1901, when a 50-year-old woman, August Dieter, presented herself to Frankfurt Hospital, brought thereby her family because of complaints of progressive confusion, paranoia, agitation, memory loss, so she could no longer identify familiar objects, most distressingly she couldn't identify her husband and loved ones, and in the medical record is a quote translated into English here which I think captures most planally her own feelings and what people afflicted by Alzheimer's go through. I have lost myself. Today we recognize that Alzheimer's is a global pattern with approximately 50 million people currently affected in all parts of the world, affects all continents, it will affect all continents to a greater degree as time progresses and we'll look at some of the details there. This translates into a new case of Alzheimer's disease every three seconds. Now because Alzheimer's disease occurs predominantly in older men and women, the demographics, the age distribution of the world's population is important to note. And so I'll show you in the slide here some of the remarkable things that have been happening to the world's population over past years. Now I grant we all recognize there's been aging but I think this illustrates in a very compelling way what has been happening. So what you see illustrated here first is in the 1950s and 1960s the percentage of the global population that is under 5, at around 15%, or is older adults over 65 and the range of 4 or 5%. And let's see what happens between 1960s not so long ago and the present day. A quite dramatic convergence, a decrease in the proportion of young kids, an increase in the proportion of older adults. So somewhere very close to where we sit here today in Davos or it's here before long, undoubtedly for the first time in human history we will see a time when there will be as many older adults defined by age 65 as younger. And if we ask any of us to project what we imagine is going to happen in the years to come, demographers do this based on what we currently know and we'll see an essentially complete reversal over the period of a century or so of this distribution of age pattern. Now quite beyond the implications for Alzheimer's disease, the societal implications of what this means in a world so changed are enormous for us all to contemplate. But in terms of the relationship to Alzheimer's, as noted, it's a disease of older people. This is one of the surveys that looked at the risk of having Alzheimer's disease, in this case in the East Boston population, but typical of what's seen around the world as a function of age. So the first age group, the younger older adults, if you will, 65 to 74, about 5% of people affected. The next decade, 75 to 84, around 20%. And over 85, about 50% nearly half affected. Now this means if we look around the room and consider those of us who aspire someday to reach 85, that one out of two will have Alzheimer's disease unless we do something to change that dynamic. This will translate, given the aging of the world's population, into a nearly doubling of the number of people who are affected every 20 years. With an enormous cost, therefore, in terms of human suffering, there is also a financial implication. If we look at the cost of caring for those with dementia, currently estimated at around 818 million, soon to increase to 1 billion. And then by 2030, some 2 billion dollars. Well, these numbers are, in fact, rather hard to capture as they translate into human reality. So let me just ask, those of you in the room here with us this week in Davos, how many have had the experience of a loved one, a family member, someone you care about who's had Alzheimer's or Alzheimer's like dementia? Well, I guess my scientific point of view may have a selected audience here. But I think nonetheless, this does reflect the fact that nearly all of this, and my hand should be up there too, have had this experience. And how many of you have further than that had the experience of helping to care for someone with Alzheimer's disease? Again, nearly all. So with this in mind, let's turn a little bit to what Alzheimer's disease is. And most importantly, the way in which recent progress and research has taken to us to a point of essentially unprecedented optimism about ways in which research can translate into opportunities to do something about this disease. So this is a cartoon, a character, a juror of the normal brain, intended to show neurons, nerve cells with elaborate connections with one another. Many would argue that this is the most complex machine or organism that exists in the world as we know it. So when Professor Alzheimer followed the first woman, Auguste, who presented in 1901 until her death in 1906, he was able to, at autopsy, look at her brain. And for the first time, identify lesions that, since that time, have been cardinal symptoms, marks of the Alzheimer's change. The first was here. So as you see, in between the neurons, outside the cells between and among them, are what he first saw in slides as plaques. In which we now know to be composed of amyloid peptides that are formed normally in the brain, but in an abnormal brain or at a normal pace leads to deposition, which appears to have some of the direct impacts on the health and connections between nerve cells that is part of the progressive process of Alzheimer's and related dementia. And he saw a second lesion, too, which he called tangles, because they look like tangles within the neurons themselves. We now know these to be composed of abnormal protein tau, which in its normal state is responsible for trafficking of molecules within the neurons in their processes that's critical to health. So plaques and tangles, the starting point of what Alzheimer's saw, and which since that time, have been hallmarks of the diagnosis. The brain grossly, meaning by gross appearance, has an abnormal appearance as well. The healthy brain, as you can see, is rich and full in terms of the gray and white matter, the cells and processes of the brain. With a relatively little in the way of space between them, but the Alzheimer's disease brain looks different, reflecting the shrinkage, the loss of cells, loss of connections, and so the greater spaces between the areas of the brain. So from that point, we'd like to talk next about progress in areas which, again, are converging to give us a new understanding and with an understanding a new way to approach Alzheimer's disease. So the first thread of research I'd like to talk about is that which is the identification of risk factors, specifically risk genes. And the importance of that is manifold, but one aspect of it is that it potentially allows us to identify people at a high risk of Alzheimer's by virtue of their genotype. And this, as you'll see, is important to strategies for learning how to test, most effectively, agents to intervene, prevent, or slow the progress of disease. And the second track we'll follow is identification of biomarkers. Now biomarkers simply refers to any biologic process that can be identified, measures, and that reflects the ongoing process of disease, in this case Alzheimer's. It may be in the form of neuroimages, which we'll focus on here, and it may be a matter of tests that come from blood or spinal fluid. The convergence of these, as we'll come back to, in theory, would allow, if we are successful, the ability to identify people who have high probability of developing dementia. And in those individuals using biomarkers to identify disease processes, ideally not when they have symptoms, but even years or decades before. And then to track with these biomarkers the progression of disease and to use biomarkers to measure the effectiveness of treatments when we try them experimentally to see if we can make a difference in altering the progression of that disease. So first, from 1906, the time of diagnosis until the first genetic discoveries in the 1990s, emphasize here three genes that were found and they're unique genes, and we'll come back to them again. So I'll describe a little about them and suggest you remember them. They're APP, which is actually the gene encoding those peptides that form the plaques that Alzheimer saw. And PS1, PS2, genes which encode two other enzymes which collaborate to cleave the protein that in turn forms those plaques. So all three of these genes functionally important because they are involved in the plaques we've seen. But they're also unique in that these are really disease causing genes. Mutations in any one of these genes in very rare families around the world cause with 100% certainty the development of Alzheimer's disease at a tragically early age in the 50s and 40s, even 30s. It's an inherited disease. So if a parent has a disease, there's a 50% chance a child will have the disease and again with 100% certainty within years, typically 40s and 50s, develop that disease. And again, you can imagine the emotional toll and the level of motivation of people with this disease of familial Alzheimer's. And again, we'll come back to this. But since the time, there's been a discovery of a large number of genes which don't cause Alzheimer's in that 100% certainty, simply inherited way. But which are risk factor genes, alterations in which either increase or decrease the probability of having Alzheimer's. I'll point out that with us today, among others is Francis Collins, the director of NIH, who also led the Human Genome Project, which allowed this kind of discovery. And in addition to just having these genes individually described, you'll see the color coding here, which identifies genes that fall into specific pathways. For example, this set, all of which are in pathways involved in inflammation and the immune response. And suggesting that this is one of the pathways that may contribute to Alzheimer's disease and again, allow us to target some of these in studies which is just now evolving. So now let's turn to the issue of biomarkers and how they are generated. And I'd like to begin by talking about one initiative in specific, the Alzheimer's Disease Neuroimaging Initiative. It's arguably iconic in the kind of public, private and global partnership it represents, I think especially relevant to all of this meeting here in Davos. In 2004, NIH together with the FDA in the United States, a variety of pharmaceutical companies, biotechnology companies, imaging companies, advocates all came together with the realization that if we could identify markers that would relate to early stage disease, this would increase our ability and probability identifying interventions. And so together, established this initiative, which you can see has grown globally, so we now have across many nations of the world the ability to look at people by common standards and to pool efforts of discovery. Among the advanced, this has allowed, comes back to what we've already taken a look at, plaques and tangles, which until recently were identified after death by staining of slides, as we've done in 1906. But now through techniques of imaging, dyes, molecules have been identified, which can be injected into an individual. We'll travel throughout the circulation and selectively bind to amyloid. So if we now use imaging techniques to show what that brain looks like in terms of distribution of amyloid, here pseudo colors, red the most intense, typify the brain of somebody with Alzheimer's disease. Similarly for tangles made up of tau, even newer imaging techniques allow us to see what previously was identifiable only after death and looking at the brain. Now, finally, the way in which these converge to allow us to do approaches for therapy and prevention that again were absolutely unimaginable just a few years ago, let me point to yet another important initiative. This is Diane, the dominantly inherited Alzheimer's network. This is a network of those families I described to you, rare families around the world in whom inheritance of a single gene causes disease at tragically early ages. The disease is so rare, in fact, it's difficult to do research in those individuals, until an effort such as this involving once more the collaboration of many brought together people from around the world in these families committed to working with researchers in these studies. And I'll just say as an aside, one of the most emotionally effective, compelling experiences that I have had is at meetings in the past years of the Alzheimer's Association annual convention in which families from around the world were brought together to meet one another and to meet with the investigators who were engaged in research with them as partners. And you can imagine people who have lived their lives with a tragedy of their family now meeting others in the same circumstance and imagine further and even more specifically what it's like to see a 30, 35-year-old man, woman who saw his or her parents at ages in 40s and 50s develop disease, maybe had an older brother or sister who may have young kids and have to decide whether or not he or she wants to know whether that gene is there, whether it's been passed on or inherited, but above all want to be there as partners with all of us and trying to do research to do something about it. So these are families with mutations and genes that are responsible for formation of amyloid. And so if there is a case in which direct causality of amyloid to disease is likely to be the case, it is in these families. Because we know in these families, years before they're on set of disease, when they're likely to get it, the given family, it's highly predictable at age 40 or 45 that symptoms will develop. We can actually, through study of many of these individuals, look at variables like the image I'm going to show you and plot what they look like 30 years before any symptoms, 20 years before any symptoms, 10 years before up to the time they develop symptoms and beyond. So watch the track which begins here at brain minus 25, means 25 years before symptoms. This looks pretty much like a normal. So the sibling who has inherited the disease looks like his or her brother or sister who did not have the gene. But watch over time, now 20 years before one can already see changes. By 10 years before, extensive changes. So up the time, this clock will stop at essentially zero, the time when symptoms first appear. The earliest time when previously we were able to begin to think about trying to treat and slow the disease in these people. The deposit of amyloid is extensive and in fact if we look through the rest of their course after symptoms and diagnosis, there's really relatively little change. So if we take that image and plot it on a graph, it looks like this. So this is the accumulation of increasing amounts of amyloid in years related to diagnosis. And you can see by the zero time when symptoms appear, that amyloid is extensive, in fact it's essentially maximal. So if we are trying to intervene in people with symptoms to stop the accumulation of amyloid, it's likely we may have been looking too late. And amyloid isn't the only thing we can look at. And this is a reflection of how complex disease and how much we've learned. Let me show you just some other markers in parallel. Here are several other markers. One of them is the accumulation of tau by imaging, which I showed you. And there are others here which represent tests in cerebral spinal fluid, for example. And some things change and go down as an adverse event with Alzheimer's. For example, there's a decrease in the volume of the hippocampus, an area of the brain that's critical to the formation of memories. So until a few years ago, we began our treatments here in the range when people had symptoms. And we have to and will continue to try to look for ways to intervene in people who were affected by the disease to change the course of that disease. But now in addition, we can look here years before the onset of symptoms and attempt interventions at a point when cell death may not have occurred, when the connections between cells may not have been so disrupted. We can intervene in the processes reflected by these biomarkers and do something about changing the course of disease. So we are now in the midst of several studies of this kind. This is one that Diane, group that I met, are the participants in the study together on investigators taking people a decade and more before onset of expected symptoms and treating them. In this case, the first treatment are those targeted at amyloid. And especially in these cases where the mutations or the formation of amyloid pathway makes some sense. But we don't know in the end what's going to be the right intervention for any one individual. We don't know what combination of interventions may be effective. So we're addressing a number of approaches. Active is the acronym for a clinical trial initiated some years ago by cognitive training to make people better in performance of certain cognitive tasks like memory, speed of processing. And it was actually a remarkably effective study. The ability of can cognitively normal men and women over age 60 and 65 was improved and five and ten years later that improvement has persisted. What we don't know is whether that will actually translate into protection against dementia. But those studies are being followed, more like them are being developed. We know that high blood pressure in middle age is a risk factor for Alzheimer's disease. We know it's a good thing to control blood pressure for many reasons by direct clinical trial. You can present deaths and you prevent cardiovascular events such as stroke and heart attack. But we are looking for direct evidence to tell us whether controlling blood pressure will actually have a similar effect in decreasing the rate of dementia or cognitive decline. And those studies are in process sprint. Some of you may have heard about was a remarkably successful study which decreased deaths from cardiovascular and all cause. The people who were involved in that study are now being followed for cognitive consequences. And we know that cardiovascular fitness and the history of physical exercise and activity is also highly protective. But that's a correlation. And what remains to be shown is whether we can devise interventions in the form of physical activity which will have such an effect. And so we're beginning here too. So let me close by taking you back to August D. The woman who came to attention to Professor Alzheimer in 1901. She was 51 years old. Remarkably early. I'll come back to what that means. What would happen if 51 year old August D appeared today for medical attention? Well, she probably would appear earlier because recognizing the symptoms we would have seen her earlier. She probably would have had scans and we almost undoubtedly would have seen the identification of plaques and tangles and their correlates and scans. We could have followed those over time. We would have done genetic testing. And remarkably, more than 100 years after her death, the slides that were examined by Professor Alzheimer identified. DNA testing was done on those slides. And we now know she has a mutation, had a mutation in PS2. So she's before us now. We've done her clinical testing. We identify that she is before us with a known familial mutation. She would be a candidate for participation in our clinical trial. Her family would be so informed. But tragically, as we stand here now, we would not yet have an effective intervention for her or for others. And what I hope we can gain from what we've gone to discuss and discussion to follow is a sense of how far we've come in understanding the disease. Why our ability now to identify disease early and track it gives us unprecedented opportunities to intervene. And why the level of hope and optimism among researchers, those affected, those who may one day be affected, ought to be higher than it's ever been before. In the end, it's all about people, as shown on the slide, to all of us. So whether it's those, essentially all of us who have family members affected, all of us who care for a personal reason, researchers, clinicians, those responsible for public policy, for financial organizations that employ and are very much committed to the care and protection of people at risk for Alzheimer's. All of us have to work together to commit to the continued research, the care and support of those people currently affected. And let me leave you with that and the challenge for all of us to work together to make these projections turn into something as positive as we all hope it's going to be, namely a real effect in intervening to change the course of dementia Alzheimer's disease. Thank you. Thank you. Thank you.