MAYA ADAM:

Welcome to Health Compass. I'm your host, Maya Adam, director of Health Media Innovation at Stanford Medicine

MICHAEL GREICIUS:

As a memory disorder specialist, when I go to a faculty party of something, I pray that they have name tags, but those sorts of things are more kind of age related. What we really worry about are repeating the same question two or three or four, or if you talk to some spouses 10 times in the course of a couple hours. So there's really no laying down of a memory for recent questions or recent things that you've said.

MAYA ADAM:

Today we're discussing a topic that touches the lives of millions Alzheimer's disease with approximately 6 million people diagnosed in the United States alone. You may even know someone who's been affected by this devastating illness. And while decades of research have brought us closer to understanding the pathological changes in the brain that are associated with cognitive decline, the field is still rapidly evolving as new findings emerge to shape our knowledge of this complex disease, scientists and physicians are continually exploring new ways in which we can halt or possibly even reverse the progression of this disease. Today we're fortunate to be speaking with two leading experts in the field of Alzheimer's research and patient care. Mike Greicius, a professor of neurology and neurological sciences, and Sharon Shaw, a clinical professor also working in this field. Together we'll explore the evolving landscape of Alzheimer's research, uncover what we know about the genetic roots of the disease, and share invaluable advice for navigating a diagnosis in a loved one. I had the pleasure of speaking with Mike gracious first to gain insights into the history of Alzheimer's pathology and its connection to our genetics. Mike, thank you for being here today to share your expertise.

MICHAEL GREICIUS:

Hi, Maya. Thanks for having me.

MAYA ADAM:

Mike, I wonder if I can start by asking you what drew you into this line of work?

MICHAEL GREICIUS:

Yeah. Well, in medical school I kind of bounced around between possible specialties. I thought I was interested in surgery and quickly ruled that out. Takes a very certain type of individual to go into surgery. And then as I was thinking about medicine related specialties, I had a class in the neurosciences in our second year where one of my mentors, Richard Mayo at Columbia interviewed a patient who had suffered a stroke and had what's called a warnick aphasia where they don't really understand what's being said to them, but they can still produce language, which doesn't make a lot of sense, but sounds like normal language. And I was really taken with this disconnection between this patient's inability to understand what was being said to her, but her kind of fluid, sort of normal sounding speech. But that didn't make any sense. And I just thought, this is a fascinating subspecialty and the mind is sort of what captivated me about neurology, and that's what sort of drew me in.

MAYA ADAM:

Is there one story or one case that stands out in your mind that sort of impacted your career, like a milestone or a moment of discovery that you'd like to share with us today?

MICHAEL GREICIUS:

Yeah, there was one case in particular I think that really kind of pushed me into genetics. So I'm a behavioral neurologist. There's neurology and then the subspecialty is behavioral neurology. And we study mostly Alzheimer's and other dementing disorders like Lewy body disease. And initially in my research, I've been seeing patients here at Stanford for about 24 years now, and my research initially focused on imaging, looking at brain networks in patients with Alzheimer's disease. But about 14 years ago or so, I met this patient who came in with early onset Alzheimer's disease, meaning she got sick, started showing symptoms in her mid fifties, which is quite early for Alzheimer's. And what was unusual about this patient is that she was brought into the clinic by her healthy father and healthy mother. Usually we refer to this in genetics as a trio where we have the two parents and the child.

But in this case, instead of being in a child neurology clinic like for muscular dystrophy where we think about trios a lot, this was in a dementia clinic and I had not seen this situation before where these two healthy people in their seventies brought in their adult daughter who was sick with a dementing illness in her fifties. And that really sort of got me thinking about what is it that either the parents have that's protective or that the daughter maybe has an extra copy of that explains her increased risk. And we started with some basic genotyping. So a OE genotyping is something that we do pretty commonly now, a OE is an important gene. It's in all cells. It basically moves lipids, fats, cholesterol from cell to cell. And it's known one flavor of APOE is known to be the strongest risk factor for later onset Alzheimer's disease.

And so it turned out that she had one copy of APOE four, and that might explain potentially why she got sick in her fifties. Her father also had an APOE four variant, just one. So we assumed that he had received the variant from, or he had passed the variant onto his daughter, and maybe he wasn't sick because we think E four has a stronger effect in women than in men. But we hadn't yet genotyped the mother. And it turns out we had a sample on the mother when we genotyped her. She had two copies of APO APOE four, and this is essentially double the risk that her daughter has. And yet she was in her seventies and wasn't sick. So there was a lot floating around genetically in this trio. But that made me kind of focus in on what was it about the mother who had two copies of this very powerful risk gene, but was healthy into her seventies while her daughter was already sick in her fifties. And that really got me going on this exploration of genetics and Alzheimer's disease.

MAYA ADAM:

And what was it about? What did the mother have that was protecting her? Do we know

MICHAEL GREICIUS:

We haven't solved it? Sadly, no. But thinking about variants that can protect against a OE four, turn my lab's energy in a new direction, we have come across a couple other variants that are very powerfully protective against a OE four. None of them are in the mother though. So this trio got us interested in this question, but we still haven't solved, cracked the case in terms of the trio. And just as a reminder, the patient who came in her late fifties died about six years later from Alzheimer's disease. So as a reminder that this is a fatal illness and it will kill patients provided they don't die of something else like a heart attack or another condition. So the patient here died of Alzheimer's disease and her parents are both still living maybe in mom now with a little bit of memory trouble in her early eighties, but still double the dose of risk and 20 years more protected than her daughter. So yeah.

MAYA ADAM:

Mike, you mentioned that late fifties is sort of considered an early onset of the disease. How does the disease progression differ when it's early onset versus typical onset?

MICHAEL GREICIUS:

Yeah, it's kind of an open question. People have looked into this a fair bit. There's some evidence, I think it's fairly solid. We have some papers in this domain two suggesting that if you carry an a OE four allele, the one that increases risk for getting the disease in the first place, it probably also speeds the course a little bit. And so when we think about early onset is arbitrarily defined as symptoms before age 65, you'll see more a OE four carriers and not earlier onset group than if you look at 80 year olds that have Alzheimer's. At some point, we think age begins to trump the genetic risk factors, right? Age itself is a very powerful risk factor for Alzheimer's. And so as we get up into our eighties, April E four plays less of a role in Alzheimer's than it does people in their fifties and sixties. So yeah, we'll see more a OE four carriers in this younger group. And I think that the evidence is pretty solid that not only do they get sicker earlier, but their course is probably also revved up a little bit, goes a little faster with the a OE four allele.

MAYA ADAM:

And Mike, you reminded us that this is a fatal illness. And I'm just curious, I wonder if many of our listeners will also be curious, what exactly does a person die of with Alzheimer's disease?

MICHAEL GREICIUS:

Yeah, it's a really basic question. It's not one that people think about a lot. I mean, just to bring it back to epidemiology, most of our Alzheimer's patients are in their seventies and eighties, and they have other conditions like heart disease or kidney problems or diabetes. And so if they get sick at 75, they might die at 80 from congestive heart failure. And so maybe in those cases, Alzheimer's, the primary cause of death. But partic, it's just easier to see it when people are in their fifties and sixties without lots of other medical conditions. And what happens is, at the end of the day, a patient in the last stages of Alzheimer's disease looks essentially exactly like a patient in the last stages of Parkinson's disease. And the last stages of Lou Gehrig's disease, any neurodegenerative disorder people end up bedbound. They typically can't handle their own secretions even.

So they're at risk for saliva going down into the lungs and that can see a pneumonia. It's called an aspiration pneumonia. So at some point, Alzheimer's, in addition to affecting the memory centers, the language centers, visual spatial centers, behavioral centers, kind of the last set of brain regions to become affected are the motor centers. And people become bedbound and they succumb typically to infections that are frequent. And people that can't move anymore, they get skin breakdown and infection that way. They might get a urinary tract infection or a blood clot, but it's much more straightforward, I think, in younger patients to see that this is what kills them.

MAYA ADAM:

And can you take us through what is the experience and maybe what should people be looking for? Signs? We hear people joke all the time, oh, I'm getting so forgetful. I think I might have Alzheimer's disease, but in the real world, what should one be concerned about?

MICHAEL GREICIUS:

Yeah, so about 70, 75% of the time, the first symptoms that pre-stage Alzheimer's disease are short-term memory related. And so this is the events of the last more than two minutes ago and less than two weeks ago, for example. That's what we think. The hippocampus, the memory center of the brain is really important for remembering things that happened more than a minute ago, but less than two weeks ago. And so people were, some symptoms that we hear about that really make us pay closer attention. Not so much I went into the garage and I couldn't remember what I was going in there for. That is common, or I'm not as great at names at parties as I am everybody as a memory disorder specialist. When I go to a faculty party or something, I pray that they have name tags. I mean, it's just such an easy thing, why torture people?

But those sorts of things are more kind of age related. What we really worry about are repeating the same question two or three or four, or if you talk to some spouses 10 times in the course of a couple hours, that's obviously really worrisome. Or similarly telling a little anecdote like the neighbors forgot to take out their trash cans this morning, and then 20 minutes later, the neighbors forgot to take out their trash cans this morning. So there's really no laying down of a memory for recent questions or recent things that you've said. And then the other piece to that is misplacing things, but way more than they used to. I mean, everybody, I have six pairs of glasses spread around my house. These people early on will lose credit cards. They lose their car in the parking lot to the point that they have to go around with security in a car to find it. So some of it's sort of similar to what we think about with normal aging, but maybe a little amplified. And then some of it is just really quite distinct, like this repetitive question asking is a very worrisome sign.

MAYA ADAM:

Okay. I'm going to dive a little bit more into the weeds with you if that's possible, and then we'll sort of zoom back out. But can you tell us what's going on as far as we know inside the brain that causes these symptoms?

MICHAEL GREICIUS:

Sure. Yeah. So we have a reasonably good take on some of the key protein players. So we do think that Alzheimer's, like Parkinson's, Lou Gehrig's, there's a common theme across these neurodegenerative diseases, which is it seems that certain proteins, different ones for each disorder start to misfold and clump and aggregate, and they can aggregate inside the brain cells or kind of next to the brain cells. So in Alzheimer's disease, there's a lot of controversy about whether these anti amyloid antibodies, for example, are working sufficiently or truly, but there's really no getting around amyloid as a key player in Alzheimer's. So even, and I think you'll see Dr. Shaw and I differ a little bit in terms of our treatment approach to antiamyloid antibodies, and I don't use them, but I'm still convinced that amyloid plays a key role. It's more question of how best to target amyloid.

So amyloid is a protein that again, we see in all cells specific smaller forms of it are really prone to sticking to one another and aggregating. And so those amyloid plaques, those collections of thousands of these little peptides, these mini proteins aggregate outside of brain cells. And then the second protein that we kind of have the most information about is a protein called tau that also can misfold and aggregate similarly to the amyloid protein. But in this case, with tau, the aggregations are actually inside brain cells. And so it's a little easier to imagine how tau aggregations might literally gum up the brain cells and their function. But amyloid, we think really sort of gets the ball rolling all of the early, super early onset. So I've mentioned my patient who got sick in her fifties, a lot of the autosomal dominant or mutations that cause Alzheimer's disease in everybody that carries them, those people get sick in their late thirties or early forties.

And all of those mutations, they occur on three genes. And all three of those genes are tightly linked to amyloid. So whether it's in these very early onset cases where the genes are directly linked to amyloid, one of them is the amyloid precursor protein, for example, or even in later onset, like APO E four, we know that people that carry one or two copies of APO E four aggregate amyloid plaques in their brain even before they get symptoms. So there's no getting around amyloid. There's a lot of questions and controversies about how best to target it, but I think amyloid gets the ball rolling, and then at some point, tau becomes involved. Inflammation in the brain probably plays a role A OE may play yet another role related to synapses. The connections between brain cells, though there's a lot, we can kind pinpoint specific proteins, but how exactly this cascade unfolds is still pretty uncertain.

MAYA ADAM:

And we talked a bit at the beginning about how quickly this field is evolving. Can you tell us a bit about how the understanding of this black theory is maybe evolving or changing? Changing?

MICHAEL GREICIUS:

Yeah. I mean, so what's been most miraculous in my career over the last 20 years is around 2004 was the first demonstration of what's called amyloid PET imaging. So previously as one kind of harrowing example, the early clinical trials that we did before we had amyloid PET imaging, we would enroll patients based on our clinical prediction. We think this patient has Alzheimer's, they're forgetful, they have some brain shrinkage on MRI, but we couldn't see plaques in life at that time. A lot of those studies were kind of underway when amyloid PET hit the scene. And what we found is that in those studies where we had only used a clinical diagnosis, 25% of the time, patients didn't have amyloid in their brain. So we were wrong about the diagnosis in 25%. And these are typically referral centers, people who specialize in Alzheimer's. So we were wrong 25% of the time.

You can imagine how hard it would be to prove that your drug worked when only three quarters of the people in the trial actually have the disease to begin with. And so that was a real revelation. This capacity to take somebody, give them a little injection of a radio labeled tracer, radioactive tracer goes up into the brain. If they have amyloid plaques, it'll bind for a little bit and then clear out, and we can take a picture of the brain while this tracer is binding to the plaques. And so that has been really game changing in a lot of ways. One is it allows us to make a more definitive diagnosis in life. Of course, it's allowed us to enrich our clinical trials for people that were much more certain to have Alzheimer's disease because they have these amyloid plaques. And I think turning a little bit to this controversy or differences of opinion about whether amyloid plaque removing therapies are working, there's no question now that these Amy anti-amyloid antibodies are removing amyloid plaque from the brain, we can see it coming out. Essentially you take a picture of somebody's brain before they get the treatment, and six months later and the amyloid plaque has come out the problem, it's not clear that the patients are doing better clinically, but for all those reasons, these new, we call them biomarkers, new ways to see if there are amyloid abnormalities or even tau abnormalities. We have tau PET now also has really changed the field. We're really good at making the diagnosis and now we need to get really good at treating.

MAYA ADAM:

Mike. What is it like between leading experts in a field like this when there is this maybe slight difference of opinion? Is it very collegial? Is there tension? I mean, how does that work? What's the atmosphere?

MICHAEL GREICIUS:

Yeah, it's funny. I'm trying to think if I would agree that there are slight differences in opinion. I mean, it's pretty stark. So I'd say there's a reasonable minority. Maybe 25% of behavioral neurologists if you did a survey, would say, I really don't think these anti amyloid antibodies are working at all. Another 20% might say, well, it's definitely getting rid of the plaque. Actually, everybody would agree it's getting rid of the plaques, but maybe another 20% would say it's got a very small effect, but I believe it's a real biological effect. And then maybe whatever that leaves 40, 50% of neurologists say, look, it's getting rid of plaques. We think plaques are what, get the ball rolling and we see a little bit of a clinical benefit. We just need to treat longer. We need to add other therapies. So they're pretty widely varying approaches or interpretations rather of anti amyloid therapy.

It's largely collegial. It's certainly collegial within our division. About three of us don't use these meds, and four of us do, and we meet every Friday and we all discuss patients that are being considered for it. We want to do this very carefully. So we do it as a team. And that's very collegial at conferences. I think especially conferences where there's a lot of pharmaceutical company participation, it's hard. I still get anxious going to the microphone saying, Hey, wait, I'm not sure that these findings are legitimate because of X, Y, and Z. It's hard to get up and sort of offer the minority opinion in these settings. It's still collegial, but you definitely feel like the odd person out a little bit.

MAYA ADAM:

Fascinating. Okay, so what are the other pieces of the puzzle? Can you talk to me a little bit more about things like genetics and ancestry and how those things play a part possibly in this disease?

MICHAEL GREICIUS:

Yeah, so like I said, I think we can't get around the fact that amyloid plays a role. Amyloid comes in a bunch of different forms. So the smallest form is when the precursor protein, the big part of the protein gets cut and it gets cut into these little, what we call peptides. They're like small parts of a protein. And the 42 building block form of this peptide is the one that tends to aggregate, but you can see that peptide by itself. We call that a monomer. So one copy of the peptide, you can see four of them binding together, you can see 12 of them binding together. And when you have four or 12 together, they're called oligomers just so you can have a single peptide, you can have four 12 of them lumping together. Then you can have proto fibrils, which is hundreds and thousands, and then you get at the last stage, you get these big chunky plaques that again, are occurring outside of brain cells, not inside of brain cells.

You can imagine there are at least six different targets along that pathway that you could try and go after. Mostly we've been going after the plaques, and I personally don't think that's working. I think those plaques might be kind of inert collections of the protein, maybe pulling these smaller species out of circulation into a sort of safe repository or something. I'm not sure, but it seems pretty clear that getting rid of the plaques hasn't helped much, if at all in patients with Alzheimer's disease. Tau I think is an interesting target. I mentioned that tau tends to cluster inside of brain cells, and if you look at a brain map of PET scan where you see the tau changes are typically the regions of the brain that are actually sick. So for example, the memory centers, the hippocampus early on, you don't see amyloid plaques in the hippocampus even though patients are forgetful and have memory trouble.

But right off the bat, as soon as people have memory problems, if you do a tau PET scan, you'll see the tau aggregating in the memory centers. So tau tends to map a lot more closely with the parts of the brain that are actually affected and sick in Alzheimer's. So tau iss a really interesting target, and people are approaching that now in different ways. There's an antibody or a few antibodies have been tried against tau. Those haven't worked too well. The thing that I'm kind of most excited about lately is an approach that if you know that a particular gene or protein is bad, just broadly defined, there are different ways now to actually knock down that specific protein. And one of them is the term is a SO, it stands for antisense, algon nucleotide, kind of a mouthful. But basically these are very targeted little collections of nucleotides, about 18 or 20 nucleotides that very specifically target what you're sure is a bad gene.

And so we've tried this. The field have tried this in Alzheimer's disease to knock down the tau protein, and this is done with a little bit of injection of this medicine into the spinal canal by a lumbar puncture. Very easy to do, very safe, doesn't hurt. It sounds scary, but it isn't. And in doing this study now kind of moving into phase two studies, it's very clear that this medicine is actually pulling the aggregated tau out of the brain. So just like the antiamyloid antibodies pull amyloid out of the brain, these assos against tau are pulling tau out of the brain. It's too early to be sure if this is working clinically, but tau is such a good target because it kind of marches in step with parts of the brain that are sick. It seems like getting rid of Taos should be helpful, but we'll have to see.

MAYA ADAM:

Wow, that's exciting. Mike, lemme zoom out again for a moment and ask you what is it like to have a conversation with someone because you study these very small components of what's going on in the brain, but then you're also caring for a human being. And I wonder what it's like to have a conversation with somebody when you have to deliver this news and whether there's a technique there or how do you approach that?

MICHAEL GREICIUS:

Yeah, I mean, well, for one thing, I try and bring an honest level of optimism to it. I mean, even if I don't believe that these anti amyloid antibodies are working, I do have faith in science, faith in for the time being the research infrastructure in the United States that we're going to deliver. I think, I don't know if it's two years or 10 years, but I think I'll be still practicing hopefully when we get something that's a lot more potent and definitive. So I have that in my sort of back pocket as I'm beginning to lay out the findings and why I think this is most consistent with Alzheimer's disease and what this means. I emphasize that this is not a rapidly changing disorder, typically. It's not like Lou Gehrig's disease or other things that move pretty quickly. We have the sort of luxury of time, and oftentimes it's pretty uncommon these days where if say on the second clinic visit, the patient and the family aren't anticipating that that's cooking anyway.

I mean, people just in the lay press see and read a lot about Alzheimer's disease and when they're presenting with a couple years of memory trouble, often it's something that they've been thinking about. Anyway. I like to think that some of these biomarkers that we can offer now, which provide really essentially definitive in life diagnosis of Alzheimer's, which we didn't have 15 years ago at least, helps limit the sort of unnecessary search and unnecessary testing and lets people focus on the problem at hand. It's some combination of those things. It comes out sort of more naturally when I don't have to deconstruct it, but it's helpful to think about the information I want to convey and how to convey it in a way that isn't serious. There's no way you can work around that, but at least that provides some hope and optimism about treatments, if not now down the line

MAYA ADAM:

For older people. Right now, both of my parents are in their eighties. Is there anything they can do to prevent the onset of this disease?

MICHAEL GREICIUS:

No, is the short answer. Different people will play up the side. I think of things differently. There are lots of studies. They're essentially all retrospective, meaning you kind of look back at how people have lived over the last 20 years and you sort of separate people with Alzheimer's disease from people same age that don't have Alzheimer's. And lo and behold, they had one or two glasses of wine rather than no wine or 10 glasses of wine, or they took statins for 10 years. These guys didn't take statins at all. The problem with all of those studies, and there are tons of them, and they're always in the New York Times Science Times Tuesday section, is that they're retrospective and somebody that only has one to two drinks per week over 30 years probably has lots of other characteristics that might be the protective ingredient against something like Alzheimer's disease.

So those are supposed to be hypothesis generating studies. You do this retrospective study and say, oh, it looks like one to two glasses of wine is protective. The next step is to actually test that in a prospective study. And that is almost never done. It's almost something. So statins, for example, NSAIDs, things that looked in retrospective studies like they were protective, haven't borne out in the definitive trial like a placebo controlled trial of a statin or an NSAID to try and slow Alzheimer's or prevent it. So I don't want to be nihilistic on this topic, but I also don't want people to spend unnecessary amounts of money on supplements and things like that. The recommendations I give are what any internist would give to their patient, a hard smart diet, as much aerobic exercise as you can do, very minimal if any alcohol, no illicit drugs, those sorts of things. But yeah, I don't foist Sudoku or crosswords on people. I think it's important to be engaged socially, but I think real world social engagement, hanging out with your family, reading books, watching a little bit of the news, but not watching eight hours of Rachel or Fox, whatever your preference is, I think that it's probably helpful almost more for mood than for cognition. Right.

MAYA ADAM:

Interesting. Okay. So in terms of genetics versus environment, we don't think there's a lot of environmental influence here, or is there?

MICHAEL GREICIUS:

No, I think there probably is a fair bit. I just don't think we're very certain what accounts for that yet. So the estimates are probably 60% or so, maybe a little bit more. 60 to 70% of Alzheimer's has some genetic component to it, but that leaves at least 30%, maybe closer to 40% of the variability in somebody's presentation. That's probably linked to environmental factors, but that's kind of broadly defined. That could be things like going through menopause that's broadly defined, non-genetic, that's more environmental. It's the internal environment in a woman, but still not genetically determined necessarily. In terms of risk factors, really, the very few things have held up and been replicated across studies. Head trauma is probably the most reliable risk factor, but even that is not particularly potent. We see people that have had lots of concussions that never get Alzheimer's and plenty of people that get Alzheimer's without ever having a head injury.

But of all the things that have been looked at, I'd say that head trauma is probably the best supported aerobic exercise, I think is a little mixed up, a little bit with vascular risk. So people who do more aerobic exercise might have less likelihood of developing small strokes, and those small strokes can contribute to dementia. But the evidence that aerobic exercise really protects against Alzheimer's disease. Pathology specifically is quite thin actually right now, but you'd still want to minimize vascular risk factors because vascular changes in the brain can exacerbate or make a dementia mild dementia look worse. Yeah. So it's tough. The environmental stuff is not well sort of sussed out yet. I don't think,

MAYA ADAM:

Mike, for getting near the end of the interview, and I just have a couple of last questions for you. The first one is, what would you say brings you the most hope in this field that you work in?

MICHAEL GREICIUS:

Yeah, so I think the advances that we've made over the last 10 or 15 years in terms of really getting a definitive diagnosis in life is really helpful. It's going to make our clinical trials much more definitive even when they're negative, right? At least we know we're trying these medicines on the right patient population. That's been a huge advance. I think patients are really motivated, certainly at Stanford. We have an Alzheimer's disease research center here. A lot of our clinical patients enroll in that. So the motivation of patients and their families to participate in trials, even when the trial doesn't involve a drug like the Alzheimer's Disease Research Center is a longitudinal study. We follow patients urine and year out. They give us to their blood, their spinal fluid. At the very end of the day, they give us their brains in donations. So we're going to get there that there's a lot of data that comes with every donation like that, every blood sample, every spinal fluid sample, certainly every brain donation.

And the other thing that gives me hope is that these Alzheimer's disease research centers, as they currently stand in the us, there are 35 of them around the country. Everybody does the same assessments and everybody deposits their data in the same repository. And so we have this real, incredibly large collection of data now that's available to researchers across the country and across the globe actually. We make these data available to everybody. So I think this has been massively crowdsourced. Now, there's tons of data and you throw AI and new approaches into the mix, and I think we're going to get to something quite definitive in terms of treatment in the next two to 10 years. I keep making it pretty broad window. I don't want to be held to account if we don't have a treatment in two years,

MAYA ADAM:

When I can imagine that this is sometimes exhausting work, and when you get to a point where you're like, we have been working on this for years and years and we're still working on it, what keeps you going?

MICHAEL GREICIUS:

It is it can be a little tough at this point. I only see patients a half day a week, in part because it is as a physician, a lot of why many of us went into medical school is to help people in a sort of concrete and obvious way. I think I help my patients and my families in various ways, but I can't pretend that I'm helping them in terms of a definitive treatment yet. And so I do need to look elsewhere for inspiration sometimes. And I'll tell you, so I mentioned this, a SO antisense oligonucleotide, just think of it as a very gene specific approach to treatment. And what's incredible to me, and this is something I had not seen in 30 years of being in neurodegenerative diseases, was that this a o approach was used in a disorder called Spinal Muscular Atrophy, or SMA.

This is essentially Lou Gehrig's disease in infants. It's one of the most really devastating neurodegenerative diseases you can imagine. It moves very quickly, and it doesn't just affect 40 year olds or 50 year olds. It affects infants, right? And this was uniformly fatal, but about five or six years ago now, the first trials using this a SO approach, were completed in SMA, and now we're seeing these kids living at age five, age six. We assume that, that they're cured. We've never seen kids with this disease at this age. And so that to me really said, look, we've taken the world's worst neurodegenerative disorder and it's been cured with this gene specific approach. This is going to work in other disorders, hopefully in Alzheimer's. And there are a SO trials now kind of underway in Alzheimer's disease targeting these various proteins. So yeah, I mean, I think, like I said, even with all my gray hair now, I used to say when I started 30 years ago, within five years, we should have something. Now I broaden that window a little bit still, but I think we're very close to delivering more definitive treatment for patients.

MAYA ADAM:

Well, we are so grateful to you for all the hard work and the day in and day out that you spend trying to solve these puzzles, and thank you so much for making the time to speak with me.

MICHAEL GREICIUS:

My pleasure. Thanks for covering the topic. It's an important one. I agree with you there.

MAYA ADAM:

Thanks, Mike.