 I'd like to welcome everybody to the medical school. I guess our AV person can turn the volume up, the microphone's on. So let me know if you can't hear me, I'll project my voice as well as possible. So welcome to Stanford, you're in the School of Medicine. This is where we give lectures to our medical students when they come to lecture. And so this is your beautiful new building here. So my name is Frank Longo. I chair the Department of Neurology here at Stanford in the medical school. I did my training up at UCSF, and then I was recruited to the faculty at UCSF. And I ended up becoming vice chair of the department there. And then six years ago, Phil Pizzo recruited me to be chair at Stanford. I've been at Stanford six years, and it's been a fantastic experience. Today we'll talk about the epidemic of Alzheimer's. We'll talk about better ways of diagnosing it, detecting it, predicting it, therapeutic options, etc. So this is a big problem for us. Of all the people in this room, one out of eight of us will develop Alzheimer's. Many of us will hopefully live into our 80s, as our colleagues in cardiovascular medicine and in cancer do such a great job. It's not uncommon for people to make it into their 80s being fairly fit. And by the time one is about 85, you've got about a 50% chance of having Alzheimer's today. So think about yourself. Think about the person sitting next to you. One of the two of you will have Alzheimer's by your mid-80s. If we don't come up with any prevention or therapeutics. Give it a little closer. Try that. Okay, so that's a big challenge. But there's a reason to be optimistic. This is a tractable, solvable problem. And it's a perfect problem for Stanford. As our president, Hennessy, does such a good job reminding us, Stanford being one of the top, or the top university in the world, is perfectly suited to tackle head on a problem like this. And I'll show you in the next few minutes how we're doing that. So I like to think about the problem of Alzheimer's, how it directly might be relevant to us. We can think about it on a larger scale. We're up to about 5.5 million people in the United States currently having Alzheimer's disease. And we're at the beginning of these curves that we'll take off. But we don't all only think about the individuals that have Alzheimer's. And I know there are a few of you here today in early stages of Alzheimer's and your families and people that we see in our clinic here at Stanford. We think about the families and the caregivers. So if we think about them, we're talking about 15 million Americans. And then if we took all of the caregivers together, that they would make up the fifth largest state in the United States. It's greater than the population state of Illinois. We think worldwide we're passing 30 million with Alzheimer's. China is about to launch into a huge boom in Alzheimer's disease. So it's a worldwide problem too. It's a solvable problem. Stanford is a great place to think about that. So what is Alzheimer's disease? What is Alzheimer's dementia? People ask me, what's the difference between Alzheimer's and dementia? So we'll define a few terms. A dementia is cognitive loss in two or more areas of cognition. Significant enough to affect in a significant way day to day function in the absence of another obvious cause. For example, the different domains that might be affected in cognition would be memory, typically what we deal with is an initial symptom. But it could be visual spatial skills, the ability to find your car after you park it, find your way home. Could be language, inability to come up with the right word at the right time. Could be judgment, so those are some of the different areas. So if you have or having difficulty in two or more areas, significant enough to cause a significant loss of day to day function, you have a dementia. Now there are several different dozen causes of dementia. It's the neurologist or the geriatrician's job to figure out what kind of dementia you have. Alzheimer's is by far and away the most common dementia, accounting for about two thirds of dementia, especially in the older age group. It's a challenge to make that diagnosis of Alzheimer's and we'll discuss some of the technologies that we're working on for that. So what happens in the brain in Alzheimer's disease? Let's take a look at that. On the left side here, we have a normal appearing brain, and on the right side is a brain that's undergone atrophy or shrinkage, which occurs in Alzheimer's disease. Now we get a little bit of shrinkage with our brain as we age. By the way, our peak cognitive performance is at age 25 or so, and then as we age we lose a little bit over time. Now certain areas of cognition get better with age. So don't worry, judgment actually gets better with age. Verbal skills actually get better with age. So what happens in the Alzheimer's brain, we get the shrinkage and if we look under the microscope at a piece of brain up there, we have two things happening. If we take this little piece of brain, we get the accumulation of amyloid plaques, brown splotches here. Amyloid is a fragment of a protein that accumulates in the brain. It probably has a normal role, but for some reason, an Alzheimer's accumulates to excessive levels and it's toxic to neurons. And no one quite knows why it's accumulating in Alzheimer's disease. The amyloid plaques, and then inside the neuron there's another protein called tau, and it accumulates in clumps called neurofibrillary tangles. And the pathologists would see these clumps of tau inside the neuron. Those are the two hallmarks inside the brain that a neuropathologist would see and looking at a brain in Alzheimer's. We can delve even deeper than that to think about what's happening in the brain during Alzheimer's by looking at the individual neuron. So the neuron has a cell body here and it has this beautiful dendritic tree where incoming synapses are arriving. A message comes through here, through the axon, down to the synapse, which is a connection from one neuron to the next. So we have messages coming in through the dendrites, down through the axon, through the synapse, and into the next neuron, the basis of our circuits. The synapse is a key structure here and the heart and soul of that synapse is the spine, this structure right here. Spines are very delicate. So here is a dendrite and here are the spines coming off that dendrite. Those are normal appearing spines. They're very dynamic. They're changing over hours. If you learn something over the next 30 minutes, you will have stabilized some of these connections. What happens is we age, and especially with Alzheimer's disease, we lose these spines. And once we lose those spines, we lose the basis of the synaptic connection. And when we lose that synaptic connection, we start to lose our memories. Interestingly, it may be the access to our memories that we are losing. Those memories might still be there. We could restore those spines. Maybe we could restore access to those memories. When does all this start? So we can think about a timeline on the bottom here of normal cognition, subjective cognitive impairment, so-called SCI, mild cognitive impairment, and finally dementia, and degrees of things happening in the brain. And one of the most exciting insights that the field has come across lately is that this process of Alzheimer's disease is starting 10, 15, 20 years before the first signs of memory loss. This is a huge new insight, and it gives us windows into therapeutics in terms of preventing the disease altogether. When I was in medical school, we thought Alzheimer started at that very first time the patient was experiencing some memory loss. It's been well-established decades before that, but that gives us a window for prevention. So basically, what's happening during our normal cognition parts of our lives, this may be starting in our 50s, in some cases even earlier, the amyloid is starting to build up in the brain. We call that the amyloidosis period. Persons perfectly fine as far as they're concerned. Then, as that amyloid builds up, it starts to have a toxic effect and we get to the degeneration phase here and we get neuronal injury starting to appear. The person still thinks they're relatively fine. And then finally, we get enough injury to those synapses and the individual has subjective cognitive impairment. They're thinking, you know, my memory's not quite what it used to be. I don't know if this is normal aging or if there's something a little extra going on here. It's one of the most common reasons why people come to our clinic at Stanford and we have a way we deal with that. We call that subjective cognitive impairment. Now not everybody with subjective cognitive impairment will go on to develop Alzheimer's, but a big portion will. And then finally, they get to the point of when there's enough cognitive loss, mild cognitive impairment. How do we define that? Mild cognitive impairment is a condition in which there is a loss of cognition in one area of function within the brain, often just memory, but it's not severe enough to cause a big loss of day-to-day function. So that's the difference between a mild cognitive impairment and a dementia. But people with mild cognitive impairment are often still working and going about their day-to-day life, but they're starting to notice a little bit of challenge with that. Now if you get a diagnosis of mild cognitive impairment, you have roughly just under a 50% chance of progressing to Alzheimer's over a five-year period. And of course, we'd like to develop therapeutics to prevent that progression. In fact, we'd like to reverse you back to normal. So genetics is a big part of influencing who gets Alzheimer's, but environmental factors are important too. Let's review some of the genetics. So Alzheimer's disease is either sporadic or familial. Most of what we deal with, more than 95% is sporadic. And that's typically an onset greater than 65 years old. And there are no family members that have had onset earlier than that. Familiar Alzheimer's disease, under 5% of what we deal with, there's a history of onset in the 40s and 50s by two or more family members. Typically the patient we're seeing has a history of onset in their 40 or 50s. We call that familial. Generally in those cases, there's a gene that runs in that family that if a person inherits that gene, they will get Alzheimer's. And so if one of their parents has it, they're at 50% risk of getting Alzheimer's. But for sporadic Alzheimer's, there are probably multiple genes involved. In sporadic Alzheimer's, the ApoE gene is probably the most dominant gene in conferring risk. The ApoE gene comes in three different forms, E2, E3, and E4. And they should have just called it one, two, three. Nobody knows why they skipped one just to make it complicated, but we call them two, three, four. And the E4 is the high risk gene for Alzheimer's. Now you can get your ApoE gene tested by commercial companies, 23andMe or Navigenics. So you can go out for a few hundred dollars and find out now, you don't have to go to your physician whether you have two, three, or four ApoE genes. We have two copies of each of our genes. So you can think about your risk. If you have no family history, your life without knowing your ApoE status, your lifetime risk is about 15% with no family history. If you don't have the E4 version of ApoE, you're about a 9% risk. Your risk comes down a little bit. But if you have the E4, your risk goes up from 15 up to 30% lifetime risk for Alzheimer's. But if you have one parent with Alzheimer's, which is a common situation, if you're a 3, 3, i.e. no E4, about a 30% risk. If you have one copy of the E4 gene, 45% risk. And if you have two copies of the E4 gene, just 60% risk of Alzheimer's. So one study showed that when people got this DNA testing and they received a result of having E4, they were six times more likely to buy long-term disability insurance, which makes sense. So we don't have time today to have a full discussion on genetic testing. The different lecture that I do, I started the neurogenetics clinic up at UCSF. You have to think carefully about doing this kind of DNA testing. Do you wanna know this? Do you want this in your medical record? Do you want your friends and family to know this? I would not do this without having a serious discussion with somebody who's had a lot of experience in DNA testing. We can talk about at the end who would like to get tested or not. Some people say, I want a treatment available before I get tested. So how do we detect Alzheimer's disease? So the most important part right now in a clinic is getting a thorough history, family history, history of the patient, a careful neurologic exam, looking for causes of dementia. And then we do some testing. And one of the tests we get is an MRI scan. And people think we get MRI scans so we can see the disease going on in the brain. This is a conventional MRI scan that one would get today. Does this patient have Alzheimer's or not? This MRI scan tells us absolutely nothing about whether this patient has Alzheimer's disease or not. It tells us they don't have a brain tumor. That's not the problem for their memory. It tells us that they haven't had a series of strokes that we didn't know about. That's not the cause of their memory loss. But other than that, it's not telling us much. But this is the state of art for imaging right now. At Stanford, we're well suited to advance this. We're working on brain imaging of the future, which I'll share with you. Now there are other scans available. One's called a PET scan. This scan has been around for about 20 years. And this scan is designed to look at metabolic function of the brain. We have a normal patient on the left here and the brighter colors are higher metabolic rates of the brain, normal brain. And on the right, we have an individual with Alzheimer's disease. And we can see toward the back part of the brain here, there's a little bit of decrease in the bright colors. It'll decrease metabolism. But it's not a precise and accurate way of diagnosing Alzheimer's. So generally we don't order PET scans because it's just not accurate enough. You can have a normal PET scan, still have Alzheimer's. You can have an abnormal PET scan and not have Alzheimer's. It just doesn't give us the accuracy that we need. But it's an attempt to get better brain imaging. A second kind of PET scan has been developed that can detect the amyloid accumulating in the brain. And this has been in the news quite a bit lately. This is called an amyloid PET scan. And there are a number of companies developing this. And on the left, we have a normal patient. The cooler colors are less amyloid levels in the brain. And on the right, we have an Alzheimer's patient. The brighter colors are higher levels of amyloid. So this scan was just approved by the FDA a few weeks ago. It'll probably be available this summer. Like most new expensive technologies, Medicare probably won't pay for it, at least initially. It'll cost a few thousand dollars. We'll have it available here at Stanford. But who should get this scan? Should anybody get this scan? The statistics here provide a lot to think about. It's estimated that in individuals who do have Alzheimer's disease, 96% of them will show amyloid in this PET scan. So that makes some sense. Of those individuals with mild cognitive impairment, they're the ones at risk for going on to get Alzheimer's disease. About two thirds of them will have amyloid on their PET scan. And we think that the ones that have amyloid are more likely to go on to develop Alzheimer's. The ones that are amyloid negative will be a little less likely to go on to develop Alzheimer's. And then finally, here's the tricky part. If we take normal people in this age range of say 65 and higher, one third will show amyloid in the brain. What do we do with that? Right now, we don't have a drug for sure that can clear amyloid out of there. Do you wanna know that about yourself? Would you do anything differently? Would you want this in your medical record? So we have to think about this before we order scans like this on individuals. How will you handle that information? So given that scanning capability, we can go back and think about this. And we remember I talked about that time of normal cognition where the amyloid's building up. Now, we have a technology that can detect that amyloid buildup 10, 15 years before people start losing their memory. Think about how to apply that. But it allows us to start to apply treatments that potentially delay onset of Alzheimer's well before the symptoms start. What are some better ways of looking at the brain? And in terms of the amyloid scan, the limitations are that it doesn't change much over time. So as we develop therapies, it may not give us a good sense of whether our therapies are successful or not. And it doesn't tell us anything about the person's cognition. Remember, a third of normal people will have amyloid, positive amyloid scans. We need better ways of actually looking at brain function, at brain networks. And one of our teams at Stanford is developing a scan of the future that I think will be much better than the PET scan, much better than the amyloid PET scan. And this is called Resting State Functional MRI Scanning. And Mike Gratius and his team here found a way to image the brain to look at networks that are functioning while people are thinking about different things or if they're just at rest and not thinking. This particular network in orange lights up in the brain when you're laying on the MRI table and we ask you to think about nothing. This network lights up. And it ends up being a very important network of subserving memory function. What they noticed in patients in early Alzheimer's disease were losing that network. And so this is the first time we've been able to look inside a living human brain and seeing the loss of cognitive network in a living person. This is much probably more powerful than looking at amyloid buildup. And you can look at these networks in 3D and it's not accurate enough to bring to the clinic yet, but this gives you an idea of the future of how we will be assessing patients that come to our clinic saying, you know, I forgot where I parked my car too many times, what's going on, we'll wanna see these networks. And then what Mike and his team showed that over time in a normal person, these networks don't decay. We have these bright colors persisting over a two-year period, but when they took patients and early Alzheimer's and followed them for two years, look at those networks that are decaying over time. So as we develop therapies, we have something to look at to see if our therapies are effective. Are they blocking out that loss of network function? Another team here at Stanford, taking advantage of the physics environment is developing high strength, high field imaging. There's a conventional MRI scan is done at 1.5T Tesla, that's the size of the magnet. 3T is getting into big, huge magnets and high resolution brain imaging. Still blurry though, this arrow's pointing at the hippocampus, part of the brain vulnerable and Alzheimer's and important for memory. At 7T, which is a tour de force of physics technology, which is well suited for our campus here, they can see the hippocampus at the resolution well enough to detect the degeneration of individual cell layers and correlate that to cognitive loss. So when that person comes to our clinic, it's not ready for the clinic yet, but comes to our clinic having lost their keys one too many times, we can look exactly at that layer of neurons in the hippocampus that are most vulnerable that are necessary for remembering where those keys are and know what's going on inside that patient. And then there are other technologies that we're developing for predicting or diagnosing Alzheimer's. Right now we can do a spinal tap. We have amyloid accumulating in the brain and interestingly as amyloid accumulates, the amyloid levels in the cerebral spinal fluid go down and the levels of the tau protein go up. It's not accurate enough to be 100% accurate diagnostic Alzheimer's test yet, but Tony Weiskore in our department is using a technique called proteomics where one could look at dozens or hundreds of proteins at the same time. So right across the top are different patients. The patients in orange are Alzheimer's, blue are normal, and then they're looking at roughly 20 different proteins here up and down there. The brighter the color, the higher the protein. And so by looking at patterns of proteins, they're up to about a 90% accuracy in predicting who will get Alzheimer's. 90% is not high enough for us. We want 99.9. And you can see the pattern in the Alzheimer's patients, the red colors are toward the top and the normal patients, the red colors are below the bottom, but there are exceptions. We can see that red Alzheimer's patient under the arrow on the right there, they didn't have the same pattern as the other Alzheimer's patients on the left. So it brings us to the area of personalized medicine. Maybe the treatment for that patient would be different than the majority of other Alzheimer's patients. And it will be customizing our treatments for this disease at some point using proteomics and bioinformatics that this demonstrates. So what can we do about therapies? Here are the conventional therapies. There are two groups of FDA approved drugs for Alzheimer's. One are called the Colnesterase inhibitors. There are three drugs, they all work pretty much the same, same similar efficacy. There's a second group that has one drug called Mementine's generic name, Namenda's the brand name. Unfortunately, these medications probably don't slow underlying degeneration or progression. We put our patients on these, they boost the neurotransmitters at the synapse and help memory and other cognitive function a little bit in some cases by boosting those neurotransmitters, but they're not slowing degeneration. Our goal is to create therapies that slow degeneration. So what's coming next in treating Alzheimer's? Well, one approach and the dominant one right now is just to lower these amyloid levels. So on the left is a brain from an Alzheimer patient. The brown spots are the amyloid plaques building up. So there are several trials going on now where the patients are given antibodies or they're being immunized so that the antibodies attack that amyloid in the brain and clear it out of the brain. And to the right is a patient that was treated with one of these antibodies. They eventually died. They looked inside the brain and they saw this sort of mothy appearance of these plaques suggesting they're being reduced. We don't know yet if this will be effective. The results probably should be coming out sometime later in 2012. If they're successful in slowing the disease progression it'll be big news. I think at best the success will be to slow disease progression a little bit. That'll be a win. That'll be a first step, but we have a long way to go. We need to stop and reverse the disease or prevent it from happening altogether. So what are some clues of coming up with better therapies and what are some things we're doing at Stanford to really create that next generation of therapeutics? I'll talk about three areas, exercise, diet and brain exercises. And one of these is by far the most powerful. Any guesses? So mixed opinion on that. Exercise. Exercise currently is the most powerful, biologically powerful drug that we have. Very powerful drug and I'll show you that. But before I get to exercise, I'd like to just mention diet is still important. There's a nice piece of salmon. Epidemiology shows people eat fish two or three times a week to lower their risk of getting Alzheimer's. I won't talk much about the brain exercises. You can buy this software and do brain exercises. My guess is probably the least effective of three. There's mixed data on that, not great data in that area. So what about the fish and diet? Some people think, well, take fish oil. It's the thought that's the omega-3 fatty acids that are important in the fish oil. There've been a couple of studies in that area. We don't have final data, but one study looked at people greater than 55 years old that had a little bit of age-associated memory impairment. So they don't have Alzheimer's or real mild cognitive impairment. Very mild stage. They took DHA, one of the main two omega-3 fatty acids, 900 milligrams a day for 24 weeks, and they found some improvement in visual spatial learning. So I don't take these too seriously unless the second study confirms this, but we have this one study so far. It gives us an idea. Another group looked at omega-3 fatty acid supplements this time 1,000 milligrams per day, twice a day for 18 months, so a total of 2,000 milligrams per day. And they did see some improvement in cognitive function only in the people who didn't have the E4, the ApoE4 gene, the high-risk gene. So the study was reported as negative of not helping Alzheimer's because if they kept all the people in one big group, but after the study, if they separated out the E4 high-risk people, they did see some cognitive effect. But again, we'd like to see that replicated. But many people take fish oil at this point. We could talk about that later. And body mass index is important. If your body mass index is abnormally high, the age-related shrinkage of the brain is accelerated. And several studies have showed that now. The best way to shrink your brain or to accelerate the shrinkage of your brain is not be able to exercise. Now, the problem is not everyone can exercise. I don't want to be overly flippant about that. People have orthopedic issues, cardiac issues, but to the extent you can exercise, it reduces shrinkage. Even if mice get overweight, they develop more Alzheimer plaques in their brain than the Alzheimer mice that we use. So let's delve into exercise and point out how it's bringing us to new treatments. This is Audrey Larry who set five new world records at Stanford at the senior Olympics. She's 75 years old. But we don't have to do this level of exercise. So for example, here's an example of resistance training in mild cognitive impairment. This study just came out. So they took women in their 70s basically who are diagnosed as mild cognitive impairment. They're at risk for going on to Alzheimer's disease. It was a six month study. Patients got, subjects got randomized at two times per week of either resistance training with weights or just balance and tone, range of motion, balance, and that's it. And they both had trainers, same gym, everything else equal. The women that did the resistance training twice a week had improved, significantly improved executive function that's the ability to multitask and association memory. So that's a powerful drug right there. And that's not running marathons. It's two times a week doing resistance training. How about walking? This study was done a one year study. They had patients in a control group. It went to the gym, had the trainer, but didn't walk. The other group walked starting 10 minutes a day and then building up to 40 minutes a day, five or six days a week per year. And then they monitored the size of their hippocampus. The red line there shows the shrinkage that we have of our hippocampus with aging, it's one or 2% per year. And that doesn't sound like a lot, but it adds up. Over 10 years, think about losing your hippocampus like that. Look what happened to the people that walked. Not only did it prevent the shrinkage, they regained hippocampal volume. Now just think if we were in our clinic and we offered you a drug that would not only stop shrinkage with aging, it would reverse the loss of volume. And what if I told you, well, like all drugs, this drug has side effects? The side effects might be less high blood pressure, less diabetes, less depression. Watch out for those side effects of this treatment. So, but before you start exercise, you've got to check with your primary care physician. I don't want people to get in trouble with cardiac or orthopedic issues. Not everyone can exercise, but it just shows you the biologic power of exercise. So when we exercise, our body makes this protein called brain-derived neurotrophic factor or BDNF that decreases with age, it increases with exercise. That's the most powerful entity we know of, of preserving and saving spines or reversing spine loss. So our group here at Stanford was the first in the world to come up with a small molecule, a drug-like compound that does, that mimics the key part of that BDNF protein. The protein's too big to use as a therapeutic. It won't get into the blood brain, through the blood brain barrier. It's not stable enough in the blood. We can't use it as a therapy, but we can design a small molecule drug to be a therapy. We've succeeded in doing that. And when we apply it to our Alzheimer mice, this is what happens. On the left we have a normal mouse. We're looking at a neuron in the hippocampus with its beautiful dendritic tree. When you spend thousands of hours looking at these dendrites, that looks beautiful. That to me is beauty. And you can see those little dots along there. Those are the spines. When we look at them in our Alzheimer mice, look at the atrophy. Look at the loss of those dendrites, the loss of those spines. That mouse does have trouble with its memory. Look what happened when we gave our small molecule. It almost entirely rescued that loss. If that mouse had been a person in a nursing home unable to recognize its family because it's lost its synaptic connections, and you were to restore those dendrites and those synaptic connections, what would that person look like? We don't know. We won't know until we try them, people. They might get discharged from that nursing home. Now they've regained their function. And we test our mice from memory. And we let them do things they like to do. They love to explore a mouse with a normal memory. You put them in there in day one. They'll recognize those identical objects. And then the next day you come along, put a novel object in there. The mouse with the normal memory will spend almost all of its time at the novel object. They love novelty. They're bored with the object they saw yesterday. We put an Alzheimer mouse in that. Spends equal time with both objects as if it had never seen that first object before. So we can really quantitate the effect of our experimental drugs with the mice. But it's thousands of hours of testing just to test one drug and one set of mice. This would take two years to do. We'd like to accelerate that. And then one of my colleagues, Tony Weiscori, has found that when he took a plasma from old mice versus young mice, when he injected plasma from young mice into young mice, the ability to form new neurons was maintained in the young mice. But when he took plasma from old mice and put it in young mice, they lost, the young mice lost their ability to form new neurons. There was something in the blood of old mice that was inhibiting this key function of the brain. And he's managed to identify it. It's this protein called eotaxin. It builds up with age. Guess what? It goes down with exercise. And we're working on ways of blocking the effect of that eotaxin. So I wanna wrap up one of the key things that we need to do in these mouse studies is be able to look at the effects of our experimental drugs in the mice in ways that we can translate to humans. So Stanford's a great place to do this because of the computer science, physics, mathematics, community. We're real good at brain imaging. In the Clark Center, we have pet and CT scans designed for mice. There are four mice there about to get their pet scan. And we can see the effects of Alzheimer's in these mice and we can see the effects of these drugs. And by using the same kind of pet scan technology that can apply to human, we can very quickly determine in human trials whether these drugs will work or not. So our goals and our Stanford team goals, and I call it a team because it includes our patients and our families and our friends. We cannot do this alone. We're breaking open new fields in brain degeneration. That eotaxin is something that's in the immune system. Normally a neurologist would not be studying something in the immune system, but we have to have a wide perspective of this to solve this problem. We have to just break open entirely new fields to bring to this fight on Alzheimer's. We're revolutionizing brain imaging and bioinformatics. You can see how important it is to image the brain in this field. Stanford's a perfect place to do that. And finally, we're enabling translation of the clinic. Only about 25% of med schools are on a main campus. Here, we're on the main campus of probably the top university in the world. Nice place to solve the Alzheimer problem. So I want to thank some of my patients that I know are here, our patients' families. Without you, none of this would be done. So thank you very much. We'll take time for questions. Are you gonna pick out people? The gentleman in the back raise your hand first. Go ahead and we'll keep the questions brief. We have about 10 minutes. Pardon me. Is there any possibility that amyloid is irrelevant or inconsequential? So the question is, is there any possibility that the amyloid is inconsequential or irrelevant? Yes, of course. It's a controversial area. Some people think that that buildup of amyloid is what we call an epiphenomenon. Has no causal role, whatever. It's associative. That it builds up, but it's not causing the degeneration of neurons. The majority of the field thinks it is an important causative factor. I personally feel that it's one of several causative factors and the therapeutics we're developing are not entirely dependent on a role of blocking amyloids. That's a key question in the field. I'm gonna try to go work my way forward, but the lady in pink right there, you were first. Yeah. Yeah, you're asking about, is there anything positive about using software for brain fitness? You know, it's still an area of study, right? There are conflicting studies. Most of the studies, when they looked at the effects of these software-based exercises, what they found was that people got better at that particular task. You'll get better at that particular task and you'll preserve the ability to do that task on that software, on that computer. But what they're not seeing much of is what we call a spillover or a generalizing effect. It's not gonna help you find where you park your car or prepare a complex meal. It just doesn't seem to be having a global effect. I don't think it's a bad thing. It might be a little bit helpful, but what I don't like to see in my clinic is our patients and our families come in. They've spent a few hundred dollars in the software. And I know what it's like to be on the internet looking for treatments for diseases. They're looking at hundreds of cures for Alzheimer's. They're doing these cognitive exercises. And then I ask a real simple question. Are you able to get out and walk? Nope, no exercise whatsoever. So I just don't like to see people missing the most powerful thing we have while they're sitting in their seat doing brain exercises, that's all. So if you're walking, it's fine to do the brain exercise. Yes. What relationship, if any, is there between Alzheimer's and the ischemic changes that you see on MRIs, you know, a flare signal showing lots of little bright spots? Do you see very commonly and very healthy people as well as others? Right, so that's a good question. The question is what's the relationship between Alzheimer's and the signals that we commonly see on MRI scans that are indicative of a little bit of vascular disease? So anybody over age 65, even age 60, doesn't have a perfect MRI scan. You see these little little bright spots the gentleman's referring to. Those are generally signs of small vascular changes that we all get as we age. There probably is some vascular contributory factors to developing Alzheimer's, there's probably an overlap. There's an entity called vascular dementia. Now in the old days, people thought dementia was primarily due to lack of blood flow and vascular issues. I think that's changed, I think it's not as common as Alzheimer's itself, but there's a set of patients we call mixed dementia. They've got some Alzheimer component and some vascular component and it's a mixture so it's not a clean way. So you've got pure Alzheimer's, you have mixed pure vascular dementias and that's in the Imogene Reflex app but we have no way of diagnosing that perfectly accurately. Yes, yes. Have you seen any difference in populations around the world which are obligated to perhaps be more walking around? Do they get a lower incidence in general of Alzheimer's? So maybe countries like Japan where they walk a lot, for example? I mean the answer to that, the question is in parts of the world where people walk more is they're less Alzheimer's and in general the answer is yes, but there are so many other factors that go along and being in the country where you walk more. The diet's different and so it's really hard to know if it's exercise per se. So that's why we do these highly controlled, the field does these highly controlled studies where we try to make everything else equal, the age, the education, history of head trauma, all the other risk factors and say you guys do the walking, you guys don't do the walking, we'll follow you for a few years. That's the only way we know if it's exercise per se. They say India has less Alzheimer's but there's a group at UCLA working on a derivative of curry as a treatment to prevent Alzheimer's and they say that's why they have less in India but they walk more in India too so it's hard to sort these things out. Back there, you had your hand up for a long time. Brain function, would you just address whether you recommend aspirin? You're asking if aspirin is helpful for brain function and I would say there's no great evidence for that and in fact as we get into Alzheimer's there can be a little bit blood vessel abnormalities but it's at risk for small bleeds in the brain and as we know if you're on aspirin you would bleed more so I wouldn't recommend taking aspirin for Alzheimer's at least. Now if your cardiologist wants you to take it for other reasons that's a different situation. I don't want to miss someone who's had their hand up a long time so I'm sorry if I'm missing people. Okay, the woman in green right there, okay. Right, that's a good question. You've been walking every day, what more can you do? What I tell people is number one, the exercise part and they always ask me how much and I would just go along with what the American Heart Association or American Cancer Society says 30, 40 minutes a day, five or six days a week as best you can without falling and breaking a hip, hurting yourself, et cetera. So that's and what form of exercise as you can see it might be many different forms whether it's resistance training, walking, we don't know exactly. Number two I would rank is the so-called Mediterranean diet and not being overweight to the one and again the Mediterranean diet's the same thing in the American Cancer Society would tell you the American Heart Association a little bit of meat but not too much complex grains rather than simple fish once or twice a week so-called Mediterranean diet. And number three, remaining cognitively engaged that's what I call cognitive exercise. It doesn't have to be sitting at a computer cognitive engagement, just doing activities with other people, taking yourself out of the cognitive comfort zone a little bit just getting out there being engaged with something somehow it might be family, grandkids, activities, some kind of engagement. I saw a recent study where they just looked at the difference, the parameter they looked at was not exercise, diet, or brain exercise. They looked at whether people had a purpose or not, whether they were passionate about something or not and that seemed to lower risk for Alzheimer's if you're just engaged with something. So that's what you can do. I admit that I take fish oil capsules I showed you some studies there we need more studies to really know about that. I wouldn't recommend it unless you talk to your primary care physician. If you had a bleeding tendency or you were on kumadin and you take a lot of that stuff they could theoretically increase bleeding. Again, I'd always talk to my primary care physician first. Those are the things you can do. Hopefully we'll have drugs coming out pretty soon that will delay onset or slow progression. We're not quite there yet. Dr. Longo, we have a person here who'd like to- Okay, yeah, help me out if I'm missing somebody. Dr. Longo, can you please comment on the relationship between diabetes and Alzheimer's? Especially you mentioned India, there's a higher rate or increasing rate of diabetes there. Thank you. So the question is diabetes and Alzheimer's, diabetes is a clear major risk factor for Alzheimer's. If you have diabetes, unfortunately, you're at much higher risk for Alzheimer's. And basically what you're left the options are have your diabetes treated as best you can and probably the exercise becomes even more important. Yes, that's a great question. What's our timetable to get these into human trials? We, what slows it down is a series of bottlenecks. So we have probably a dozen of these small molecules that we're excited about. It takes us about two years to test one of them. It takes us two years. Testing them in mice is very labor-intensive. We have whole teams of students and technicians that are ready to shoot me at any time. The hours they put into this and it's one at a time and two years from now, we'll know if that works. What I'd like to have is 10 of them that we know that works to bring into the clinic, right? And I think ultimately the more things we try and people, the more bigger chance we're gonna get to something. So two years in a mouse, then if it looks effective in a mouse, so far we've taken our drug that it's been the best in the mouse. Then we have to do safety studies that the FDA requires. So we're just wrapping up FDA studies right now on one of our favorite molecules. That's taken another two years. We've done that with an NIH grant and formal rat and dog testing to look at safety. We'll be submitting that package to the FDA this summer. I'm so excited about this because this is never done in academics. People in academics usually study mechanisms and say they will serve as a basis for a treatment someday. They publish a paper and they're done. And about 10 years ago, we decided, no, we're not done. Because every day I'm in clinic, I get humbled by my patients. We're not done until I can give them something to cure the disease. And so we said, no, we're gonna actually get a drug to people. So it's been a long journey, but we'll be submitting to the FDA this summer for permission to do the first human trials. The human trials will be phase one, phase two, phase three. Phase one, normal humans, usually college kids volunteering, looking at safety. Phase two, the first, and that takes about a year. Phase two, first Alzheimer patients, two or three years, get an idea if it's working or not. If we develop the brain imaging, that's designed to accelerate phase two. Because right now when we test it in Alzheimer's patients, we give them the drug for 18 months and then have them do cognitive pencil and paper tests. Takes three or four years to finish that study. But if we can give an Alzheimer person one of our drugs, do a PET scan and in one hour say, drugs working in the brain, fast acceleration, but it's kind of Stanford technology that'll get us there. So anyway, two or three years in phase two, then phase three, another three years, that's the big population. Phase three works, FDA approves it, one more year into people. So what I showed you in mice, maybe six years into people, but I'd like to do more than one drug at a time and hopefully we can expand our capability of remove these bottle necks, get a lot of these drugs in the mice, get a lot of them through the FDA into people. Thank you, Dr. Walgo. Thank you very much. The preceding program is copyrighted by the Board of Trustees of the Leland Stanford Junior University. 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