 Well, let's begin by asking anyone on the panel if they have a question. Okay. A wonderful presentation, and I'm once again delighted to be a student. So thank you for the lesson. In the manuscript that my colleagues and I have been working on, Human by Design, we've been asking the scientists involved to step out of their traditional role, which is to think in terms of how to treat diseases and disorders. And instead, think about or ask the question, how might the human body have been designed differently so that this problem does not occur? In this particular case, how might the human brain have been wired or designed differently so that we would not have Alzheimer's disease? Well, let's say it's a wonderful question. And obviously, like anything, any answer we scientists would give, it depends on one's perspective very much. It depends on what turns out to be the cause of Alzheimer's and the real mechanism underlying it. I presented evidence in my viewpoint on that. And so I would say that if we had designed the process by which we cut up proteins a little bit differently so that we don't create highly hydrophobic fragments of proteins, then it's my opinion that we would not have encountered a particular disease we call Alzheimer's. So I'm squarely in the camp that the buildup of this small protein is what triggers Alzheimer's, even in the many people whose cause we don't know. That is with the aging process. In the 70s and 80s, this gradual buildup is a sine qua known, is necessary for the development of the disease that we call Alzheimer's. So it would be a molecular design issue to cut up proteins more effectively, to maybe make one more cut after the so-called beta and gamma secretase cut liberate that little red box in my diagram to cut that red box more efficiently so that I couldn't detect a beta in your blood. When you're 5 or 50 or 80, I can right now detect it just fine. And indeed, there's some interesting evidence from some of my colleagues at other universities that a beta levels rise a little bit over time. So I would say that would be how I'd redesign the system. But you could also think of many other answers like let it all happen the way it does and protect the neuron from the apparent bad effects of this molecule. Yes, I also enjoyed your presentation very much. You just beautifully described the Baptist point of view as you put it. But I wonder whether you can briefly describe the current research from the point of view of Taoist persuasion. Right. So I'll do two things. One is I'll try to do that and then also mention another thought or a series of thoughts that are neither Baptist nor Taoist. So the Taoist thought was that it's the neuron that of course is at the root cause of failure synapses and it's in the neuron that Tao protein aggregates. And that the A beta buildup might happen but that the Tao protein is actually the true sine qua known and requirement for the cuda grotto the neuron for interference with synapses. And the Tao protein is an excellent position to do that. So the Taoist perspective I think is a more important role for Tao than you would see in my cascade, a role posted at the top. Now a very important lesson from genetics occurred and that is that in 1997, 98, three groups discovered mutations in Tao. And those mutations lead to several different diseases that include the syndrome called frontotemporal dementia. A syndrome in which there is lots of Tao buildup, enough to cause profound dementia and the death of the host. But no A beta buildup and even that, everything we say in science is controversial. Even then someone can come up and say, well, I found one case of a Tao mutation that there was some A beta buildup. And my response would be, well, was that just age related A beta buildup? Or was it moved to the Tao mutations? But by and large, most people say Tao mutations don't seem to lead during the course of the patient's remaining life to A beta buildup. So my response would be, well, that's interesting. Tao mutations themselves can cause profound dementia that looks like Alzheimer's and kills the host. But it isn't the condition that we've agreed upon together to call Alzheimer's disease because it lacks one of the pathological hallmarks. It's again nomenclature. Therefore, I think the cascade goes from A beta to Tao, not from Tao to A beta, that's how we think of it. The other approach though, and the whole idea of Taoists and Baptists is becoming a bit stale, frankly. And I said it a little bit maybe to get in a one liner and get a little laugh. The fact is that this is old hat and that we've come together as a field to recognize that there's a highly complex set of reactions and that neither A beta or Tao, in some people's minds, may be so critical as people like I think they are. But that a whole bunch of other processes make neurons vulnerable. And yes, sure at the end, the buildup of a sticky protein is bad news. But the fundamental reason the patient goes on to get the condition called Alzheimer's disease is because they have some neuronal vulnerabilities. A strong argument in favor of that idea is that there are brains full of amyloid plaques and sometimes even tangles. And we understand those patients were walking around doing just fine. Now, the response of people like me to that, and I'll close after that, is that, sure, that's true. But if I show you a woman who's 90 who was killed in a motor vehicle accident has the most terrible looking coronary arteries with terrible atherosclerosis. But never had a twin givangina, you would not say to me, well, atherosclerosis has nothing to do with heart attacks. So I would rest my case that way. Dr. Whitehouse. Can I just follow up, Dennis, on this issue we were talking this morning when you said Alzheimer's disease is largely a disease. You used the word largely. You just said what we now call Alzheimer's disease. And in your talk, you did describe the buildup that occurs in dogs and monkeys and people with age. So I guess I would ask you in that context, what is it that you think is so unique about Alzheimer's that makes it a disease and not a condition that is part of brain aging? Well, it's just a tough question to answer and probably my answer won't be terribly satisfactory. The earlier we look and Ron Peterson here at the University of Minnesota and John Morris and Washu and others and you yourself, Peter, have noticed that the A beta syndrome is preceded by a condition called mild cognitive impairment, which is the slightest trouble with episodic memory, for example, in one form of it. And there's been pathology on patients who died with that, that they have this process. So we would have perhaps in the past said they don't have Alzheimer's disease and in fact they don't, but they have something that might be a harbinger of it. Or they have something I can't put my hands on. We're going backwards earlier and earlier. And it could be that something about living long in primates, leads to the buildup of this protein, a lack of clearance. Maybe it's some problem with insulin degrading enzyme I'd like to think or whatever. And I think monkeys and dogs do get this process. Whether they get the condition we call Alzheimer's disease depends on their cognitive testing because the term disease needs to be applied after we are sure that there's a true impairment of behavior in everyday life. So I think there are preforms of Alzheimer's that don't deserve the title Alzheimer's, but I have to tell you, they look a lot like this process under the microscope and under the biochemist lens. Let's go to some questions from the audience here. Here's kind of an old one. What is the significance of any of aluminum found in tangles or in their blacks? So the question of aluminum has raised its ugly head for a long time. My mentor Mike Shalansky assigned me to look at the effects of aluminum in rabbits and I put quite a bit of aluminum sadly into the nervous system of rabbits and found that it did not induce tangles of the sort we see in Alzheimer's, but a different kind of a aggregate. So that was actually the starting point, that is the idea that aluminum causes tangles in animals that led Donald Crapper McLaughlin in the 1970s to check the brains of Alzheimer's victims and find elevated aluminum at least on brains. It's my opinion that a lot of work subsequently didn't really have that theory pan out. That's a terrible pun. And that is that my wife and I still do cook in aluminum pots and pans and you and drink aluminum, drink coke out of aluminum cans. There might be some evidence that in some places in the country that have high aluminum in the water as a clarifying agent, that aluminum finds its way to tangles and is sequestered there. But there are other areas where scientists don't find elevated aluminum and the Alzheimer's looks clinically the same and pathologically the same. So it's my opinion that we have little evidence that aluminum is an important or toxin of some sort in Alzheimer's. Okay, another one. Are the plaques found throughout the brain or do they occur in a limited area? Well, it's interesting. The mature plaques that Alzheimer called attention to are found in the areas you might think them to be in the frontal and temporal and parietal cortices of the brain, especially the association cortices and in hippocampus and amygdala. But early plaques and those will be the type that I showed you in that 12 year old Downs patients brain are called diffuse plaques. They're sort of like we like to think loosely fatty streaks of cholesterol in the process we call atherosclerosis. These precursor lesions are found in many more areas, including areas like the cerebellum and the striatum, we call it, which are important for detailed movement control that we don't usually implicate in Alzheimer's. So the amyloid can be deposited more widespread. Okay, so another question like that. It says if the pathology of Alzheimer's involves blunting a synaptic function, why is the predominant clinical effect specifically on cognitive rather than more diffuse loss of cerebral function? Right. I really don't have a satisfactory answer to that. The short kind of answer would be, well, the lesions that Alzheimer described do occur more in the areas important for memory and cognitive function. They don't occur in the substantia nigra that is implicated in Parkinson's disease, but that doesn't tell you why they occur there and not in the other areas. So selective vulnerabilities in these different brain diseases is one of our weakest topics. Okay. Another question. Can a brain MRI definitively identify Alzheimer's disease? I think some of these questions will be covered in the afternoon session at 6.30, which I'm planning to attend, by the way, and listen in on. But the answer is an MRI will show some shrinkage of the cortex of the brain and the lethation of the ventricles, but it won't be specific for Alzheimer's. Other dementias could look like that. You can get a fairly decent idea with a good eye, but it's not near as good, I think, as imaging the lesions of Alzheimer's. We want to be where people are in liver disease and heart disease, where they image the actual pathology in vivo. And I think work like I mentioned briefly from Bill Klunk and colleagues may get us there. We have a number of questions that kind of come down to the nature and nurture sort of thing. This is, are you at the point in your research where you could say that this disease is hereditary or caused by affected external factors such as smoking, drug use, or environmental factors? I'm sorry. It's another key question. It looks like it's going to turn out to be both, broadly speaking. I listed four genes that the field agrees upon. There are actually several other genes that there's not full agreement about, and altogether those genes might account for arguably a quarter of the cases of Alzheimer's disease in the country. And only one is really important, APOE4, this little debate that inheriting one allele of APOE4 from mom or dad heightens your likelihood of Alzheimer's about two to five-fold, inheriting two alleles from mom and dad, and heightens your likelihood of striking five to 12-fold or 15-fold in some studies. But beyond that, there must be a lot of other genes out there we haven't identified, or there are truly non-genetic factors. And I'm the first to tell you that non-genetic factors that are part of time on the planet do heighten your likelihood of Alzheimer's. It is somehow linked to longevity, but I don't know what those factors are. OK. And we have another number of questions about this. Can you say more about prevention of Alzheimer's disease? Do you have any treatments that you recommend at this point? At this point, what I tell my patients in my clinic on Tuesdays is that, number one, you should select your parents very carefully. Number two, you should consider taking vitamin E, which we debated earlier. It's a little bit of a chivalry in our field that high doses of vitamin E might be associated with prolonging the time until you enter a nursing home or have some other untoward event, although there's really little evidence that vitamin E directly has a benefit for cognitive function, per se. But it might do something generally for your health, but it's not potent. There are drugs that we use now in inflammatory disease, drugs like ibuprofen that, again, through the lens of some controversy, look like that might have a role in lowering the amyloid protein in the brain. But no one is ready to say, everyone go out at age 60 and take 600 milligrams a day of Motrin. I'm not saying that today, I'm saying the opposite, we don't know that yet. But there might be preventatives coming up as we do more research. Right now, maybe Peter can offer me some additional ones. I just wanted to add that there are epidemiological studies, which are not conclusive, that suggest your mother was right. So eating a diet that's healthy, physical exercise, mental exercise, and absolutely, for sure, attending Nobel conferences will prevent Alzheimer's disease. I'll finish with one last question here that's of some local significance here. It says, what significance is Snowden's research with the nuns of Mankato, which is 12 miles from here? Has this contributed in any way to your findings? Well, absolutely. His work is separate from the molecular biology and mouse genetics that we do for a living in my lab. But the fact that he's, for example, made the point that the Alzheimer process might begin in people in religious orders much earlier than we here to forethought is something that I have to think about. So it influences me, basically. And it makes me wonder whether is that true? Is it actually the case that someone who has an entrance exam to the novitiate? A clue to whether they might develop Alzheimer's 30 or 40 years later is already present there? Or is it their neural reserve is different than the next person who enters the religious order who doesn't get Alzheimer's disease, etc.? This research in the religious order studies has listed a number of epidemiological clues that we biologists have to pay attention to. Well, I believe we'll call it to a close here for this afternoon. We will reassemble at 6.30, thank you very much for coming. Thank you gentlemen, what a wonderful day.