The future of Alzheimer’s treatment
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S-T-A-N-F-O-R-D dot E-D-U. Thanks very much. But I'm optimistic that we're going to get to small molecule therapies that can cross the blood brain barrier and are less of a sledgehammer effect, not just knocking tau down, but impacting the way tau's interacting with cells.

This is Stanford Engineering's The Future of Everything, and I'm your host, Russ Altman. If you enjoy The Future of Everything, please follow it in the app that you're listening to right now. It'll make sure that you never miss the future of anything. Today, Mike Gracious of Stanford University will tell us that the recent approval of Alzheimer's disease drugs by the FDA may be a little disappointing. The evidence that they're going to work is not very strong. He's not a believer. But he's going to tell us that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the FDA is going to make sure that the

but he is a believer that our research infrastructure is starting to generate new ways to measure the disease and intervene that may lead to better treatments in the long run. It's the future of Alzheimer's disease. Before we get started, remember to follow this podcast in the app that you're listening so that you'll always be alerted to new episodes and you'll never miss the future of anything.

Many of us have seen what Alzheimer's disease can do and its devastating effects on families. We may have a friend, family member, or colleague who suffers from the disease. We really don't understand the cause of Alzheimer's disease. And in fact, we know that there are molecules, they're called amyloid, tau, APOE, that are involved in the disease. But the treatments have been hard to find despite huge investments in research.

Indeed, the FDA has recently approved some drugs for Alzheimer's disease, but there are a lot of doubters that these drugs are really going to make a difference. Well, Michael Gracious from Stanford University is a professor of neurology and neurological sciences and an expert on Alzheimer's disease.

He's gonna tell us why he doesn't think the latest generation of drugs is really gonna make a dent in the Alzheimer's disease epidemic. But he will tell us that there are new ways of measuring the disease and new leads for other treatments that may pan out and lead to the kinds of treatments that we all wanna see.

Mike, you're an expert at Alzheimer's disease. It's something that many of us have dealt with in our families, friends, colleagues. What is our current understanding of the causes of Alzheimer's disease? Yeah, first for us, thanks for having me. It's something we've been studying now for more than 100 years since the first case was described. And we have a pretty reasonable take on some of the key players, I think. So beta amyloid is a protein that's been implicated early on. There's a second protein called tau.

But beyond identifying these single proteins, we still don't have a great sense for this sort of pathogenic pathway and where it would be best to intervene. So it's been cobbled together over many decades, but I'd characterize it as still an incomplete understanding.

Which is amazing, given the prevalence of the disease and how devastating. And I know there's been a huge public investment in research. So you mentioned these two magic words that we see in the news all the time. And I think they're relevant because I think we're going to talk about approaches towards therapies that are very much hinged on these. So tell me a little bit about this amyloid and tau. What are they and why do they get the headlines?

Sure. So amyloid comes from a protein, and it comes from a gene called amyloid precursor protein, which everybody has. The protein is made in many different cells. It's still remarkably unclear what the primary role of this protein is in cells, but it was implicated early on in Alzheimer's disease because some of the nastiest mutations that cause very early onset of disease actually occur on this gene, so amyloid precursor protein itself.

You may know that patients with Down syndrome who have three copies of chromosome 21, that's where the amyloid precursor protein lives. If they live long enough, and these days they are past 40 or so, essentially all of them develop Alzheimer's disease pathology. And we think that's because they have this extra copy of the amyloid precursor protein gene. So all the early genetic evidence, there are two other genes that are tightly linked to amyloid precursor protein genes.

All the early genetic evidence points very directly to amyloid precursor protein and its product, beta amyloid. So there's no getting around, you know, an early role of amyloid in this process. Tau, the second protein, comes from a gene called MAPT.

microtubule-associated protein tau. And like the gene name suggests, tau is an important protein for sort of stabilizing microtubules. These are the sort of inside skeleton of cells that are really critical, again, throughout the body and also, you know, obviously in the brain.

Okay, so those are our players and they're both kind of headliners when we read about what I want to ask you about, which is people want treatments, right? We were used to having treatments for our diseases and we read about, and there's been some high profile approvals recently and I want to get to those. But before that, what are the challenges of even thinking about, I imagine the challenges of thinking about a treatment for Alzheimer's disease are very significant because this is a long process that starts

well before you get clinical symptoms. And so I can imagine that just thinking about how you would discover drugs, how would you do tests to make sure the drugs work? So maybe tell me what are the challenges in developing of therapies, and then we can go to these newly approved drugs and how promising they are. Okay.

Sure. Yeah. I mean, I think there are several. I sort of feel like an apologist for all brain disorders, right? I mean, it's not only Alzheimer's that's lagging, right? We'd love to have stronger therapies for Lou Gehrig's disease or ALS. We've made some headway in Parkinson's and epilepsy, but we don't have curative treatments. And one big difference, we kind of envy the cancer world for all these incredible treatments that have come out in the last 10 or 20 years.

One big problem, as you know, is it's tough to get drugs across the blood brain barrier. So the brain sort of protects itself, you know, presumably from infections and has this very tight barrier that's hard for things to move across, including drugs. So that's one big obstacle that we face that, you know, we don't, you know, physicians who treat cancer patients, for example, typically don't face drugs.

A second big problem specific more to Alzheimer's disease is that the mouse models are really, for lack of a better word, crummy in Alzheimer's disease. And we end up throwing at least two, often three, nasty human mutations into these mouse models so that they get amyloid, but then they also get tau. Even with all these nasty mutations, there's not a great sort of degeneration of neurons that happens typically.

Age is hard to model, which is a big factor in Alzheimer's disease. So the mouse models are really limited. They're not useless. I don't want to be nihilistic about it. But what we can glean from mouse models is pretty restricted, I think. And it's sort of, I think, mainly those two issues, blood-brain barrier and really no great animal models that have slowed us down.

If we did have, let's say, and we'll get to these drugs, I don't mean to delay the discussion, but if we have a therapeutic, is it clear how to do trials with something that is supposed to stop something from happening maybe 10 or 20 or 30 years from now? You don't hear about clinical trials that

last for 30 years. So, and especially now with what you just said about the mice not being a great model, how do you build confidence that you can stop this disease from spreading or developing when it's such a long timescale?

Yeah. And that's a, you're right, a third sort of tough piece that's, I think, not unique to Alzheimer's disease. I think Parkinson's, for example, also probably has a long prodrome, but we've really mapped it out. I mean, one of the huge advances in the last 10, 15 years in Alzheimer's disease is our ability to really map the disease in life with what we call biomarkers, which is just a funny name for tests, basically. And this has been, you know, something that should be celebrated and has really helped our clinical trials as kind of, you

you know, unfavorable as the outcomes have been, I think the trials are getting run better and better because of these biomarkers. So now we can identify people, like you said, 10, 15 years before we expect them to get symptoms. So when the amyloid pathology first kicks in, we think it's another, you know, five or 10 years before we see the tau pathology, and then another five years before people actually start to show, for example, memory symptoms.

So we have this long prodrome that we've known about, but now we can actually kind of map out. And that, on the one hand, is a very powerful tool and should help us run these trials better. But to your point, there aren't a lot of pharmaceutical companies that are interested in running 10-year or 15-year trials of true primary or secondary prevention. They're too expensive to

Things move very slowly in Alzheimer's disease. It would take large sample sizes and years and years to run those studies, which would, you know, at some level be optimal, but they're just not that pragmatic.

Great. And let's come back to those biomarkers because I know you're excited about them and that there has been this explosion of innovation in that area. Let's go to these drugs. So there's been some recent approvals even within the last couple of weeks in different regulatory regions. What are the current –

Why are we seeing this in the news so much? What is the controversy about these drugs? What do they do? I presume it has something to do with amyloid and or tau. And then how well do they work and how excited are people about them? Yeah, so it has, you know, I sort of,

preface these sorts of conversations with this notion that we, in respect to the pharmaceutical industry, we gave them this target from mouse models, which was to get rid of amyloid plaque. And 10, 15 years later, they actually delivered and they're getting rid of amyloid plaque in the brain, which

which in and of itself is miraculous. The real unfortunate piece of this is it seems like getting rid of amyloid plaques really isn't helping the clinical picture. And there could be a bunch of reasons for that. One might be, and this argument is still made, you know, where it's just not starting early enough, right? If you

identify people in your trial who have amyloid plaque and have even mild cognitive impairment, that means that plaque's probably been in place for at least five years or 10 years. So could you define for me plaque? This is a new word, and we know a little bit about amyloid, but just tell me what an amyloid plaque is. Yeah, right. So amyloid exists in several different forms, sort of a spectrum of forms. So the basic form is what we call a monomer, just one copy of this 42 amino acid peptide, so 42 little building blocks.

of this small piece of the protein that we call a peptide. There are monomers. Monomers can join together to form dimers or tetramers or what are called oligomers. So different numbers of these peptides kind of clump together. And at the end of the road is this large collection of monomers all lumped together and taking on a particularly...

insoluble state, meaning thousands of these peptides that are really hard to pull apart. That's what we mean by it. And they're kind of mucking up the cell is my understanding. That's one of the big hits against amyloid plaque as a target is they're not actually in the cells, they're between the cells. And that's a really salient point, I think. But yeah, the notion is that they're mucking up the works, even if they're not in brain cells themselves, they're nearby and they might be interfering with communication between cells for

Okay, so I'm sorry I interrupted you, but now we know what a plaque is. It's this mucking up big kind of conglomeration of multiple amyloid molecules. And you said that, I liked how you put it, that you gave a challenge to the pharmaceutical, you, the field, gave a challenge to the pharmaceutical industry, let's get rid of those plaques, and it sounds like they have drugs that can do that.

They have drugs that can do that very well. So this is now 15 years into or 10 years into the anti-amyloid antibodies in humans. And as it will kind of come out over the course of our discussion, I'm actually an anti-anti-amyloid antibody. There you go. I got that position. But the history has been informative. I think we've learned a lot along the way. And what we've seen is that antibodies,

So we give these typically as an infusion, you know, in a vein in your arm. Antibodies aren't great at crossing the blood-brain barrier. That's one problem. But if you give a big enough dose in the periphery, enough will get in. And those antibodies that particularly target the plaque form or the sort of pre-plaque form of amyloid have actually proven quite good at removing it. So over, you know, 16 weeks, 24 weeks, people will go from amyloid positive, many of them to amyloid negative. So, you know,

I don't think anybody has, would contend the fact that these things are very good, especially the two or three most recent ones at removing amyloid plaque from the brain. So that part's sort of unassailable and that's the target that we gave big pharma and they hit it. And then, you know, the sort of dispiriting piece of this is that it's really not impacting clinical outcomes. And this is where things get a little more controversial in terms of

What constitutes a meaningful clinical outcome? Can we really believe the results at face value, which I have some trouble doing? And even if we did take them at face value, would it be worth it? But I think that question, you know, if we take it at face value, would it be worth it, is important.

One that we can table because. And I just want to highlight the use of the word worth because these are not cheap drugs. And so people are making potentially life altering decisions about the allocation of their resources, their money to either buy these drugs or not. And they're looking for guidance about, well, will this help me or my relative or my loved one, you know, not suffer from this disease? And it sounds like the answer there is still unclear. Yeah.

Yeah, I mean, the answer to me is it's not going to help them. And I don't recommend it for my patients. I don't prescribe it. I think the answer for people who prescribe it is, you know, this is not curative. It may slow the progression of disease by a small amount over, you know, six or 12 or 18 months.

But, you know, I think everybody who prescribes this openly and honestly makes it clear that patients will continue to decline. That was true across all the trials. Nobody stabilizes. Nobody gets better. But, you know, for me, I'm not even convinced that there's a meaningful separation between active treatment and placebo for these studies. Yeah. So it's really interesting because you've written a detailed analysis, which I've read, of, you know, kind of your questions about these trials that were used as the evidence. And...

Your analysis is very detailed, but I wonder if you can give us, I think there were like three main points that you made. And could you summarize, because I think they're very accessible, like, okay, that makes sense. That is a problem. And so maybe could you summarize for a non-expert what those problems with the trials were? Yeah. So one of the first big hurdles that I think people have to get over or come to understand is that

In none of the trials is there a correlation between how much amyloid is removed in a given subject and how likely that subject is to do clinically. So if you believed, and this is despite the fact that the FDA, in a pretty controversial decision, declared amyloid plaque as a biomarker that was likely to predict cognitive outcome.

That was very controversial because we've known for a long time from postmortem studies, detailed postmortem studies, that where you see this amyloid plaque in the brain, we already mentioned it's not inside cells. But even regionally where you see it in the brain are not typically the parts of the brain that get sick early on. So, for example, the hippocampus, which is the memory center, which is sort of ground zero for Alzheimer's patients.

Pathology actually doesn't have amyloid plaques in the early stages. Parts of the medial prefrontal cortex up here, which are spared functionally for a long time in Alzheimer's disease, are one of the first places to lay down amyloid plaque. So there's a big disconnect regionally, which neurologists always care about, you know, between where you see plaque in the brain and which parts of the brain are sick.

TA, which we'll get to, actually tracks very closely with the parts of the brain that are sick. But in any case, you know, the FDA decided amyloid plaque is a biomarker that's likely to predict cognitive outcome. And so they could sort of fast track some of these studies.

But we know from postmortem studies that this wasn't the case. We learned again with the advent of these PET scans where we can see amyloid plaque in living humans that, you know, once again, we learned that where you see the plaque isn't, you know, the parts of the brain that are sick. So, for example, people that have a very language predominant initial presentation for Alzheimer's, their memory might be OK, but they have lots of word finding, lots of language trouble, etc.

If you look at their brains, the parts of the brain that are sick are in the left hemisphere, right, the language hemisphere. Their tau pattern will show that. There'll be more tau in the left brain than in the right brain. But their amyloid PET scan pattern will look exactly like the amyloid PET scan pattern of somebody that has a memory presentation or somebody that has a visual spatial presentation. Amyloid plaque is always laying down in the same places, and they're not really associated with a sick brain.

Very good. Okay, that's very clear. So it's like a smoking gun that's in the wrong place. And so it's just not adding up from your neurological knowledge of where you should be seeing problems and where you are seeing problems. Right, exactly. And now we've kind of learned it the hardest way, I think. So there was postmortem data, then there was imaging data, which confirmed that postmortem data plaque isn't a good target. And now we've been removing and people really aren't doing better.

But I think the one piece that people really still don't understand because it's sort of swept under the rug is this notion that if you look at, you know, a thousand patients in a trial, there is no, we'd like to see a correlation. Those that had the most amyloid removed should have done the best in terms of their clinical outcome. There's no correlation across the three, you know, FDA approved anti-amyloid antibodies. None of them show this, you know, expected correlation. Yeah.

Yes, that harkens me back to these postulates. When you're trying to prove that something works, there should be kind of a dose-response curve, that if you get more of the effect, you should get perhaps more of the benefit, and you're not seeing that in these trials. One final thing I want to ask you about before we take a break is...

You talk about functional unblinding, which I thought was a very interesting phrase. And you think that that could also be a dynamic in some of these trials. Can you tell me what that is? Yeah. So, you know, functional unblinding refers to the double blind, which is, you know, part of the bedrock, one of the bedrock principles of clinical trial science. We want, you know, ideally a placebo controlled, randomized, double blinded study, which means that

You know, you either get placebo or active treatment, and neither you nor the physician or the people doing the measurements are aware of which treatment you're on. That's the blinded part. Okay. And this is critical because everybody, you know, if you're in a trial, if you have an illness, you want to do better. Your physician wants you to do better. There's a large placebo effect just from being in a study, right? And so maintaining the blind is really critical to how we interpret the results at the end of the study and did the blind work, right? Yeah.

And so what is functional unblinding? Yeah, so functional unblinding occurs in any trial where there's, for example, an adverse event that's much, much more common in the active treatment group than in the placebo group. And ahead of time, patients, or in our case, sometimes their study partners, their spouses, the physicians are aware of this. And so in these anti-amyloid antibody studies, there's a very serious and sometimes fatal adverse event called

I think, REF or amyloid-related imaging abnormality. It's like a PR, you know, dream name. Makes it sound really nice, but it's actually, it can cause brain swelling or brain bleeding. And several of these cases have been fatal. So, it's a very serious adverse event. It's, you know, much, much more common in the active treatment group than in placebo. And importantly, in terms of the function on blinding, when this happens in the studies,

The dosing is halted and people get more frequent safety MRIs. So the patients contacted, their study partners contacted to say, hey, you're not coming in next week. We're holding the dose. So it's a pretty strong signal. So they can kind of figure out, oh, I'm getting the real thing. I'm on the real juice. Right, exactly. And that is a perfect setup for the placebo effect.

And now they get excited and they, as you said, they want to do well. So they start reporting, Hey, I think I'm feeling a little better. Maybe I'm doing a little bit better on my tests. And then your, your study is now not really double blinded and you have all of these placebo efforts coming in. That's exactly right. And you know, and the main outcome measure for essentially all of these studies is something called the CDR. Some of the boxes, it's a clinical rating scale, but the important part about it for the functional and blind piece is that it's very subjective and

So part of it is interviewing the patient. Part of it is interviewing the study partner and asking questions like, how is their memory this month compared to two months ago? So very subjective, very prone, I think, to potential placebo bias. This is The Future of Everything with Russ Altman. More with Mike Gracious next.

Welcome back to The Future of Everything. I'm Russ Altman, and I'm speaking with Mike Gracious from Stanford University. In the last segment, Mike told us why he's not very excited about the recently approved antibodies to the amyloid protein. He thinks that maybe tau or other genes might be better targets for new therapies. And indeed, using the new ways of measuring the disease, there have been some interesting new discoveries of ways to intervene that might lead to treatments that are a little bit more effective.

In the long run, we may be taking not only statins for our cholesterol, we may be taking drugs to ward off dementia in the future. So Mike, functional unblinding, we just had a good discussion of that. And just to wrap that up, you believe that there might be a large effect from that functional blinding that actually explains much or all of the signal that they thought they were seeing of efficacy of these drugs?

Yeah, that's exactly right. And so, you know, it's been very tough to get these data. The sort of lack of transparency and availability of these data is frustrating. But what we did is just looked at how common one of these side effects is ARIA, this brain swelling across the different trials. And we found that those trials that had the most ARIA, the highest percentage of patients with ARIA actually had the best ARIA.

counter-intuitively the best clinical outcomes. And that to me is a big warning sign that a lot of what we're seeing might be driven by functional unblinding. We got finally data on one trial that was negative but that has some aria, so we're going to actually map out this effect and get a better sense. But right, I think these very small differences between active treatment and placebo would probably reduce close to nothing if functional unblinding were better accounted for. Gotcha. Now, this is a little bit of a technical detail, but I'm just curious.

Short of getting the terrible effect of ARIA that you're discussing, are there more benign side effects that might also be cluing the participants in? Like, I'm not having this devastating thing where they're calling me in for tests, but I'm having some headaches or something that's making me think I'm getting the antibody, the active ingredient, so to speak. Yeah, I think that's a good question. And the bigger...

The most common one in some of these trials is actually an infusion reaction. So just, you know, at the site, this is sort of a foreign body coming in and sometimes the body can respond to it. People can get shivers. They can get a small fever. They can get shaking. It's a pretty obvious thing that the patient and the caregiver know. And that's also much more common with active treatment than placebo. Yeah. Yeah. We, we,

My wife and I are at the age where we take the shingles vaccine, and there's no doubt for me when I've taken a shingle. - You know when you get the real deal. - Yeah, there's no doubt that you don't have to tell me whether I got a placebo or not. Okay, let's talk about tau. So to summarize, you and many of your colleagues are not fans of these antibodies against amyloids, but in your previous comments, you were hinting that tau, for example, it correlated better with the locations that you as a neurologist

we're kind of expecting to see some damage. So is Tau a potential target? And let's talk about how to go forward.

Yeah, I think tau is a potential target. As you pointed out, tau is, it sort of walks in lockstep with the parts of the brain that are sick. So the hippocampus, the memory centers are ground zero for tau pathology and Alzheimer's in its purest form is a memory disorder, right? So tau, for those reasons, seems like a good bet. I'll just add that the sort of third sort of, for me, nail in the coffin of the anti-amyloid antibodies is that the strongest effect side, this most recent one, denanamab,

They looked at 18 months. They saw a very small but statistically significant difference versus placebo in the clinical outcome. But they also looked at tau in the frontal cortex at 18 months in several hundred subjects on placebo and active treatment, and there's zero difference. Everybody continued to accumulate tau. So that, to me, is another indicator that this really is not disease modified.

Okay. But tau itself, yes, I think is a potentially really important target. There's an ongoing study now of something called an antisense oligonucleotide. These are basically little targeted collections of the building blocks of DNA, for example, that can target very specifically a protein. These are given as a lumbar puncture, so slightly invasive, but easy to do.

And what we've seen, so it's targeting tau and it's meant to bring tau down. We've seen that, number one, it is bringing tau down in patients, which is important in their spinal fluid, but it's also actually pulling tau out of the brain. So we have a tau PET scan where we can see where tau is accumulating. And people that get the active treatment, this tau knockdown treatment, we're actually seeing tau come out of the medial temporal lobes, the hippocampus and memory centers, for example. So that to me is very encouraging information.

As a neurologist who's been in neurodegenerative diseases for 20, 25 years now, the first real miraculous study that I saw was an antisense alginucleotide that was used in a disease called SMA. This is basically Lou Gehrig's disease in infants. It's like the world's worst imaginable neurodegenerative disease. And with this antisense approach,

into the spinal fluid, that seems to be all but cured, which was really revelatory, I think, to a lot of us working in order to generate diseases to say there's hope out there.

So that's exciting. And it's exciting to hear about this oligonucleotide antisense that seems to be working. If these things really continue to look good, what is treatment going to look like? Because I can imagine that you have somebody who's feeling pretty good. They're in their 40s or 50s. And you tell them this bad news that they're at a high risk of Alzheimer's disease. And you want to start this treatment, which is like not trivial. Right.

so forget about the trials um are we looking at a future where people will be kind of preemptively treated for a disease that might not affect them for 20 or 30 years and like is there any precedent for that i mean i guess people who are taking statins you know cholesterol medications so that they don't have a heart attack in 20 or 30 years that's a similar idea are we looking at that kind of future for neurodegenerative diseases so i think that's a great uh

you know, an allergy actually, right? Like, you know, I'm on a statin and it's going to reduce my risk of having a heart attack by 15% over the next 10 years. That's kind of an abstract thing to envision, but it works and people use them all the time. I think something like an antisense oligonucleotide that's infused into the spinal fluid every, you know, three months is probably not going to be a preventative 20-year treatment. But I'm optimistic that we're going to get to small molecule therapies

that can cross the blood brain barrier and are less of a sledgehammer effect, not just knocking tau down, but impacting the way tau's interacting with cells. We haven't talked about it yet, but APOE is another really big player in Alzheimer's disease.

We have some recent work suggesting that people that are born with only one copy of APOE rather than the normal two might actually be protected, particularly if they've knocked down the APOE4 allele. That's the high. It sounds like APOE is one of these things. I think I read a paper, I think that you were on, where for people who for some reason genetically don't even have APOE, they have a very good future in terms of not getting Alzheimer's disease.

Right. Yeah. So this is we made use of these really wonderful publicly available databases, which the NIH has put together kind of timely thinking about NIH funding over the next four years. An invaluable resource, including postmortem autopsy data. And we found that in one instance, somebody who should have had one copy of APOE4, which is the risk variant for Alzheimer's disease,

That copy was knocked down genetically at birth. And this person died at 90. They were still healthy, no cognitive impairment, and had no amyloid plaques either in the brain or in the blood vessels, really essentially unheard of. So, yeah, I think there's an expectation that if you carry one or two copies of this APOE4 variant, knocking it down, like with an ASO or with a small molecule, should be possible.

at least looked at, I think that's a promising approach. But that really is exciting because I'm sure you're aware that there's been other discoveries where they just found out in the wild. They found people who lived a long time, never had any problems like heart attacks. And that led directly to the discovery of the latest generation of cholesterol medication. So that's a really...

a really exciting thing. Let me end with a very basic question, which is what is under the control of all of us that we can do to, while we're waiting for you guys to work out all the treatments, and thank you for your efforts, by the way, what can regular people do just in their everyday life behaviors or habits that might help them in terms of pushing back or delaying or stopping the onset of Alzheimer's disease?

If anything, if anything. I mean, so first off, I would warn people away. I think there's a lot of snake oil. You can waste a lot of money on the internet with, you know, vitamin regimens and Sudoku software and stuff like that. I do think it's important to be physically active, but we would give that advice to anybody, whether they're at risk for Alzheimer's or not. Um,

So physically active, good aerobic exercise. There's a notion that there's Alzheimer's and also some vascular changes in the brain that can sort of make the dementia worse or start earlier. And that vascular piece in particular, I think, is better control with good exercise, heart smart diet, you know, more more fish and vegetables, less red meat, controlling your vascular risk factors. So cholesterol, keeping it down, blood pressure, diabetes, no smoking, all sort of pretty generic, but I think powerful things.

I definitely do not recommend that people get tested for the APOE4 gene, which 23andMe has done for a long time, I think, too, as a disservice to the community.

Only because currently we don't have preventative treatments. And my advice to somebody is going to be the same, the advice I just gave, whether they have an E4 allele or not. All it will do, I think, is make you anxious. So make you anxious. Please don't get tested yet. Very good. I was wondering, I actually have my genome on a hard drive and I haven't checked ApoE4 for that reason. And I feel validated.

I have not had it checked myself. I told my parents not to check it. They, of course, checked it. And then before I could stop them, told me what theirs were. But anyway, yeah, I really don't think it's worth it at this point. One day it will be, but not yet. Great. So there you go. The doctor is recommending healthy eating and exercise. It helps not only your heart. It might also help your brain.

Thanks to Mike Gracious. That was the future of Alzheimer's disease. Thank you for listening to the Future of Everything podcast. You know, we have more than 250 episodes in our back archives, so you can get a ton of discussions about a ton of topics, all of which are relevant to the future of everything.

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