S2 Ep1: What do we know about Alzheimer's disease and what brings us hope?

0:06Welcome to Health Compass. I'm your host, Maya Adam, Director of Health Media Innovation at Stanford Medicine.

0:14Michael Greicius:As a memory disorder specialist, when I go to a faculty party or 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, ten 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. 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.

0:54And 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 Gracious, a professor of neurology and neurological sciences, and Sharon Shaw, a clinical professor also working in this field.

1:41Together, 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.

2:11Michael Greicius:Hi, Maya. Thanks for having me. Mike, I wonder if I can start by asking you what drew you into this line of work? Yeah, well, in medical school, I, you know, kind of bounced around between possible specialties. I thought I was interested in surgery and quickly ruled that out. It takes a very certain type of individual to go into surgery. And then I was thinking about sort of medicine-related specialties. I had a class in the neurosciences in our second year where one of my mentors, Richard Mayhew at Columbia, interviewed a patient who had suffered a stroke and had what's called a Wernicke's 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.

2:54Michael Greicius:And I was really taken with this disconnection between, you know, 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, you know, this is a fascinating subspecialty. And, you know, the mind is sort of what captivated me about neurology. And that's what sort of drew me in. 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? Yeah, there is one case in particular, I think, that really kind of pushed me into genetics.

3:36Michael Greicius:So I'm a behavioral neurologist, right? 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-50s, which is quite early for Alzheimer's.

4:11Michael Greicius:And what was unusual about this patient is that she was brought into the clinic by her healthy father and healthy mother. And usually we refer to this in genetics as a trio, right, 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, you know, these two healthy people in their 70s brought in their adult daughter who was sick with a dementing illness in her 50s. And that really sort of got me thinking about, you know, what is it that either the parents have that's protective or that the daughter, you know, maybe has an extra copy of that explains her increased risk.

4:55Michael Greicius:And we started with some basic genotyping. So APOE genotyping is something that we do pretty commonly now. APOE 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 sort of later onset Alzheimer's disease. And so it turned out that she had one copy of ApoE4, and that might explain, you know, potentially why she got sick in her 50s. Her father also had an ApoE4 variant, just one. So we assume that he had received the variant from, or he had passed the variant on to his daughter, and maybe he wasn't sick because we think E4 has a stronger effect in women than in men.

5:38Michael Greicius: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 ApoE4, and this is essentially double the risk that her daughter has, and yet she was in her 70s and wasn't sick. So there was a lot kind of 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, you know, into her 70s while her daughter was already sick in her 50s. And that really got me going on this exploration of genetics in Alzheimer's disease.

6:15And what was it about, what did the mother have that was protecting her? Do we know?

6:20Michael Greicius:We haven't solved it, sadly, no. But, you know, thinking about variants that can protect against APOE4, turn my lab's energy in a new direction. We have come across a couple other variants that are very powerfully protective against APOE4. None of them are in the mother though. So she sort of, this trio got us interested in this question, but we still haven't solved, you know, cracked the case in terms of the trio. And just as a reminder, the patient who came in in her late 50s died about six years later from Alzheimer's disease. So as a reminder that this is a fatal illness, and it will kill patients, you know, provided they don't die of something else like a heart attack or another condition.

7:03Michael Greicius:So the patient here died of Alzheimer's disease, and her parents are both still living, maybe mom now with a little bit of memory trouble in her early 80s, but still, you know, double the dose of risk and 20 years more protected than her daughter. So, yeah. Mike, you mentioned that, you know, late 50s is sort of considered an early onset of the disease. How does the disease progression differ when it's early onset versus typical onset? 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 too, suggesting that if you carry an ApoE4 allele, the one that increases risk for getting the disease in the first place, it probably also speeds the course a little bit.

7:54Michael Greicius:And so when we think about, you know, early onset is arbitrarily defined as symptoms before age 65. You'll see more ApoE4 carriers in that 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 80s, ApoE4 plays less of a role in Alzheimer's than a dozen people in their 50s and 60s. So yeah, we'll see more ApoE4 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, you know, goes a little faster with the ApoE4 allele.

8:40And 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?

8:54Michael 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 70s and 80s, 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, right? And so maybe in those cases, Alzheimer's isn't the primary cause of death. But particularly, it's just easier to see it when people are in their 50s and 60s 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, in the last stages of Lou Gehrig's disease.

9:37Michael Greicius:You know, any neurodegenerative disorder, people end up bed bound. They typically can't handle their own secretions even. So they're at risk for saliva going down into the lungs. And that can seed a pneumonia, what'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 bed bound. And they succumb typically to infections that are frequent in people that can't move anymore. They get skin breakdown and infection that way.

10:11Michael Greicius: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. Yeah. And what is, can you take us through sort of what is the experience and what maybe, what should people be looking for, for signs? You know, we hear people joke all the time, oh, you know, I'm getting so forgetful. I think I might have Alzheimer's disease, but like in the real world, what should one be concerned about? Yeah. So, you know, about 70, 75 % of the time, the first symptoms that sort of pre-sage Alzheimer's disease are short-term memory related.

10:53Michael Greicius:And so this is the events of the last, you know, 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, you know, remembering things that happened more than a minute ago, but less than two weeks ago. And so people worry some symptoms that we hear about that really make us, you know, pay closer attention. Not so much I went into the garage and I couldn't remember what I was going in there for, right? That is common. Or I'm not as great at names at parties as I am in my, everybody like as a memory disorder specialist, when I go to a faculty party or something, I pray that they have name tags, right?

11:28Michael Greicius:I mean, it's just such an easy thing. Like 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.

12:00Michael Greicius: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, right? But these people, you know, 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, right? 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. 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.

12:39But can you tell us what's going on as far as we know inside the brain that causes these symptoms?

12:46Michael 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, like 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, you know, 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.

13:22Michael Greicius:So even, you know, and I think you'll see Dr. Shaw and I differ a little bit in terms of our treatment approach to anti-amyloid antibodies. But, and, you know, I don't use them, but I'm still convinced that amyloid plays a key role. It's more a question of kind of how best to target amyloid. So amyloid is a protein that, you know, 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.

14:02Michael Greicius: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 mentioned my patient who got sick in her 50s. 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 30s or early 40s. And all of those mutations, they occur on three genes, and all three of those genes are tightly linked to amyloid.

14:48Michael Greicius:So, you know, 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 ApoE4, we know that people that carry one or two copies of ApoE4 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. ApoE may play yet another role related to synapses, the connections between brain cells.

15:25Michael Greicius:So there's a lot. But, you know, we can kind of pinpoint specific proteins, but how exactly this cascade unfolds is still pretty uncertain. 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 plaque theory is maybe evolving or changing? 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.

16:08Michael Greicius: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 that's, you know, 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.

16:47Michael Greicius:And so that was a real revelation, this capacity to take somebody, give them a little injection of a radiolabeled 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.

17:24Michael Greicius:And, you know, 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 anti-amyloid antibodies are removing amyloid plaque from the brain because 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 is 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.

18:01Michael Greicius: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. 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 like? Yeah, it's funny. I'm trying to think if I would agree that there's slight differences in opinion. I mean, it's pretty stark. So, you know, I'd say there's a reasonable minority, maybe 25 % of like behavioral neurologists, if you did a survey, would say, I really don't think these anti-amyloid antibodies are working at all.

18:45Michael Greicius: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, you know, it's got a very small effect, but I believe it's a real biological effect. And then maybe, you know, 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, you know, widely varying approaches or interpretations rather of anti-amyloid therapy.

19:19Michael Greicius:It's largely collegial. It's certainly collegial. Like 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, you know, it's hard. I still get anxious going to the microphone saying, hey, wait, I'm not sure that, you know, these findings are legitimate because of X, Y, and Z. Like it's hard, you know, to get up and sort of offer the minority opinion in these settings.

19:57Michael Greicius:It's still collegial, but you definitely feel like the odd person out a little bit. 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? 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.

20:37Michael Greicius:And the 42 kind of building block form of this peptide is the one that tends to aggregate. But it can be, 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. So you can have a single peptide. You can have four or 12 of them lumping together. Then you can have protofibrils, which is hundreds and thousands. And then at the last stage, you get these big, chunky plaques that, again, are occurring outside of brain cells, not inside of brain cells.

21:13Michael Greicius:And so 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, you know, 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.

21:47Michael Greicius: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, 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 is a really interesting target and people are approaching that now in different ways.

22:26Michael Greicius: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 ASO. It stands for antisense algonucleotide, 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.

23:01Michael Greicius:We, the field, have tried this in Alzheimer's disease to knock down the tau protein. And this is done with a little bit of an injection of this medicine into the spinal canal via 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 anti-amyloid antibodies pull amyloid out of the brain, these ASOs 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 tau should be helpful, but we'll have to see.

23:48Wow, that's exciting. Mike, let me zoom out again for a moment and ask you, what is it like to have a conversation with someone? Because, you know, you study these very small components of sort 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?