Ronald C. Petersen, M.D., Ph.D., Director, Mayo Olmsted Study of Aging: Thanks very much, both Essa and David, for giving us a feel for where we are, how we fit in, and where we're going in the future. So what I'd like to share with you this afternoon is kind of an update on how we're doing, how you are doing, and give an insight as to where this study fits into the bigger picture in the world of aging, dementia, cognitive impairment, Alzheimer's disease, and then share with you some very new data that we have that's, i think, pretty exciting for the field. And, again, you should take responsibility for it.
How many of you were here last year? Reasonable. okay. very good. Thank you for coming back and putting up with us again. But I'm going to share something with you that was there last year and I want to ask you why you haven't acted on it, but that's a whole other issue. Here are my disclosures.
The left-hand column is why I'm cheating, lying, and stealing with you and all. But I do some work with the pharmaceutical industry because I think it's important for them to have sort of our input on what's going, what's relevant for the field. And I want to learn from them where they're headed with regard to the design of new therapies. On the right-hand side is our funding from the federal government and from several philanthropic support as well. But I want to highlight one in particular, the yellow one that's outlined here is what's called the Alzheimer's Clinical Trials Consortium. And this is funded by the National Institutes of Health.
It's a public-private partnership, meaning academic centers and the pharmaceutical industry are working together to design better trials for clinical studies, and I'm one of the principal investigators on that, and hence, because it's a public-private partnership, the NIH precludes me from taking more than a buck and a half from any of those companies on the left. So, and what I said last year and is still existing today is this, this is what I drive. So, if I were really on the take from these companies, would I be driving a 1986 Dodge Diplomat? This is a nice car, don't get me wrong, and it's serviceable, functional, it's for sale. It was for sale last year, and nobody took me up on it, so I bring it back this year, and I'm not trying to sell anything here, but it does have radio, it does have air conditioning. You can't have them both on at the same time, but that's sort of a nuance.
But, you know, so it works, and here I am. I'm either off to the golf course or liquor store or someplace. So keep that in mind as we talk. I mean, we just gave you $2 million, and so one of you can't spring for this particular. Anyway, that's another issue. So really what the point of today is to really thank you for your participation. As David and Issa said, it's an important study, but without you, it doesn't mean anything. And one thing I sometimes we overlook is that this study has been going on, as they said, for 20 years. Its predecessor went on for 20 years before that. So it really has been ongoing for three or four decades. And your participation has contributed to the field and all that. But it's also contributed to a lot of us individually. Some of us have literally built our careers, our academic careers on the basis of this study.
Many of my colleagues over the years have really gone from instructor to assistant to associate to full professor at the Mayo Clinic College of Medicine because of this study. That's another contribution that you've made to individuals in this community as well as to the field as a whole. And here are the two guys who started it with, you know, I was there back in 1986 when we started it, too. But Emery Kochman on the left and Len Curlin on the right. They've been gone, unfortunately, for almost 20 years now. But they were the folks who really put the stake in the ground back there and said, you know, we can contribute to the field by getting this study established. So we really owe a lot of thanks to them. So here's where I'd like to go this afternoon. I'll be brief on a lot of these topics.
You know about some of it, but because there are some new individuals here, I want to give some of the basics of the study as well. So let's start with an overview. So this is the Mayo Olmstead Study of Aging, sometimes called the Mayo Clinic Study of Aging, Mayo Clinic Olmstead Study of Aging. And it's a population-based study in Olmsted County, Minnesota. Now, what does that mean? A population-based study means that we do a random sample of people who live in this community. There are a lot of good studies out there, aging studies. Harvard has them. Johns Hopkins has them. The University of California, San Francisco, great studies. Good data come from them. But those studies rely on people volunteering for them due to media ads and the variety of social media, say, join our study. And they do it. And that's good. And that's fine.
But you're going to get a very select population who volunteers to participate in one of those studies. So the avenue that we take is that because we have this thing called the REP, the Rochester Epidemiology Project, which is a project that's been going on for over 60 years here, which takes into account all of the patients of the Mayo Clinic, all of the patients of the Olmsted Medical Center, and puts them together as a resource to really study, use information from them because basically everybody who lives in Olmsted County, almost everybody, gets their care from either Mayo or the Olmsted Medical Center. And that gives us complete capture of people who live here and enables us, gives us the infrastructure to be able to do a random sample of people. So we invite you to participate. Thank you for agreeing to that.
And the participation rate is good because of the generosity of people who live in this county. So over the past 20 years, then, we've seen over 7,500 people. We keep about 3,000 people active in the study at any given time, and we sample six decades of aging across the universe. So, again, Mayo Clinic, Olmsted Medical Center, but really it's you. If you didn't agree to participate when you get that letter, then we're stuck in the mud. So the fact that you've given your time year in, year out for this is absolutely critical to the success of the study. Now, as we've talked in the past, with the tumultuous times in Washington right now, federal funding is uncertain. And in fact, we've had some interruptions in federal funding, even though we've been funded for four decades. There have been some interruptions in that in recent years.
So we're on now what's called a no-cost extension, which means we're still getting some funds, but not a great deal. As of a couple of weeks ago, we put in a new grant application for the continuation of the Mayo Clinic study of aging. But with the federal uncertainty, it's hard to know. I mean, people are talking about slashing the NIH budget by like 40%, so you know that's going to have a potential impact. Nevertheless, we're continuing. We will continue to write grants and we'll try to get funded, continued funding from the National Institutes of Health. But as a safety net, we have generosity from our philanthropic partners. So the GHR Foundation in Minneapolis has been with us for years and years and years. We'll continue to, we hope, go forward. They understand the predicament we're in and are willing to help. Since last year, we can bring on the Bill Gates Foundation.
Gates Ventures has said, no, we think the Mayo Clinic study of aging is absolutely critical for the field, and we want to help you through these times. And so they're giving us millions of dollars over the next few years to support the study. Duncan Alexander and his family out of Chicago have been instrumental in funding us over the years, understand the predicament also, and are willing to help us out. And then many other individual donations to the Mayo Clinic have kept us alive. So we're okay for right now, not forever, but we're okay for the next few years with regard to funding and the safety net of keeping the study going. So nothing's going to change. We're continuing to see everybody on the same frequency. We're adding new people. If people drop out, we're trying to keep the cohort at 3,000 people.
And as you know, if you've been here last year, we've also expanded the study because of diversity issues that ESA was talking about to include the University of Mississippi in Jackson, Mississippi, to get an African-American cohort from Mississippi to complement what we're doing up here so that our data that we generate here perhaps will be more generalizable beyond just Olmsted County, Minnesota, to a broader population. So all of these opportunities, I think, are out there, and hopefully we're going to be able to take advantage and expand with them. So let me give you a little bit of a recruitment update then. So when we started, the top part of this slide is the 70 to 89-year-olds. Initially, when we started in 2004, we randomly sampled 70 to 89-year-olds because that's kind of where the action was.
But as the field evolved and biomarkers for aging, biomarkers for Alzheimer's disease became available, we dropped down to age 50 and then ultimately down to age 30. Because we realize, and I'll expand on this a little bit later, that some of these biologic processes that are involved in aging and Alzheimer's disease really begin many, many years before people become symptomatic. So sampling younger age ranges becomes clinically and scientifically important. So this was the start back then, and then we've continued on. I just met somebody in the lobby who's been with us since day one. I think she's 92 or something like that. She's been with us. And so as you'll see, she's been with us for 17 cycles. She's been seen that many times. That amount of data is absolutely, extremely valuable to us and to the field in terms of what's the natural course of aging.
So 70 to 89, 50, and 30-year-olds as well. So what does the study involve? You know it. You live through it. And David just sort of gave you a capsule of that. When people come in, everybody gets a three-part evaluation. The left-hand column here is the study coordinator who goes over your personal history, your medical history, your family history, your medications, and puts all that information together. There's a little bit of testing with you. The middle column are the physicians who do the mental status exam and the neurologic exam. The right-hand column is the one you love. Remember these 15 words? Remember them again? Remember them again? Remember them again? That kind of stuff.
So at the bottom then, all three inputs come together with individual assessments, judgments on how you're doing, and then we get a consensus conference every Tuesday afternoon out of The northwest clinic where we sit around the table and argue about whether or not, gee, i think they did this, did that, are they normal, what's their diagnosis, things of that nature. So, this is an ongoing process that we've had for years and years and this is the stuff that we acquire. And, you go through and give us your information and David said how many questionaires you have and all that. All of this is optional. You can drop out of anything if you want.
We want you to keep going if at all possible, but this information, we got this, we got this much stuff, study coordinator, what the physician does, what the psychometrist does, and then some optional things, imaging, lumbar punctures and things of that. So, we appreciate that this is a big investment on your time, your part, and we appreciate your willingness to help us out. So over 20 years then, this is the cumulative curves of individuals participating in the study and over 7,700 people have been seen, ages 30 THROUGH 90. We focus on 60, 70 and 80 year olds. The different color bars are men and women. We randomly sample people stratifying for an equal number of men and women. So, this is total participants and these are the active participants again, the 3,121 people as of last week who are currently participating in the study.
So, we greatly appreciate your willingness to help us out because this is the substrate from which all of the data are generated, participation rates, a longitudinal study of aging. So, we really, really, really want you to continue to participate, again, because that's how we determine trends and the like. And, 85% is great. The younger folks, it's a lower rate, these are busy people out working and doing all kinds of things. But that rate is adequate for that portion of the study. So, here's a putative cognitive continuum of people who are aging normally, as most of you are. Some will develop this thing called mild cognitive impairment. Some will go on to dementia. So dementia means that I'm not functioning as well as I used to. I can't do my usual activities because my thinking skills are not quite what they used to be. That's dementia, mild, moderate, severe. Back up a step.
Mild cognitive impairment is kind of in between. And usually it means that I'm not remembering as well as I used to. Maybe not as well as I ought to, yet other things are okay. I'm functioning okay. I'm still paying the bills, doing my taxes. I'm driving maybe less efficiently than I used to, but I'm still doing it. That's kind of that in-between state. These are clinical pictures. It doesn't mean you have Alzheimer's disease, but it's a clinical continuum. And as we assess people each Tuesday afternoon on that continuum, Then we try to say, okay, this person's mild cognitive impairment might be due to, and there's where we bring in certain biomarkers to try to explain why somebody is having a little bit of difficulty. So that's the big picture. Now, what's happened over the years then, we've acquired a lot of stuff from you. We've seen 7,700 people, and we have blood.
We have MRI scans on many of you. We have blood DNA, so genetic information on most of you, and we have blood samples at each visit on most of you. And what that's led to is outlined here in the yellow, again, over 31,000 blood samples. So you can imagine people who have been in the study for years and years and years, we get blood on them each and every year. It adds up to a lot of important information. But the value of longitudinal blood samples every year has enabled us to really get a picture of what's happening biologically in aging as well as in Alzheimer's disease. And I'll get to that in just a minute when we talk about some of the recent studies we've done on blood-based biomarkers for Alzheimer's disease. We have over 1,300 lumbar punctures on people, 9,000 MRI scans.
6,100 amyloid, PIB means amyloid PET scans, 4,100 glucose PET scans telling us about the function of the brain, and 3,800 tau PET scans. So this is such an enormously rich treasure trove of information that helps us understand what normal aging is because you're randomly sampled from the community as well as what's abnormal when things start to happen along the lines of Alzheimer's disease and others. So let's turn a little bit to that. What have all this information that we've acquired over the years, what has that contributed to? Well, let me just stop and say, I gave you the clinical picture, mild, normal aging, mild cognitive impairment, dementia. Now, what about Alzheimer's disease? Alzheimer's disease is one cause of why that picture changes over time, why people become cognitively impaired. It's only one picture, but it's an important one for many people.
So what's Alzheimer's disease? Now we define it by the presence of this protein in the brain called amyloid that produces the plaques and the tau protein, which produces the tangles. So Alzheimer's disease is a plaque-entangled disease in the brain, and it's caused by these proteins. When I started, the only way we could make the definition, the definitive diagnosis of Alzheimer's disease is after we followed a person that passed away, had an autopsy, and we looked at the brain under the microscope. And under the microscope, we see plaques and tangles and say, ah, definite Alzheimer's disease. Fast forward, now we can see those plaques and tangles, the amyloid and tau protein in living people. We don't have to wait for an autopsy. We can do it by PET scans. We can do it by the lumbar punctures and maybe now in the blood.
So that's how the field has advanced over the course of this study and enabled us to be much more precise now with our clinical diagnosis. You have mild cognitive impairment. What's it due to? Well, it might be due to Alzheimer's disease because we have these biomarkers now that are confirming the presence of those proteins. Now, these things happen in normal people as well, so that's opened up a big avenue for us to investigate these processes. And in particular, Angela Lunde, when she was sent out the invitation for this event, asked you, do you have any questions, things that you'd like us to address and answer? You gave us a bunch of inquiries, which are very good, insightful, important, And one of them was, which struck me, was how has this study contributed to the national picture or the global picture of aging and Alzheimer's disease?
How has it contributed to the knowledge in the field out there beyond Minnesota, beyond Olmsted County? And it has. One way are the Jack curves. What are the Jack curves? One of our colleagues who's been with us for 40 years, Cliff Jack, is a neuroradiologist, lives over in the Opus building, and he's been an MRI expert, a PET scanning expert, and he has generated a set of hypothetical curves of how Alzheimer's disease evolves in a person, meaning what are the pathologic processes that start out. So, first thing that he picked up was A-beta means amyloid, amyloid in the fluid, amyloid in a PET scan that we can see. The tau protein in fluid, the tau protein in a PET scan. After that, then, we see the damage done to the brain that's reflected in MRI scans showing shrinkage, or FDG PET, which shows function of the brain, how the function is changing.
But it's only after all of these things have played out over years that we start to see clinical changes. So the forgetfulness, the memory, the thinking changes happen way to the right, and all this other stuff has been going on for years and years. The good news on that is that gives us a window of opportunity to intervene. So can we intervene on those pathologic processes to prevent or delay the clinical presentation? So these are the so-called Jack curves, and he came up with this, and they've been revised. The first set were in 2010, 2013. These were revised in 2022. But basically the same concept is there. It's been refined as we've learned more information about the performance of these biomarkers. The basic construct is there. But where did that come from? Where did his thinking, the conceptualization that he and the team put together to generate these curves? It came from you.
The data that he observed that we followed over decades now of people aging in Olmsted County gave us the kind of thinking that this is how these things play out over time. And the realization of this really came from the data, the information, your contributions to the field. So the answer to the question, has the Mayo Clinic study of aging contributed to our general knowledge about aging and Alzheimer's disease, this is one manifestation. So, again, thank you for what you've done. And you should be proud of that because it's moved the field forward enormously. So here's what one of those amyloid imaging scans looks like. We're looking at the brain from the top down. The top is the face, the bottom is the back of the head, the amount of redness on these scans reflect amyloid positivity in the brain.
You can see that on the left we have a person with normal, person with mild cognitive impairment, A little bit of redness in the middle and a lot of redness on the right hand side, somebody with dementia. Here's a tau PET scan from the front on, again, the redness on the right is a positive scan, the lack of redness on the left is a negative scan. So those are the imaging tests. Now what about this spinal fluid stuff? I talk about lumbar punctures. Some of you have volunteered for the lumbar punctures. The lumbar punctures give us cerebral spinal fluid that circulates around the brain and And it has an index of the amyloid protein and tau protein in the spinal fluid. This is produced now a test that Mayo Clinic laboratories commercializes and sells nationally and internationally as a spinal fluid test for Alzheimer's disease. Where did those data come from?
Where did the cutoff scores for amyloid and tau positive and negative come from? The Mayo Clinic study of aging. Again, those of you who have done a lumbar puncture contributed to that knowledge about how we use that particular index. Now, the new kid on the block are the blood tests. So blood tests have evolved over the last several years, become very popular, exciting, new looks at what's going on in the brain. So a blood test may give us an index, again, whether you have amyloid in the brain or whether you have tau in the brain. Why? That can tell us the prediction between the blood test and a positive amyloid PET scan is very high, such that the blood is reflecting what's going on in the brain. So we can predict who's going to be amyloid positive. Can we use the blood test to make the diagnosis, the biologic diagnosis? Maybe.
I don't think we're there right now, but that certainly is on the horizon as these tests get more sophisticated. that we, in fact, will be able to use a blood test to tell whether somebody has amyloid and tau in the brain. And now we have new therapies, I'll get to those in just a minute, actual therapies for Alzheimer's disease specifically that reduce the amount of those proteins in the brain, treat somebody with the drug, and, in fact, the levels are lowered. Wouldn't it be nice if we could follow the effectiveness of those therapies with a blood test? Do we do that in the medicine? All the time. If some of you have elevated cholesterol, you're probably on atorvastatin. Lipitor has a cholesterol-lowering blood. That's what we do. We measure your blood, see what your level is, give you the drug, measure your effectiveness or the effectiveness of the drug later on to lower cholesterol.
Works all the time. That's where we're headed with these tests for Alzheimer's disease. One of the more recent papers just published this past year by the Mayo Group shows that because studying you, meaning people who are aging typically in the community, you have hypertension, you have diabetes, you have COPD, you may have some degree of renal failure, kidney failure. Your kidneys are not working as well as they used to because of your hypertension. That's going to influence the reading on one of those amyloid blood tests for Alzheimer's disease. So because we study the general population, we have measures of these other medical things going on. And in fact, we can now tell the field, be careful interpreting those blood tests for Alzheimer's disease in people who may have a bit of kidney failure, just a little bit. And, in fact, this one shows.
What we're plotting here is the amount of kidney failure on the x-axis in the middle panel there are A-, people who are amyloid negative, so they don't have Alzheimer's disease. But the blood test is indicating they might have Alzheimer's disease if they have a degree of kidney failure. So the inaccuracy of the test needs to be measured in the context of medical problems, which, again, we, you, can tell the field because we're studying across the population. So thank you for that. Now, ESA already mentioned this, but I changed this slide. Olmsted County is 77% white. Last year, I presented the slide that says 82% white. So the county is becoming more diverse, and that's good for our ability to study the generalizability of some of the findings that we're getting from the study of aging.
And as I mentioned, we've expanded to the University of Mississippi, University of Mississippi Medical Center. Again, the same procedures that we're using here in Olmsted County, we've exported to Mississippi, and colleagues down there are acquiring a cohort of individuals, about 1,000 African Americans and 1,000 whites in the South to complement what we're doing up here. And we're also studying the other factors Issa mentions, not only how much biology you have in the brain, but it's a lot of social factors like how were you raised, what were you exposed to, what were your lived experiences growing up? Does that influence your likelihood of having cognitive impairment, having Alzheimer's disease? We'll be able to look at that by expanding our populations. Okay, let me just say a few words again.
This is not all about Alzheimer's disease, but let me share a couple of thoughts on where Alzheimer's disease is going with respect to treatments. So, as I mentioned, we now have disease-modifying therapies. So these are medicines that actually work on the underlying disease process, amyloid and tau. These drugs lower the amount of amyloid in the brain. So here's an example of a different drug, aducanumab, one of the first kids on the block. The top two pictures of both columns now is baseline. The redness is the amount of amyloid in the upper left. In the upper right is somebody one year later on placebo. No treatment. Go to the bottom row, bottom left. Somebody's starting the treatment with redness because of amyloid in the brain. Treated for 18 months with one of these drugs, the lower right-hand corner shows the clearing of that amyloid protein from the brain.
So, in fact, these drugs do what they're supposed to do. They remove amyloid from the brain. So, one of them is the Slocanumab drug, and here's an index of the top line is somebody who's receiving placebo, No change in the amyloid level. The bottom line is somebody or a group of people who received the amyloid drug for 18 months, and the amyloid is removed in 60%, 70% of the people completely removed from the brain. Okay, the question is, so what? What does that do for them clinically? The answer there is it slows the rate of progression of the disease. It doesn't stop the process, it doesn't make the person better, but it slows down the rate at which the disease is progressing. Going back to the heart analogy, if you take Lipitor, does that mean you're never going to have a heart attack? No, not necessarily.
But if you were destined to have a heart attack at age 72, untreated, you take the Lipitor, now that heart attack may not occur until 76, 78, 80. That's important. You've delayed the clinical impact of that pathologic process. You haven't stopped it, but you've delayed it. Here, that's what we're thinking, that these drugs may, in fact, postpone the progression of the disease. The rate at which a person would go from mild cognitive impairment to dementia is slowed, and we can keep the person at his or her current functioning level for a longer period of time. So these aren't magic. They're not the end of the day, but they're important steps in the right direction. Now, they do have side effects. The bottom lines there talk about Aria-e, aria-h. E means edema, H means hemorrhage or bleeding. They can cause swelling in the brain. They can cause bleeding in the brain.
We have protocols to monitor that, to try to prevent that from occurring and do what we can. And I think we've done pretty well with that thus far. But they're not benign drugs. They do have some side effects that need to be taken into account. The other drug basically is the same story. Again, different studies here, different groups. The flat line on top is untreated. The bottom line is the effect of the drug on removing amyloid from the brain. And here's the clinical impact again, slowing down the rate of progression by about 30% over the course of 12 to 18 months. So, again, they do what they're supposed to do. They have similar side effects, and we have to take that into account. I'm going to get to, at the end, a little impact of what the study of aging has done for this decision-making process. But the end-all, be-all is not all drugs.
Their lifestyle factors can have an important impact, and these are slides loaned me by Angela lundy on the study that was presented this past summer at an international conference showing that the u.s. pointer study, which was a lifestyle study, actually showed that by certain lifestyle modifications, you can slow down the rate of progression of dementia, of mild cognitive impairment. Is it Alzheimer's disease? We don't know that specifically, but we do know that the clinical progression can be modified by certain lifestyle interventions. so here we're talking about physical exercise, cognitive exercise, nutrition, and health monitoring. so we can do some things. what are the best ones for you? Generally physical activity is probably the single element that's most impactful on trying to alter the trajectory of cognitive aging.
In general, higher levels of physical activity are associated with better cognitive function, aerobic exercise, resistance training, stretching. And it doesn't have to be marathon running. We can do it with maybe 150 minutes of brisk walking a week. 150 minutes can have an impact. There's a study reported in Nature Medicine just this past week showing that steps per day, the magic number, 10,000 steps per day, nothing magical about 10,000. It showed that if you did 4,000, 5,000, 6,000 steps, that's beneficial for you as well. So it's sort of a graded continuum, but you can do something, and you can do something later in life as well. So physical activity is probably the best one. Cognitive exercise is probably important.
Staying involved, challenging yourself, doing something that's a little more novel for you, trying to actually get out of your comfort zone with some of the intellectual activities you do, do some new things. Be careful of the brain games. A lot of people out there, a lot of companies are selling this exercise, that exercise for your brain. Are they good? Hard to know whether they're actually beneficial. On the other hand, doing something is better than doing nothing. And I always emphasize with patients to try to find an activity that you like, that's fun, that's enjoyable, so that you'll do it day in, day out, because you like doing it, and it's probably good for the brain. On the nutrition side, it does matter what our diet is, But I think if we just think about what's good for the heart is good for the brain is probably the best advice we can take.
And these brain supplements, nutraceuticals, the Prevagenz of the world are probably not worth it. It's a multi-billion dollar industry trying to get people to boost their brain power with that or the other thing. If you do not, we did a study with AARP a few years ago, the Global Council on Brain Health, brought together experts from around the world on this topic of nutraceuticals and supplements. And they told us at the end of the day, if you don't have a deficiency state, meaning if you're not low in B12, low in vitamin D, low in calcium, it isn't going to help you to boost above the normal levels. There's no benefit of that, but you do need to boost your deficiency state to get into the normal rate. So lifestyle factors can be impactful, taken in conjunction with medications, if appropriate.
Okay, one topic here that we've talked about in the past, which is a legitimate concern, is giving you back information that's useful for you. If you have the imaging studies, the MRI results will go into your medical record. The glucose PET scan results go into your medical record. You and your primary physician can act on those as might be appropriate.
The other tests, blood tests and all, what we're doing now is because there are drugs available for people at the mild cognitive impairment stage due to Alzheimer's disease, disease, we are now contacting people, and if we think you have a memory impairment beyond what we would like to think is probably normal for you, doesn't mean you have a problem, but we want to share that information for you, we'll send you a letter, give you the opportunity to come in, talk to us on the phone, come in and talk to us in the office about might you be eligible for one of these drugs, we're more than happy to do that. So we are returning that kind of results. The blood test results are a bit more dicey right now because while they're available, we're not supposed to share them with people who are cognitively normal because there's no medically actionable advice that we can give you on that.
If you're cognitively impaired, that's a different story. So we're trying to keep up with the field on with return of results, but clearly it's more important. If you have questions, give us a holler. Talk to your primary care doctor. He or she can get in touch with us, and we're happy to share this information for your own benefit. So it's a rapidly changing environment with regard to return of results these days. But we're mindful of what you're asking for. Okay, let me wrap up then with some new research that's really hot off the press, so to speak. And this is a paper that literally is not out, it's going to be published next Wednesday or Thursday, a journal called The Lancet Neurology, one of the most popular, widely read journals in the world, and we've got this study that's coming out next week on Mayo Clinic's study of Aging.
And what it is, is a prediction formula for cognitive impairment. And again, because you have participated, it's allowed us to do some unique prediction formulas. So, sorry, I apologize. Careful. You may know about the Framingham heart risk score. Your primary doctor may have said, gee, you're a male, 72 years old, your cholesterol is this, you're a smoker. your risk of having a heart attack in the next X years is thus and so. Your risk of dying from this is thus and so. Popularly used. We're trying to generate, it's not ready for prime time yet, but we're trying to generate that kind of a risk tour of developing cognitive impairment, mild cognitive impairment in particular, over the next several years. So why is this a big deal? Because the study is unique. We have excellent participation rates with you, and because you are patients here, Mayo, or at Olmsted Medical Center.
And why that's important and why that's unique to this study is most studies of aging, good studies, people drop out. We don't want you to, believe me, but people do drop out. For whatever reason, they drop out. Once they drop out, they're lost to follow-up. We don't know what happens. That's not the case here because you, thank you, have given us permission to follow you passively through the medical record. Either at Olmstead or at Mayo, we can follow you. Ninety-eight percent of you have said, yeah, go ahead and do that. That's okay. So if you're 82, you've been in the study for six years, thank you, but you say, that's enough. I'm done. I'm out of here. Okay. Thank you very much. But we continue to follow you. So if you develop dementia in the medical record at age 88, that's still important information for us.
And so we can take your unimpaired at 82, dropped out of the study, develop dementia in the medical record at 88, we can, we meaning people smarter than I, the statisticians in our group, can model that you likely went through mild cognitive impairment, maybe at age 84 to age 87, something of that nature. So we can build the model that here's what happened to you, cognitively unimpaired dementia, that you went through the MCI stage. That enables us to develop a prediction model of you because in this paper, we found that two-thirds of the people who developed dementia who were in the Mayo Clinic study of aging, two-thirds of them had dropped out of the study. So if we were only modeling the people who remain in the study, only one-third of them would have been captured with dementia, and we would have underestimated the prediction of these various factors that go into the model.
So, because this is a unique situation where we, because you're our patients and we know who you are, we know what happened, even if you drop out of the study, we can do a complete modeling exercise of cognitive impairment. Complete medical follow-up, and again, the folks much, much smarter than I, Terry Therneau, Ming-Hu, people like that who are the statisticians, have done this thing called hidden Markov modeling. I have no idea what that is, but they were able to use that kind of modeling procedure to develop this, in fact, design. So, again, what we can do is tell somebody who's, again, this is not for prime time yet, hopefully will be, but not yet, somebody who's normal, what's the likelihood they're going to develop mild cognitive impairment in five years, ten years, or in their life? Similarly, what's the probability they're going to develop dementia five years, ten years in life?
So here's the complete model here, right? All of us is all of us. Cognitively unimpaired at some point in time, we may go on to mild cognitive impairment. We may go on to dementia. We may be cognitively impaired and die. We may develop mild cognitive impairment and die and dementia and die. So because nobody gets out of the game alive, we're all going to go down one of these pathways. And again, because we have capture on everybody, we can model this. So one of the elements we're putting in the model right now is the amyloid PET score. For those of you who have had amyloid PET scans. So in the upper right, the CL means centeloid. It's just a metric of how much amyloid is in the brain. So the centeloid scale goes from 0 to 100. Zero, none, 100, amount of amyloid in the brain with fully developed Alzheimer's disease. The cutoff between normal and not normal is about 25.
So below 25, you're pretty normal. 25 and above, you have degrees of amyloid in the brain. So upper right is centeloid 5, no redness. Middle is centeloid 50, some amyloid redness. Upper left is centeloid of 100, a lot of amyloid in the brain. So that's one of the prediction factors that goes into the model. And that's enabled us then to generate these kinds of curves. So on the bottom axis here, we have age. On the vertical axis, we have the likelihood you have that condition, cognitively unimpaired.
And the colored curves are: blue is no amyloid. Yellow is modest amyloid. Orange is a lot of amyloid. And, you can see the curves change by the amount of amyloid in the brain. But, in the upper left, cognitively unimpaired. These go out to 100 years of age. So, by 100 years of age, most everybody, if they live that long will be cognitively impaired. The upper right is death. If you live to 100, that's your likelihood but the probability of dying goes up with age. The bottom curves then sort of reflect what happens your likelihood of developing mild cognitive impairment with age or dementia with age. They go up to the early 80s or mid-80s, then they drop off. Why do they drop off? Because people die at those ages. So the likelihood of developing cognitive impairment is reflected by the upward rise in those. Okay, a couple more here.
This is again, blue. Is age 65, yellow is age 75, orange is ag85. We're plotting amyloid level on the bottom and on the vertical axis the probability, the likelihood of developing mild cognitive impairment. so it goes up with age and it goes up with amyloid level. and here we get cutesy about it and we try to break this out, different ages, by sex; men, women, apolipoprotein, E-levels, centeloid levels. So we get fairly sophisticated with it. But all this leads to this particular model. And here is the model, and we're going to run through a short video here. The model puts in sex, age, centeloid level, and your genetic thing of apolipoprotein E. So, and what this tells you is then what the curves are, the likelihood of your developing mild cognitive impairments. So, Jim, if you could run the video for a little while here.
So we're putting in here a woman who's a carrier of the apolipoprotein E genotype. Age we're putting in here is 65. 5, and the low amyloid level of a centeloid of 5, and then these are the curves that are generated, and we see, you can stop it there, Jim, and we can see that the probability of developing mild cognitive impairment in 10 years is only 7%, and of dementia is only 21%. Again, this is a 65-year-old person who has no amyloid in her brain. So relatively low probability. Go ahead and start it again, Jim. Now we're going to change it to a woman who's a carrier who is age 75 and has a centeloid level of 40. Stop it there. And now you can see the curves are bumping up. The probability is going up. And we can see in 10 years now, the probability IS 28 % That the person is going to develop mci and 17% That they will develop dementia.
So, now as you enrich it with age and you enrich it with amyloid, the likelihood goes up. and in the last one, Jim, go ahead and kick it forward. Now we're talking about 100 centeloid level in an 80-year-old woman. And, now when we calculate, again and her curves are much higher, so you stop it there, and we're looking at 71% Of likelihood of developing mci. So, the point is, you can run it out, Jim, thanks. So, the point is that we can develop these curves now that will give you a probability of having a clinically significant event, namely developing mild cognitive impairment. Who wants to know this? Well, if you're amyloid positive and you're at 65, 75, 80 years old, and somebody says to you, do you want to take one of these drugs that lowers the amyloid in the brain? Well, should I or shouldn't I? I mean, there are side effects, bleeding, swelling. They're expensive.
Do I really want to come in every two weeks or four weeks for an intravenous infusion? Well, it depends. Because now you can look at this formula and say, well, if I don't, the probability of me developing mild cognitive impairment is thus and so. And we can make it very individualized to help people make decisions that could be important for them with regard to their prognosis and health care in the future. So anyway, the point of this, and I apologize if I went into too much detail there, is that the data that you have generated, the fact that you have enabled us to follow you with this information and then follow you in the medical record has enabled us to develop this kind of modeling, which is unique, again, for the field. So let me stop then by saying that here's where we're going.
I think we've got more work to do with regard to the development of these biomarkers, evaluating these biomarkers. We're taking vascular risk factors into play. We're going to evaluate a model that's out there that Cliff Jack and his team developed to see if, in fact, we can shed light on where this is going. Now, some of the other questions that you threw at us, I tried to cover prevention. Lifestyle things are important. People ask about infections and Alzheimer's disease. It's a hypothesis out there. I don't think it has a lot of credibility. But insofar as infections can affect inflammation in the body, inflammation in the brain can impact these processes. I've talked a bit about supplements, talked about return of results. AI we're using in our imaging studies.
You can imagine how much information is collected in an MRI scan with zillions of these little voxels of information and similarly on PET scans with the glucose metabolism. So we have been using AI to, in fact, help people with the diagnosis, differential diagnosis, and also prognosis of what's happening. So AI is part of the picture, and then I've already mentioned what we've done on the national scene. So let me finish then with this. This is why I usually wrap up and say, cognitively normal, mild cognitive impairment, dementia. What impacts that as we age? Well, the amyloid process in the brain, talked a lot about that. That Tau process in the brain, we've talked about that. But there are other factors, something called alpha-synuclein, which forms Lewy bodies, which are happening in aging, form Parkinson's disease or Parkinsonism along the way.
Another protein called TDP43 can produce memory problems in the brain that look like Alzheimer's disease, not Alzheimer's disease. We're developing biomarkers for that. Vascular disease as well. MRI scans give us a lot of information. Something called CSF dynamics, the way the spinal fluid flows around the brain is a factor. And I'm sure there are other issues. So this is Alzheimer's disease. What's circled there? It's important. And it may be the only factor that's going on in a particular individual. But it's only part of the picture for many, many people. Most people as they age will have a confluence of these different factors impacting their aging. So what are we doing? We're trying to develop biomarkers for each and every one of those components because we think that where this is going to lead us is to therapies for each of these components.
So it's almost certainly the case that cognitive impairment as we age down the road and therapies are developed will result in combination therapy, multiple drugs plus lifestyle stuff to impact our cognitive trajectories and maybe down the road we'll be getting a lipid screen now for LDL, HDL, triglycerides, maybe we'll get a cognitive screen, amount of amyloid, tau, TDP43, alpha-synuclein and the like. That's what you've been contributing and I think this is where the field is going thanks to your help. But I need to really acknowledge the people who do all the work. These are the folks out at the Northwest Clinic who gather all this information, deal with you one-on-one, and hopefully answer your questions as to what's going on. But you, through them, have contributed to the data. The clinical research coordinators are the folks who do the interviews and deal with you one-on-one.
You've already met David there on the bottom. The psychometrists are the lovely people who ask you to remember this 15-word list time and time and time again. They're really nice people. They just have a tough job. That's all. The research fellows are the doctors who do the neurologic exam and ask you about your medical history. The associate clinical researchers are the folks who are involved with scheduling and putting everything together, make sure we're all on the same page, and vascular accesses. Raina is the one who draws blood on you. Out there. the study personnel, the managers, Steve, Angela, and Josie kind of run the show, keep us all on track as to what we're doing. Nick is one of the coordinators. Sarah is an IT programmer. You can imagine how much data is generated by this study.
She puts it all in the computer and the statistics and data analysts are the people who, again, are smarter than we and try to put all of it together. We also have the Alzheimer's Disease Research Center housed at the Northwest Clinic. A lot of people go back and forth and work on both of them, but this is another whole research endeavor out there that you're supporting as well. And, then, these are the folks who write the papers and do all the famous things and get credit for everything, but they really are working on the backs of the people on the previous five slides.
So, I want to thank you again. And, as we close and finish up here, we'll be out, our staff will be out in the lobby out there. If you have questions, we're more than happy to visit with you, answer any questions if we can answer them for you. Don't forget your phones, your glasses, and everything as you leave here. Give us feedback.
Please, give us feedback on this venue. Was this better, worse or whatever, because we're trying to accommodate you as well as possible. And, then finally, remember we've given you two million dollars over the last ... So, when you go home and you think about, is this something I can see in my future, ignore the sticker. I'm willing to talk. So, thanks very much for coming.