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Front Row - Dr Tanzi
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Front Row - Dr Tanzi
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ALEX PHILIPPIDIS: Howdy, and welcome to a new video series from Gen Edge. I'm Alex Philippidis joined by Kevin Davies and our contributing editor, Malorye Branca.
KEVIN DAVIES: Howdy, welcome to the Gen Edge Team. You are, as I well know because we've worked together before, a Boston-based science journalist, and you're hosting a new three-part mini series, the series we're calling Front Row. What's the focus of this first series?
MALORYE BRANCA: Well, it's one of the most exciting areas in biotech and pharma today, Alzheimer's research. And I'm looking at some hot spots, some areas that will perhaps advance this field in further ways than it has already gotten. Recently , we felt like we were at the cusp in terms of Alzheimer's disease that some doors are opening up. And here, we're focused on those doors.
KEVIN DAVIES: Great. It's a three-part series. You've got three amazing guests on it. Tell us who they are and why you selected them.
MALORYE BRANCA: Well, I'm just delighted that these people were available. And among them, we have Dr. Rudy Tanzi, who is one of the most storied researchers in this field. And he has some exciting news about Alzheimer's genetics. We also have R Nolan Townsend, who's the CEO of Lexeo Therapeutics. And they are advancing a gene therapy for Alzheimer's, which is something that we hadn't even dreamed of a few years ago.
MALORYE BRANCA: So that's very bold work, and we're excited about it. And finally, we have Dr. Henrik Zetterberg, who is from Gothenburg University. And he's working on the cutting edge of blood tests for this disease. And that's something that we absolutely need if we're going to forward this.
ALEX PHILIPPIDIS: As the controversy around Biogen's Aduhelm has showed, Alzheimer's is a very closely watched area of biotech. Malorye, what are some of the main takeaways of this series?
MALORYE BRANCA: Well, this is-- as I said earlier, this is one of the most exciting times. But there are still some pieces of the puzzle that need to be put in. It's like we've broken open the amyloid theory, which has been a whole over four years hurdle. And now what's going to happen once we open these doors and if we have these other pieces, which are better genetic understanding, some testing of gene therapies, and some realization of what that can do.
MALORYE BRANCA: And then again, maybe one of the most important pieces, which is blood tests because Alzheimer's is a disease that it's very difficult to tell when it started, how far it's progressed.
ALEX PHILIPPIDIS: Sounds like a very interesting series, Malorye. Thanks. And without further ado, here's part one a Front Row from Gen Edge.
MALORYE BRANCA: Dr. Tanzi, it's a delight to speak to you again, and to talk about this really important topic. It seems like Alzheimer's disease after many years of very sort of hard news has become sort of a positive area again. And your research looks like it's one of those. So can you tell me, what are some of the things that are making people optimistic about Alzheimer's disease research again?
RUDY TANZI: Well, there's optimism, there's also controversy with the idea of which hypothesis about the disease is correct. I like to say that if you follow the genetics, you won't go wrong. But the genetics doesn't just tell you what needs to be addressed, it also tells you when it must be addressed. And it's that second part of when to address each pathology that a lot of folks just miss.
RUDY TANZI: And they want to just be binary and say, this is right and that's wrong and throw out the baby with the bathwater. I'm first referring to amyloid, beta amyloid. I discovered the beta amyloid gene back when I was a student at Harvard from a thesis named it APP. With two others, I discovered the presenilin genes. These are all the early onset familial genes. All of them said amyloid. They all just-- whether it was APP, the precursor of amyloid or the presenilin, which cut at the gamma secretase site to make A-beta of amyloid or a beta amyloid, amyloid was it.
RUDY TANZI: And then APOE came around as the major late onset risk factor. And again, APOE was found because it found amyloid in the cerebrospinal fluid. And APOE controls the release of amyloid from the brain, the clearance. So we can't deny that amyloid triggers this disease. Now, what I've learned early on in genetics is that genes that cause early onset forms of disease usually tell you about events that come early, that you have to treat preferably, with early detection, early intervention.
RUDY TANZI: Take cholesterol. Brown and Goldstein first found a mutation in the LDL receptor that led to high cholesterol, and a family with a rare mutation that had very early onset hyperlipidemia. Well, you have to treat cholesterol decades before you get heart disease. You don't wait till you need a bypass or have congestive heart failure to say, OK, now I'll pop my first statin lipitor.
RUDY TANZI: And this is exactly analogous in Alzheimer's. The amyloid genes are early onset genes. Even double APOE4 is relatively early, mid 60s. So amyloid, the genes tell us you have to hit amyloid a decade or two before symptoms. And all the imaging, brain imaging shows thatt, that the amyloid starts rising even after 40 years old, decades, up to two or three decades before symptoms.
RUDY TANZI: By the time you have even the mildest mild cognitive impairment, amyloid's peaked and is already plateauing. So amyloid is something you have to hit early.
MALORYE BRANCA: Does that explain why there has been so much failure in Alzheimer's disease clinical trials?
RUDY TANZI: Absolutely. Yeah, in some cases the amyloid drugs didn't work well. But there have been amyloid therapies that clear amyloid just fine. Take even Aduhelm or aducanumab from Biogen. You may not know that actually it was Rob Moir, who passed away a couple of years ago, from my lab who first inspired aducanumab. He discovered [INAUDIBLE] antibodies to Abeta oligomers that protect you against Alzheimer's.
RUDY TANZI: And Roger Nitsch in Switzerland started the company, Neurimmune, and talked to us and said he's going to go after those antibodies. And he found one and reversed translated that to aducanumab and license that to Biogen. So scientifically, it's great to be an early part of that story. I'm not financially involved at all by the way. But as well as anybody would tell you, if you're going to use an antibody to hit amyloid, using it in a patient who's already symptomatic is difficult even in the adjunct trials.
RUDY TANZI: One trial had marginal improvement in cognition, one had none. Previous amyloid trials had no cognitive improvement. So the FDA very carefully approved it for removing amyloid not for treating cognition. And said, let's see if removing amyloid helps. Well, I'm telling you right now, that if it's only removing amyloid in folks who are symptomatic, good luck. But if you use it for early detection, early intervention, then you're going to see a result.
RUDY TANZI: The problem is it's easy to get somebody Lipitor, give millions of people Lipitor if they have high cholesterol. It's not as easy to give 38 million people. That's how many we think have amyloid in their brain without symptoms right now. Thirty-eight million in the US. It's hard to get 38 million people a drug that cost $56,000 a year. So that's the problem here.
RUDY TANZI: The silver lining is that this decision has opened the door now for trials on cheaper, safer drugs that can remove amyloid just as well that are exponentially less expensive, that are safer. And if we get one of those approved, then we can argue, hey, it's best to use this early. Let's do early detection. First, a blood test. If you get a result, verify with imaging or maybe not.
RUDY TANZI: And then take this little drug. It's actionable. We're going to bring your amyloid back down. Now, for the people who have very high amyloid levels when you do that early detection, they may be candidates for the immunotherapies like [INAUDIBLE] et cetera. Because they have so much amyloid, you have to hit with the antibody first.
RUDY TANZI: Then in a serial combination, you bring them to some other drug like I'm working on gamma secretase modulators that then maintain that amyloid down, check again after year. So I think that's going to beat it. This is where this very awkward period right now is going to land. It's a silver lining. Jerry Garcia once said, with every silver lining, there's a touch of gray.
RUDY TANZI: Well, a touch of gray is that meanwhile, people may try to mortgage their homes to get dad aducanumab, who's got an advanced Alzheimer's. And it's not going to help them. They're up $56,000. So that's the bad side.
MALORYE BRANCA: Looks like your study. One of the questions that I had is what was the difference between the previous genetic studies, the GWAS, and your study? Why were the earlier studies not as productive? And how did you bring new light to this?
RUDY TANZI: Well, the earliest studies were highly productive. The earlier studies told us that amyloid initiates the disease. And that hasn't changed, and that's still the reigning paradigm. The only controversy that has come is when we treat amyloid in full-blown patients, we don't make them better. And to me, that's like saying, hey, I treated this patient who has congestive heart failure with Lipitor.
RUDY TANZI: He didn't get better. No, you had to do it beforehand. That's the [? big ?] thing. So the early genetics are going to tell us what to do for early detection, early intervention. See if you have amyloid brewing in your brain. Amyloid quickly causes tangles, look for the tangles. These are initiating pathologies. Plaques and tangles, amyloid causing tangles, initiating pathologies.
RUDY TANZI: Then those tangles have to spread like brush fires for decades setting off neuroinflammation. These are forest fires. That's what causes the symptoms. So in a patient who's symptomatic, forest fires or neuroinflammation are just blazing, and you're hoping that you'll make them better by stomping out the brushfire of the tangle or blown up the match of the amyloid that started it.
RUDY TANZI: That's what a misconception is everywhere.
MALORYE BRANCA: What does your study bring to this? What new does it bring to this discussion?
RUDY TANZI: Well, if you look at the next big gene we found in my lab, it was 2008, we found the first gene that controls neuroinflammation. So if you look at GWAS hits, the GWAS genes, most of them are bringing us to neuroinflammation. What GWAS has done on late onset Alzheimer's, and if you remember what I said, the early onset genes tell us what the earliest events you have to hit preferably pre-symptomatic like amyloid tangles.
RUDY TANZI: The late onset genes in GWAS are telling us what you need to hit later. Neuroinflammation, microglial activation, astrogliosis . So we found the gene CD33. That's an Alzheimer's gene in '08. I remember Time Magazine called it a top 10 medical breakthrough of the year. And we laughed because we said, we don't even know what this gene does.
RUDY TANZI: And then we figured out later on that CD33 is on switch for the microglial cells to be activated. So normally, the microglial cells are housekeeping. At night while you're sleeping, they're eating amyloid, cleaning up your brain. For those who remember the commercials who are old enough to like scrub your bubbles, you eat up the amyloid while you sleep. Well, while they're cleaning up amyloid, if they start eating, by chance, some pieces of neurons that died, that gives them a signal that neurons are dying.
RUDY TANZI: And they're still programmed the way they were 30,000, 40,000 years ago. If neurons are dying, assume-- the important word is assume, it's an infection and wipe that part of the brain out. That's neuroinflammation. So when the microglial cells get activated, and then they turn on the astrocytes, you get astrogliosis, this whole program is meant to protect the brain, because it's been evolutionary conserved for tens of thousands of years.
RUDY TANZI: These microglial cells didn't get the memo. That now, we live until 80. Neurons can die for other reasons like amyloid and tangles in your brain that [? started ?] at 50. So when they see neurons dying, they just say, wipe that part of the brain out. Neuroinflammation is now meant to protect you. But I like to call it auto innate immunity. Your innate immune cells in your brain, your only immune protection and your brain turns against you--
MALORYE BRANCA: So it's a natural process that is gone awry just because people are living too long.
RUDY TANZI: And it's similar to COVID. COVID doesn't kill you. COVID causes cytokine storm and inflammation in lungs and vessels. That's what kills you. Same thing in Alzheimer's. The plaques and tangles don't cause the disease. They initiate the original cell death, deposits of amyloid that activate the microglia. Now, in the brain, the microglia cause cytokine storm.
RUDY TANZI: Those cytokines turn on the astrocytes. Now, you have active glia everywhere that are causing neuroinflammation. That process kills 10 times more neurons than the original plaques and tangles that initiated this decades before. And it's very analogous to football. I work with the New England Patriots as a brain health advisor for them.
RUDY TANZI: I figure if I want to watch football, at least I have to try to help if I have a chance. And the thing with football or boxing is that they get tangles not from amyloid but from bangs to the head. Bangs to the head lead directly to tangles. And think about the fact that a player gets those bangs to the head in their 20s or teens, maybe 30s or if you're Tom Brady, 40s.
RUDY TANZI: But it takes decades of those tangles spreading like brush fires. The match here was the bang to the head. The tangles are the brush fires. They spread for decades. Then finally, you get enough off neuroinflammation, forest fire to get chronic traumatic encephalopathy or CTE. Well, Alzheimer's is-- both CTE and Alzheimer's are tauopathies.
RUDY TANZI: These tangles spreading that cause the disease. But in Alzheimer's, amyloid induces it. That's the most common form of dementia. In CTE, a rare form of dementia is head bangs. At the end of the day, the tangles take decades of spreading brush fires and you have to get enough forest fires of neuroinflammation genes like CD33, TREM2, et cetera, that then caused the bulk of the cell death from these symptoms.
RUDY TANZI: So to me, it's pretty clear cut. That's why I'm optimistic. Because we can see the timeline. And we can see the timeline because we created brain organoids, Alzheimer's in a Dish. We got away from mice. Mice have led us astray in this field. I tell people, mice are not humans. Take a look at a mouse, take a look at a human.
RUDY TANZI: It's pretty obvious. You're better off learning chronic order of events and molecular mechanisms in brain organoid systems like the ones we first published in [INAUDIBLE] in 2014 called Alzheimer's in a Dish.
MALORYE BRANCA: Let's go back to the study where-- the more recent study. What's new about the genetics of Alzheimer's that you've discovered using this genome wide scan?
RUDY TANZI: Well, we've discovered a number of different genes. The bulk of the new genes we and others have discovered over the last, let's say, decade or two, brought us away from amyloid, which is more the early onset Alzheimer's and the early trigger of disease to neuroinflammation. So we found CD33 in '08. [? Ecogenetics ?] found TREM2 in 2013. Now, there's been many, many different neuroinflammation genes.
RUDY TANZI: And that's when you take GWAS, where you're taking common SNPs common polymorphisms [INAUDIBLE] various [? intensive ?] association. You may not notice but way back when I was a kid, 1980 with Jim Gusella, he and I found the first five SNPs ever in the genome back when no one was doing this. And I was 20. He was 25.
RUDY TANZI: And we found the Huntington's disease team with the first five SNPs miraculously. So I've been working on SNPs and variants since they began. And now, I was so amazed when I did my first GWAS saying, wow, I'm testing a million SNPs at a time. And the GWAS takes the most common SNPs, 20% of the population for each one, and they're equally spaced on the genome. And you scan the whole genome for hits.
RUDY TANZI: And that's where we see these neuroinflammatory genes popping up. Most recently, we said, hey, what if we use whole genome sequencing as [INAUDIBLE] so whole genome sequencing, guess how many SNPs you look at a time? Fifty million, 60 million. You're looking at all of the variation in each person's genome.
RUDY TANZI: Each genome yields about 50 to 60 to 70 million variants in each person. Now, you can say what if there are rare variants? And why is this so important? What if they're rare variants that are only present in 1% of the population that will cause the disease? So for the first time because of whole genome sequencing in bulk, we could do this analysis.
RUDY TANZI: Our GWAS where the input is not some chip that somebody built at Illumina, where they hand-picked common SNPs and spaced them out. The whole genome is used. We said, let's see if the dark matter of the genome-- I call it the dark matter because GWAS told us about x number of genes, and they still only account for about half of the story. And we think a lot of the missing part of the genetics is in the rare variants where each variant is a 1% of the population or less.
RUDY TANZI: Actually, most of these rare variants have frequencies of like 0.0003, very rare. So for the first time, we could do this. And to our surprise, what we found was that the 12 genes that came out with the highest significance brought us back away from neuroinflammation to synaptic genes. Genes that involved with neuronal function, synaptic function, synaptic maintenance.
RUDY TANZI: And now, we said, well, we were always so surprised in the field, we didn't land on how can Alzheimer's or synaptic disease not involve synaptic genes? Because the original four genes were all the amyloid. The GWAS genes, the common SNPs were mostly neuroinflammatory. And what was missing was genes involved with synaptic function and maintenance, et cetera. So to find those, we said, finally, here they are.
RUDY TANZI: It looks like its rare variants in those synaptic genes that are involved. Whereas, it's common variants for neuroinflammation. And that to me makes sense because neuroinflammation is the end game of all neurodegenerative disease. It's like the misfolded proteins-- this is very important. The misfolded proteins initiate the disease. Alpha-synuclein causing Lewy bodies in Parkinson's or Lewy body disease.
RUDY TANZI: TDP-43 in ALS, amyloid in tangles and Alzheimer's. So these misfolded proteins kill x amount of neurons. But once that triggers neuroinflammation over the coming decades, the neuroinflammation kills 10x. And without the neuroinflammation, you do not get the symptoms. So without the initiating pathology, you don't get the neuroinflammation. But without the neuroinflammation, you don't get the symptoms.
RUDY TANZI: You will have a resilient brain. We have seen it over and over. But once in a while, people die in their 80s. No dementia when they die. You look in the brain and they have tons of plaques and tangles. You say, wow, how did they not have Alzheimer's? It's always the same answer. They were spared of neuroinflammation.
RUDY TANZI: Their microglial cells stayed [? calm and ?] carried on, housekeeping and cleaning at night rather than becoming reactive and saying, wow, neurons are dying, wipe out the area. They never took off the housekeeping apron and put on the SWAT team outfit. OK. So most people didn't get the disease.
MALORYE BRANCA: Pharma companies have been very stoic in sticking with Alzheimer's for quite a while. And they've had taken a few body blows. Let's be generous there. But just recently, Lilly said, they're refocusing. What do you think is happening? Are people catching on to what you're saying? Is there going to be a new focus, a new generation of drugs? Or are they just going to keep trying the same things?
RUDY TANZI: To be honest, most of the big pharma still follow each other. So Biogen got aducanumab approved. And an approval is an approval. There's a chance to make money. So Lilly has an antibody that's just as good maybe even better than [INAUDIBLE]. There are smaller companies too, like one I worked with called, ProMIS, that has an immunotherapy against Abeta oligomers.
RUDY TANZI: Whether it's a pharma company or a small company, amyloid is still a big target, because the FDA just set a predicate. They approved a drug that removes amyloid based on x amount of removal of amyloid or the x amount of time that's documented by PET scans. This opens the doors. Anybody can come in and say, here's my drug.
RUDY TANZI: I've removed amyloid just as fast over the same time period just as much using the same PET scan. Approve me too. What's the FDA supposed to say? They already set the precedent, aducanumab. So companies who want to approve drugs would be foolish not to follow that example. My warning to companies and to patients and families with this disease is that hitting amyloid, it's a crapshoot as to whether you're going to make somebody better.
RUDY TANZI: Most would say it's not even a crapshoot. It's a guaranteed loss. You have to also hit the right form of amyloid. That's why I like to work with this smaller company, ProMIS. And I do have equity in that company. I'm a consultant for disclosure. Because they're targeting the oligomeric Abeta that I think is the most dangerous to synapses versus the plaque Abeta, which I think you should let lie.
RUDY TANZI: The plaques are more or less inert and neutral. And maybe then you might see some greater effects on cognition. But the bottom line is that most of us who have been in this field like myself, 40 years, amyloid comes early. And amyloid does its job early. And by the time you have even earlier signs of dementia or mild cognitive impairment, amyloid is already peaked, plateaued, and if anything, even has to go down a little bit.
RUDY TANZI: You have to hit it on the way up a decade two, maybe three decades before. So that's where these antibodies and the amyloid that Lilly and Biogen and others are making is going to be useful. The question is, can you make it cheap enough to use it for secondary prevention?
MALORYE BRANCA: Also, can you detect it early enough?
RUDY TANZI: Yes, you can. We have C2N in Wash U, Randy Bateman's company with Dave Holtzman. They have a IP mass spec, relatively expensive Abeta test for the blood, but it mirrors pretty well what's happening in the brain. So I could see the future being that at some age, you get a blood test to see how your amyloid is. If the results look alarming, you might check further with a PET scan.
RUDY TANZI: And then the doctors decide OK, for your age, you're in the upper 90 percentile for amyloid. You need the antibody. We got to perform liposuction on your amyloid. We've got to suck it out of the brain. OK. So you're going to get the antibody. Then after that, we're going to keep the amyloid low with the equivalent of a statin for amyloid.
RUDY TANZI: Maybe it's going to be my gamma secretase modulator since the small molecules will last man standing even though we're academia, we were funded by the NIH blueprint. Based-inhibitors are not safe. Gamma secretase inhibitors are not safe. We always bet on gamma secretase modulators that Steve Wagner, my colleague and I for 20 years. And we're finally going to go into phase 1 over the coming year.
RUDY TANZI: So I think we're going to win that battle. But you might get on a cheap little white pill like gamma secretase modulator after the antibody does its work, maintain, check a year or two later to see how you're doing with the blood test. If it looks like you're OK, great. It doesn't, let's do another scan. So we're going to monitor amyloid buildup. And if your amyloid is high, we're going to check your tauopathy, your tangles, things like phosphate tau 217 or 181 or 231.
RUDY TANZI: And if that looks high, you're going to go get a tauopathy imaging test. And it may be that if it's so bad, you might need immunotherapy to stop tau propagation. So a lot of companies now are using antibodies to stop the spreading of propagation of tau, but they're now disappointed that doesn't make patients better. It doesn't make patients better because it's part of the initiating pathology.
RUDY TANZI: The tangle is just a brush fire that's lit by the match of amyloid or the bang to the head. You have to hit that decades before.
MALORYE BRANCA: Do we know what time?
RUDY TANZI: Well, companies have to realize that these initiating events happen anywhere from one to two to three decades before symptoms. And they have to stop just following each other like lemmings off the cliff. OK. Saying, oh, someone is starting doing tau propagation antibodies. We have to do that too. Think for yourself.
RUDY TANZI: Look at the overall data, read some papers, look at the brain imaging data, look at what's happening. Don't try to treat a pathology that happened two decades ago to get the cascade going now that somebody has full-blown dementia. In a full-blown dementia case, look at what's happening. It's rampant neuroinflammation causing synaptic damage and cell death. You have to put that fire out, or you have to protect against that fire.
RUDY TANZI: So the first example of success in protecting against a fire was a company I started just seven years ago called Amylyx, A-M-Y-L-Y-X. I own equity in the company. I'm a co-founder. But seven years ago, two kids from Brown University, they were kids, undergrads, came to see me for a science project. And we talked about ideas about how to protect neurons against neuroinflammation, protecting cell death at the level of mitochondria and the endoplasmic reticulum, the ER.
RUDY TANZI: We did some early experiments. And I was amazed that these two drugs that we were testing, one to prevent mitochondrial apoptosis, the other to prevent ER-driven apoptosis. We put them together, and you could put a hydrogen peroxide on neurons in our dish, kill them all, and these two drugs together, not alone, save 90% to 95% of them. So we decided to go for ALS first, because it's a quicker route to trial.
RUDY TANZI: And it's a very devastating disease unmet medical need. So we did a phase 2 ALS trial, 150 patients, and it worked. We did it at Mass General. My chief, Merit Cudkowicz, ran the trial at the Healey Center. We published the trial in the New England Journal of Medicine, successful trial. And now, this little company, Amylyx, is looking at probable-- I wouldn't say guarantee, but it's looking very good for approval in Canada, Europe, and the US hopefully over the coming year or so.
MALORYE BRANCA: And that's for ALS.
RUDY TANZI: I don't want to make any formal statements on behalf of the company. But at this stage, they're saying that they have a chance for approval now for ALS. And you can try this in-- now, they're trying to get Alzheimer's and other diseases. First time, yeah--
MALORYE BRANCA: When we talk about Alzheimer's, are we talking about a range of diseases or are we talking about one condition?
RUDY TANZI: The disease is heterogeneous in many ways. How do you initiate the disease? In some folks, they're making normal amounts of Abeta amyloid and tangles like the general population. But they have genes that ramp up their neuroinflammatory response when that time comes. Others have genes that just ramp up the amyloid early on. Others, like we just recently found in our newest genetic study, have genes that make synapses more vulnerable to amyloid and neuroinflammation from the whole genome GWAS.
RUDY TANZI: So there's many different routes to get there. But in the end, it's neural inflammation that takes you out. If you want to treat a patient who's symptomatic, no matter how you got there, you have to stop neuroinflammation or protect against it--
MALORYE BRANCA: But if you're treating a patient--
RUDY TANZI: --along the way--
MALORYE BRANCA: --pre-symptomatic, if you are trying to prevent the disease, you need different range of drugs?
RUDY TANZI: Exactly, Malorye So it's a pre-symptomatic early intervention stage. That's where heterogeneity comes in. So in some folks, it may be more important to stop amyloid. In some folks, it may be more important to stop the tau pathology from spreading. My guess is if you have drugs that safely promote amyloid clearance by microglia like a little white powder that does what [INAUDIBLE] does for 100 times less money, or when you have a drug that stops the tangles some spreading, any drugs to stop initiating pathologies-- I think despite the heterogeneity,s we're seeing heterogeneity in how the tangles spread, the type of tau phosphorylation, despite that heterogeneity, if you have drugs that promote the clearance of amyloid that's initiating or hit the amyloid production like gamma secretase modulators, or drugs to stop the tangles from spreading, they're going to be useful in everyone despite the early heterogeneity.
MALORYE BRANCA: But you're seeing this as an anti-cholesterol, but it's something that people will take. They'll be deemed at risk. They'll take a preventative medicine and that will reduce their risk.
RUDY TANZI: That's right. Yeah. I see it exactly analogously to checking your cholesterol when you're young and taking care of your cholesterol levels decades before you might get heart disease. That's how we put a big hit on heart disease. And remember, no one believed Brown and Goldstein when they first showed this one family, early onset hyperlipidemia, and they said, it's the LDL receptor mutation, maybe cholesterol has something to do with heart diease, they got the same criticism that we got when I discovered and others discovered the familial Alzheimer genes.
RUDY TANZI: And we said, it's amyloid. And this controversy and the media loves it. They love to whip up the controversy and make scientists look like stupid kids fighting with each other. But the smart scientists don't do that. They don't look at whether something's involved. They look at when it's involved. That's the mindset change we need.
RUDY TANZI: Not whether, when. And when tells you when to hit that pathology, whether it's secondary prevention pre-symptomatically versus what you have to do in a patient who is suffering right now, we have to hit neuroinflammation or protect neurons from oxidative stress. You have to always look at the [? potential ?] order of things and then determine when to hit. And this is something that pharma has not done well.
MALORYE BRANCA: No. They really follow each other. What are the next big questions? Your paper was a revelation in terms of steps forward and our understanding of Alzheimer's disease. But what are the outstanding questions? What are the next things that we need to solve?
RUDY TANZI: Well, I think when you look at-- thanks for your words about the paper. I think it was a unique study to use. It was the first study to use whole genome sequencing as input for GWAS, where you're capturing all the rare variants. And we were surprised as anything to see instead of hitting amyloid genes or neuroinflammation genes like we've seen in the past from the early studies in the 80s and 90s on getting to amyloid to the GWAS studies, it's that neuroinflammation to finally see synaptic genes.
RUDY TANZI: I think what these groups of genes tell you what are the best targets for either preventing the disease or treating the disease? So if you're going to hit all the first four genes we found in the 80s and s say, amyloid, so you can try to stop amyloid production safely. I think our gamma secretase modulators that don't block gamma secretase but that allosteric modulators of the gamma secretase docking site, so you make small Abetas rather than longer Abetas that are less prone to form amyloid.
RUDY TANZI: We shift from longer Abeta to shorter Abeta. We don't just hit gamma secretase with a sledgehammer like Lilly did and got in trouble. But beta secretase hit it with a sledgehammer. You can't. These enzymes are too important. Instead of hitting with the sledgehammer, you have to tweak them with the jeweler's screwdriver. That's what we're doing with the gamma secretase modulator.
RUDY TANZI: And then you have drugs that can promote microglial clearance of amyloid. That's what Aduhelm does. But we have many drugs from our drug screens and from Alzheimer's in a Dish model, the brain organoid model, where we could do what Aduhelm does with cheap little white powders and nutraceuticals just as well. And we're testing that in mice now to see if those could become a replacement that's cheap enough that you could use it for secondary prevention in 38 million people.
RUDY TANZI: That's our goal. That's how we're going to prevent the disease. But in terms of treating the disease, I like for example what Denali, and Alector, and AbbVie are doing. They're targeting the main neuroinflammation genes like CD33, trying to turn it off with an antibody. For disclosure, I do have-- I'm the inventor on the issued patents for CD33 gene therapy and immunotherapy.
RUDY TANZI: So I have to disclose that. But I like what the idea of activating TREM2. That's something that using Christian Haas' antibody to activate TREM2. So I think now that there are some companies who are ahead of the curve like AbbVie doing the deal with Alector on CD33 and TREM2. Denali doing CD33 and TREM2. I don't know how much of big, big pharma are doing it other than them, but that's the way forward for treating patients is that you have to learn from the neuroinflammation genes.
RUDY TANZI: Then finally, these new genes we found from whole genome sequencing based GWAS, the synaptic genes would tell us how we might provide resiliency to synaptic [INAUDIBLE] Because at the end of the day, no matter how you get there in Alzheimer's, the degree of dementia correlates with the degree of synapse loss. So that's why I tell everybody when I write my books on the side, build up your synaptic reserve with the same rigor and vigor as you build up your financial reserves.
RUDY TANZI: Because the more synapses you make, the more you can lose before you lose it. Because you want to build up those synapses, because they're going to get hit as you get older. But suppose with these new genes we found from the whole genome sequencing GWAS, we can learn exactly what the target to provide resiliency and synapses to make them less likely to die in the face of amyloid, tangles, and neuroinflammation.
RUDY TANZI: So I think have to look at-- the genetics is always telling us the targets. But importantly, the genetics also tells you when you have to hit that target. And the earlier the onset of the genetics, the more you're into secondary prevention area. The later the onset of the genetics in terms of age of onset, the more you're into treating patients right now.
RUDY TANZI: It's a rule of thumb that people forget.
MALORYE BRANCA: What kind of barriers does this raise? Are people going to volunteer for these trials?
RUDY TANZI: Oh, yeah. So I'm a co-director of the McCance Center for Brain Health at Mass General Hospital. We're doing trials right now on supplements, nutraceuticals that we find work in our Alzheimer's in a Dish model. We created these 3D [? nueroculture ?] models. For the first time, we could show--
MALORYE BRANCA: The organoids?
RUDY TANZI: --the organoid. It's more of a 3D culture, because it doesn't have the same development as an organoid. It's more amenable to drug screen. We call them 3D cultures you can call them organoids. But we get a plaque in four weeks. These are stem cell-based neurons. They have to be mature neurons. IPS drive neurons do not work in this model. They're too immature.
RUDY TANZI: We have to use either the human embryonic stem cell line derived neurons or direct fibroblasts to neuron neurons. IPS derived neurons don't work. So we put the Alzheimer's genes in these neurons. You get amyloid plaques in four weeks, wait about a week you get full-blown tangles, [INAUDIBLE] some endogenous tau. We could show for the first time what mice did not show us. Amyloid directly induces tangles.
RUDY TANZI: We have to be honest, the most referenced paper in our field, the amyloid cascade hypothesis, was a hand hand-waving argument for why mice didn't get tangles. We now know mice don't get tangles after you put amyloid genes in the brain, because they can't make tangles. They have the wrong isoforms of tau. You need 50-50 3 BP, four BP tau like the adult human brain to get a tangle.
RUDY TANZI: They don't have it. So people said, OK, well, we're going to speculate from amyloid to tangles as 10 arrows. And it takes so long, the mice don't live long enough, thus, the amyloid cascade hypothesis. Most referenced paper in the field. All mainly driven by a hand-waving argument to explain away why amyloid looks like the cause of disease.
RUDY TANZI: All the genetic says this, but the mice won't get tangles. Well, now, we know they can't make tangles. You do it in a dish model, amyloid makes tangles directly. And then if you add in microglial cells on the side, you can see they get recruited once neurons start dying with plaques and tangles, and microglial cells come in. They start eating synapses and axons. They activate the astrocytes.
RUDY TANZI: The astrocytes [INAUDIBLE] synapses. The whole thing is modeled in a dish in five weeks. So this has made drug screening, supplement screening, nutraceuticals, natural products screening 100 times faster, 100 times cheaper. You can't--
MALORYE BRANCA: Do you have volunteers who are taking these drugs?
RUDY TANZI: Well, we have. Right now, we're at the stage where we spent five years and many millions of dollars. Cure Alzheimer's Fund and the NIH funded this [INAUDIBLE] Cure Alzheimer's Fund the best research foundation really on the planet for Alzheimer's in terms of high-impact research. And they funded this. And now, we have like over 100 approved drugs and natural products, we've identified to either stop the amyloid production safely, induce microglial clearance of amyloid like Aduhelm, stop amyloid from inducing tangles.
RUDY TANZI: Forty different drugs would do that. The amyloid is there, but you don't get tangles downstream. We can prevent that. Then we have about 40 drugs that prevent the reactive astrocytes and microglia that cause--
MALORYE BRANCA: These are all in development?
RUDY TANZI: These are all identified in the dish model. And now, we put together a task force with Cure Alzheimer's Fund to pick out which of the drugs and natural products are safest and most efficacious to stop platform clinical trials. So we're talking to, for example, Howard Feldman at UCSD and the National Alzheimer's clinical trials. We're setting up our own thing at Mass General. We already started one of the trials on one of the natural nutraceuticals at the McCance Center.
RUDY TANZI: One of this is already ongoing. So we're making that shift now into saying now that we can screen for approved drugs and natural products using these dish models so quickly, and we can target exactly what pathology we want and pick out combinations. That what we did with Amylyx. Amylyx, it's very likely over the next year going to get approved for ALS and they're doing an Alzheimer's trial now.
RUDY TANZI: It was picking two drugs, one drug, one natural product, one protected mitochondria, one protected ER. There was a taurine analog called [INAUDIBLE] that protected mitochondria. It was a short chain fatty acid phenylybutyrate to protect the ER from the unfolded protein response. And then those two drugs together led to a successful ALS trial and protected neurons against oxidative stress and neuroinflammation.
RUDY TANZI: So now, we're trying to repeat that saying, let's see if we can hit amyloid that way, tangles that way, amyloid induced tauopathy, tangles spreading, microglial activation, the ability of microglial cells to activate astrocytes, neuroprotection. But now, it's 100 times faster, 100 times cheaper, because we have these dish models. And we don't have to depend on mouse models, which were unreliable to begin with.
MALORYE BRANCA: Well, yeah, that sounds like a huge hurdle that you've overcome. Is there anything else that you see in your way between now and taking these to the final finish line?
RUDY TANZI: Money. Look, it's hard to get companies to fund repurposing trials. If you're going to repurpose a drug, or add it, or do a combination of a repurposed drug and an actual product, you have to start a small company that then generates intellectual property around that combination like Amylyx did. But big pharma won't come in until you do that combination. You get the idea that it's efficacious.
RUDY TANZI: So that's what Amylyx already did. So we're on our own to-- so luckily, we have folks like the Cure Alzheimer's Fund, the NIH, other philanthropic donors, who are helping to find these early platform trials. And if you get the right combination, yeah, then you launched a biotech company around it. You get the IP around it. Then you get pharma interest.
RUDY TANZI: But it has to start organically. But that's where we're at. We have our list. We're checking it twice. We're going to go-- not go on to pilot--
MALORYE BRANCA: Are you doing any more genetic studies?
RUDY TANZI: We're always doing genetics. I've never stopped doing genetics since finding the first SNPs in 1980 out of college. And we're doing more whole genome sequencing. In fact, we just analyzed 30,000 whole genome sequences, both common SNPs and rare SNPs. And we just identified five or six more genes that reach genome wide significance that we're going to write up for publication very soon. So it's important to keep that pipeline of genetics coming in, because those are the targets you have to hit.
RUDY TANZI: But pharma has to get it through their heads that a target tells you not just what to hit, but when to hit it.
MALORYE BRANCA: Exactly.
RUDY TANZI: You can't just wait for-- the elephant in the room here, Malorye, is with Alzheimer's and neurodegenerative diseases. We wait until the brain degenerates to the point of dysfunction before we treat it. So we're reactive. Imagine if we did that with diabetes. We said, we're going to wait until you lose half of your [? eye, ?] your beta cells, and your pancreas. And then we're going to treat you.
RUDY TANZI: Well, imagine if we did that with heart disease. We're going to wait to see when your heart doesn't-- starts to get clogged up and doesn't work very well. Then we're going to try to treat you. And that sounds absurd. But that's what we do in Alzheimer's. So that's why we started this McCance Center to be proactive. Early detection, what are the indicators of brain health? I started a company called REACT Neuro, where we have a modified VR device that does a VR neuropscyh exam, eye scanning, and voice analysis.
RUDY TANZI: So it can predict Alzheimer's or brain health issues decades before problems. We're hoping that this device that takes two minutes to do the brain health exam will be in every single doctor's office someday. That when you go for your physical every year, at the end, you get your mental. You get two minutes of-- think about it, your doctor gets from the neck up.
RUDY TANZI: Like Patrick Kennedy says, there's no checkup from the neck up. They get from the neck up and they look at the holes in your head, mouth, nostrils, eyes, ears. OK, you're fine. Isn't there something up here under my skull? Yeah, we don't do that. So we want to change that. We want to get to the point where you see early changes in the brain, early detection just like we do for the heart, the pancreas, or the lungs.
RUDY TANZI: Early detection, early intervention. And use the right drug at the right time. So that's the goal. And we just hope pharma will adopt this mentality and stop just being reactive and chasing the next big drug that fails and works with us to do this. That's my hope.
MALORYE BRANCA: Well, that's fascinating. I have to say thank you first of all, the body of your work and for the time that you've spent with us today. And I will circle back with you with some fact checks. I'm sure that it was just fascinating talking to you again Thank you so much.
RUDY TANZI: Well, thank you for having me, Malorye. I enjoyed the conversation.
MALORYE BRANCA: Take care.
RUDY TANZI: Thank you. [MUSIC PLAYING]
Segment:0 .
[MUSIC PLAYING]
ALEX PHILIPPIDIS: Howdy, and welcome to a new video series from Gen Edge. I'm Alex Philippidis joined by Kevin Davies and our contributing editor, Malorye Branca.
KEVIN DAVIES: Howdy, welcome to the Gen Edge Team. You are, as I well know because we've worked together before, a Boston-based science journalist, and you're hosting a new three-part mini series, the series we're calling Front Row. What's the focus of this first series?
MALORYE BRANCA: Well, it's one of the most exciting areas in biotech and pharma today, Alzheimer's research. And I'm looking at some hot spots, some areas that will perhaps advance this field in further ways than it has already gotten. Recently , we felt like we were at the cusp in terms of Alzheimer's disease that some doors are opening up. And here, we're focused on those doors.
KEVIN DAVIES: Great. It's a three-part series. You've got three amazing guests on it. Tell us who they are and why you selected them.
MALORYE BRANCA: Well, I'm just delighted that these people were available. And among them, we have Dr. Rudy Tanzi, who is one of the most storied researchers in this field. And he has some exciting news about Alzheimer's genetics. We also have R Nolan Townsend, who's the CEO of Lexeo Therapeutics. And they are advancing a gene therapy for Alzheimer's, which is something that we hadn't even dreamed of a few years ago.
MALORYE BRANCA: So that's very bold work, and we're excited about it. And finally, we have Dr. Henrik Zetterberg, who is from Gothenburg University. And he's working on the cutting edge of blood tests for this disease. And that's something that we absolutely need if we're going to forward this.
ALEX PHILIPPIDIS: As the controversy around Biogen's Aduhelm has showed, Alzheimer's is a very closely watched area of biotech. Malorye, what are some of the main takeaways of this series?
MALORYE BRANCA: Well, this is-- as I said earlier, this is one of the most exciting times. But there are still some pieces of the puzzle that need to be put in. It's like we've broken open the amyloid theory, which has been a whole over four years hurdle. And now what's going to happen once we open these doors and if we have these other pieces, which are better genetic understanding, some testing of gene therapies, and some realization of what that can do.
MALORYE BRANCA: And then again, maybe one of the most important pieces, which is blood tests because Alzheimer's is a disease that it's very difficult to tell when it started, how far it's progressed.
ALEX PHILIPPIDIS: Sounds like a very interesting series, Malorye. Thanks. And without further ado, here's part one a Front Row from Gen Edge.
MALORYE BRANCA: Dr. Tanzi, it's a delight to speak to you again, and to talk about this really important topic. It seems like Alzheimer's disease after many years of very sort of hard news has become sort of a positive area again. And your research looks like it's one of those. So can you tell me, what are some of the things that are making people optimistic about Alzheimer's disease research again?
RUDY TANZI: Well, there's optimism, there's also controversy with the idea of which hypothesis about the disease is correct. I like to say that if you follow the genetics, you won't go wrong. But the genetics doesn't just tell you what needs to be addressed, it also tells you when it must be addressed. And it's that second part of when to address each pathology that a lot of folks just miss.
RUDY TANZI: And they want to just be binary and say, this is right and that's wrong and throw out the baby with the bathwater. I'm first referring to amyloid, beta amyloid. I discovered the beta amyloid gene back when I was a student at Harvard from a thesis named it APP. With two others, I discovered the presenilin genes. These are all the early onset familial genes. All of them said amyloid. They all just-- whether it was APP, the precursor of amyloid or the presenilin, which cut at the gamma secretase site to make A-beta of amyloid or a beta amyloid, amyloid was it.
RUDY TANZI: And then APOE came around as the major late onset risk factor. And again, APOE was found because it found amyloid in the cerebrospinal fluid. And APOE controls the release of amyloid from the brain, the clearance. So we can't deny that amyloid triggers this disease. Now, what I've learned early on in genetics is that genes that cause early onset forms of disease usually tell you about events that come early, that you have to treat preferably, with early detection, early intervention.
RUDY TANZI: Take cholesterol. Brown and Goldstein first found a mutation in the LDL receptor that led to high cholesterol, and a family with a rare mutation that had very early onset hyperlipidemia. Well, you have to treat cholesterol decades before you get heart disease. You don't wait till you need a bypass or have congestive heart failure to say, OK, now I'll pop my first statin lipitor.
RUDY TANZI: And this is exactly analogous in Alzheimer's. The amyloid genes are early onset genes. Even double APOE4 is relatively early, mid 60s. So amyloid, the genes tell us you have to hit amyloid a decade or two before symptoms. And all the imaging, brain imaging shows thatt, that the amyloid starts rising even after 40 years old, decades, up to two or three decades before symptoms.
RUDY TANZI: By the time you have even the mildest mild cognitive impairment, amyloid's peaked and is already plateauing. So amyloid is something you have to hit early.
MALORYE BRANCA: Does that explain why there has been so much failure in Alzheimer's disease clinical trials?
RUDY TANZI: Absolutely. Yeah, in some cases the amyloid drugs didn't work well. But there have been amyloid therapies that clear amyloid just fine. Take even Aduhelm or aducanumab from Biogen. You may not know that actually it was Rob Moir, who passed away a couple of years ago, from my lab who first inspired aducanumab. He discovered [INAUDIBLE] antibodies to Abeta oligomers that protect you against Alzheimer's.
RUDY TANZI: And Roger Nitsch in Switzerland started the company, Neurimmune, and talked to us and said he's going to go after those antibodies. And he found one and reversed translated that to aducanumab and license that to Biogen. So scientifically, it's great to be an early part of that story. I'm not financially involved at all by the way. But as well as anybody would tell you, if you're going to use an antibody to hit amyloid, using it in a patient who's already symptomatic is difficult even in the adjunct trials.
RUDY TANZI: One trial had marginal improvement in cognition, one had none. Previous amyloid trials had no cognitive improvement. So the FDA very carefully approved it for removing amyloid not for treating cognition. And said, let's see if removing amyloid helps. Well, I'm telling you right now, that if it's only removing amyloid in folks who are symptomatic, good luck. But if you use it for early detection, early intervention, then you're going to see a result.
RUDY TANZI: The problem is it's easy to get somebody Lipitor, give millions of people Lipitor if they have high cholesterol. It's not as easy to give 38 million people. That's how many we think have amyloid in their brain without symptoms right now. Thirty-eight million in the US. It's hard to get 38 million people a drug that cost $56,000 a year. So that's the problem here.
RUDY TANZI: The silver lining is that this decision has opened the door now for trials on cheaper, safer drugs that can remove amyloid just as well that are exponentially less expensive, that are safer. And if we get one of those approved, then we can argue, hey, it's best to use this early. Let's do early detection. First, a blood test. If you get a result, verify with imaging or maybe not.
RUDY TANZI: And then take this little drug. It's actionable. We're going to bring your amyloid back down. Now, for the people who have very high amyloid levels when you do that early detection, they may be candidates for the immunotherapies like [INAUDIBLE] et cetera. Because they have so much amyloid, you have to hit with the antibody first.
RUDY TANZI: Then in a serial combination, you bring them to some other drug like I'm working on gamma secretase modulators that then maintain that amyloid down, check again after year. So I think that's going to beat it. This is where this very awkward period right now is going to land. It's a silver lining. Jerry Garcia once said, with every silver lining, there's a touch of gray.
RUDY TANZI: Well, a touch of gray is that meanwhile, people may try to mortgage their homes to get dad aducanumab, who's got an advanced Alzheimer's. And it's not going to help them. They're up $56,000. So that's the bad side.
MALORYE BRANCA: Looks like your study. One of the questions that I had is what was the difference between the previous genetic studies, the GWAS, and your study? Why were the earlier studies not as productive? And how did you bring new light to this?
RUDY TANZI: Well, the earliest studies were highly productive. The earlier studies told us that amyloid initiates the disease. And that hasn't changed, and that's still the reigning paradigm. The only controversy that has come is when we treat amyloid in full-blown patients, we don't make them better. And to me, that's like saying, hey, I treated this patient who has congestive heart failure with Lipitor.
RUDY TANZI: He didn't get better. No, you had to do it beforehand. That's the [? big ?] thing. So the early genetics are going to tell us what to do for early detection, early intervention. See if you have amyloid brewing in your brain. Amyloid quickly causes tangles, look for the tangles. These are initiating pathologies. Plaques and tangles, amyloid causing tangles, initiating pathologies.
RUDY TANZI: Then those tangles have to spread like brush fires for decades setting off neuroinflammation. These are forest fires. That's what causes the symptoms. So in a patient who's symptomatic, forest fires or neuroinflammation are just blazing, and you're hoping that you'll make them better by stomping out the brushfire of the tangle or blown up the match of the amyloid that started it.
RUDY TANZI: That's what a misconception is everywhere.
MALORYE BRANCA: What does your study bring to this? What new does it bring to this discussion?
RUDY TANZI: Well, if you look at the next big gene we found in my lab, it was 2008, we found the first gene that controls neuroinflammation. So if you look at GWAS hits, the GWAS genes, most of them are bringing us to neuroinflammation. What GWAS has done on late onset Alzheimer's, and if you remember what I said, the early onset genes tell us what the earliest events you have to hit preferably pre-symptomatic like amyloid tangles.
RUDY TANZI: The late onset genes in GWAS are telling us what you need to hit later. Neuroinflammation, microglial activation, astrogliosis . So we found the gene CD33. That's an Alzheimer's gene in '08. I remember Time Magazine called it a top 10 medical breakthrough of the year. And we laughed because we said, we don't even know what this gene does.
RUDY TANZI: And then we figured out later on that CD33 is on switch for the microglial cells to be activated. So normally, the microglial cells are housekeeping. At night while you're sleeping, they're eating amyloid, cleaning up your brain. For those who remember the commercials who are old enough to like scrub your bubbles, you eat up the amyloid while you sleep. Well, while they're cleaning up amyloid, if they start eating, by chance, some pieces of neurons that died, that gives them a signal that neurons are dying.
RUDY TANZI: And they're still programmed the way they were 30,000, 40,000 years ago. If neurons are dying, assume-- the important word is assume, it's an infection and wipe that part of the brain out. That's neuroinflammation. So when the microglial cells get activated, and then they turn on the astrocytes, you get astrogliosis, this whole program is meant to protect the brain, because it's been evolutionary conserved for tens of thousands of years.
RUDY TANZI: These microglial cells didn't get the memo. That now, we live until 80. Neurons can die for other reasons like amyloid and tangles in your brain that [? started ?] at 50. So when they see neurons dying, they just say, wipe that part of the brain out. Neuroinflammation is now meant to protect you. But I like to call it auto innate immunity. Your innate immune cells in your brain, your only immune protection and your brain turns against you--
MALORYE BRANCA: So it's a natural process that is gone awry just because people are living too long.
RUDY TANZI: And it's similar to COVID. COVID doesn't kill you. COVID causes cytokine storm and inflammation in lungs and vessels. That's what kills you. Same thing in Alzheimer's. The plaques and tangles don't cause the disease. They initiate the original cell death, deposits of amyloid that activate the microglia. Now, in the brain, the microglia cause cytokine storm.
RUDY TANZI: Those cytokines turn on the astrocytes. Now, you have active glia everywhere that are causing neuroinflammation. That process kills 10 times more neurons than the original plaques and tangles that initiated this decades before. And it's very analogous to football. I work with the New England Patriots as a brain health advisor for them.
RUDY TANZI: I figure if I want to watch football, at least I have to try to help if I have a chance. And the thing with football or boxing is that they get tangles not from amyloid but from bangs to the head. Bangs to the head lead directly to tangles. And think about the fact that a player gets those bangs to the head in their 20s or teens, maybe 30s or if you're Tom Brady, 40s.
RUDY TANZI: But it takes decades of those tangles spreading like brush fires. The match here was the bang to the head. The tangles are the brush fires. They spread for decades. Then finally, you get enough off neuroinflammation, forest fire to get chronic traumatic encephalopathy or CTE. Well, Alzheimer's is-- both CTE and Alzheimer's are tauopathies.
RUDY TANZI: These tangles spreading that cause the disease. But in Alzheimer's, amyloid induces it. That's the most common form of dementia. In CTE, a rare form of dementia is head bangs. At the end of the day, the tangles take decades of spreading brush fires and you have to get enough forest fires of neuroinflammation genes like CD33, TREM2, et cetera, that then caused the bulk of the cell death from these symptoms.
RUDY TANZI: So to me, it's pretty clear cut. That's why I'm optimistic. Because we can see the timeline. And we can see the timeline because we created brain organoids, Alzheimer's in a Dish. We got away from mice. Mice have led us astray in this field. I tell people, mice are not humans. Take a look at a mouse, take a look at a human.
RUDY TANZI: It's pretty obvious. You're better off learning chronic order of events and molecular mechanisms in brain organoid systems like the ones we first published in [INAUDIBLE] in 2014 called Alzheimer's in a Dish.
MALORYE BRANCA: Let's go back to the study where-- the more recent study. What's new about the genetics of Alzheimer's that you've discovered using this genome wide scan?
RUDY TANZI: Well, we've discovered a number of different genes. The bulk of the new genes we and others have discovered over the last, let's say, decade or two, brought us away from amyloid, which is more the early onset Alzheimer's and the early trigger of disease to neuroinflammation. So we found CD33 in '08. [? Ecogenetics ?] found TREM2 in 2013. Now, there's been many, many different neuroinflammation genes.
RUDY TANZI: And that's when you take GWAS, where you're taking common SNPs common polymorphisms [INAUDIBLE] various [? intensive ?] association. You may not notice but way back when I was a kid, 1980 with Jim Gusella, he and I found the first five SNPs ever in the genome back when no one was doing this. And I was 20. He was 25.
RUDY TANZI: And we found the Huntington's disease team with the first five SNPs miraculously. So I've been working on SNPs and variants since they began. And now, I was so amazed when I did my first GWAS saying, wow, I'm testing a million SNPs at a time. And the GWAS takes the most common SNPs, 20% of the population for each one, and they're equally spaced on the genome. And you scan the whole genome for hits.
RUDY TANZI: And that's where we see these neuroinflammatory genes popping up. Most recently, we said, hey, what if we use whole genome sequencing as [INAUDIBLE] so whole genome sequencing, guess how many SNPs you look at a time? Fifty million, 60 million. You're looking at all of the variation in each person's genome.
RUDY TANZI: Each genome yields about 50 to 60 to 70 million variants in each person. Now, you can say what if there are rare variants? And why is this so important? What if they're rare variants that are only present in 1% of the population that will cause the disease? So for the first time because of whole genome sequencing in bulk, we could do this analysis.
RUDY TANZI: Our GWAS where the input is not some chip that somebody built at Illumina, where they hand-picked common SNPs and spaced them out. The whole genome is used. We said, let's see if the dark matter of the genome-- I call it the dark matter because GWAS told us about x number of genes, and they still only account for about half of the story. And we think a lot of the missing part of the genetics is in the rare variants where each variant is a 1% of the population or less.
RUDY TANZI: Actually, most of these rare variants have frequencies of like 0.0003, very rare. So for the first time, we could do this. And to our surprise, what we found was that the 12 genes that came out with the highest significance brought us back away from neuroinflammation to synaptic genes. Genes that involved with neuronal function, synaptic function, synaptic maintenance.
RUDY TANZI: And now, we said, well, we were always so surprised in the field, we didn't land on how can Alzheimer's or synaptic disease not involve synaptic genes? Because the original four genes were all the amyloid. The GWAS genes, the common SNPs were mostly neuroinflammatory. And what was missing was genes involved with synaptic function and maintenance, et cetera. So to find those, we said, finally, here they are.
RUDY TANZI: It looks like its rare variants in those synaptic genes that are involved. Whereas, it's common variants for neuroinflammation. And that to me makes sense because neuroinflammation is the end game of all neurodegenerative disease. It's like the misfolded proteins-- this is very important. The misfolded proteins initiate the disease. Alpha-synuclein causing Lewy bodies in Parkinson's or Lewy body disease.
RUDY TANZI: TDP-43 in ALS, amyloid in tangles and Alzheimer's. So these misfolded proteins kill x amount of neurons. But once that triggers neuroinflammation over the coming decades, the neuroinflammation kills 10x. And without the neuroinflammation, you do not get the symptoms. So without the initiating pathology, you don't get the neuroinflammation. But without the neuroinflammation, you don't get the symptoms.
RUDY TANZI: You will have a resilient brain. We have seen it over and over. But once in a while, people die in their 80s. No dementia when they die. You look in the brain and they have tons of plaques and tangles. You say, wow, how did they not have Alzheimer's? It's always the same answer. They were spared of neuroinflammation.
RUDY TANZI: Their microglial cells stayed [? calm and ?] carried on, housekeeping and cleaning at night rather than becoming reactive and saying, wow, neurons are dying, wipe out the area. They never took off the housekeeping apron and put on the SWAT team outfit. OK. So most people didn't get the disease.
MALORYE BRANCA: Pharma companies have been very stoic in sticking with Alzheimer's for quite a while. And they've had taken a few body blows. Let's be generous there. But just recently, Lilly said, they're refocusing. What do you think is happening? Are people catching on to what you're saying? Is there going to be a new focus, a new generation of drugs? Or are they just going to keep trying the same things?
RUDY TANZI: To be honest, most of the big pharma still follow each other. So Biogen got aducanumab approved. And an approval is an approval. There's a chance to make money. So Lilly has an antibody that's just as good maybe even better than [INAUDIBLE]. There are smaller companies too, like one I worked with called, ProMIS, that has an immunotherapy against Abeta oligomers.
RUDY TANZI: Whether it's a pharma company or a small company, amyloid is still a big target, because the FDA just set a predicate. They approved a drug that removes amyloid based on x amount of removal of amyloid or the x amount of time that's documented by PET scans. This opens the doors. Anybody can come in and say, here's my drug.
RUDY TANZI: I've removed amyloid just as fast over the same time period just as much using the same PET scan. Approve me too. What's the FDA supposed to say? They already set the precedent, aducanumab. So companies who want to approve drugs would be foolish not to follow that example. My warning to companies and to patients and families with this disease is that hitting amyloid, it's a crapshoot as to whether you're going to make somebody better.
RUDY TANZI: Most would say it's not even a crapshoot. It's a guaranteed loss. You have to also hit the right form of amyloid. That's why I like to work with this smaller company, ProMIS. And I do have equity in that company. I'm a consultant for disclosure. Because they're targeting the oligomeric Abeta that I think is the most dangerous to synapses versus the plaque Abeta, which I think you should let lie.
RUDY TANZI: The plaques are more or less inert and neutral. And maybe then you might see some greater effects on cognition. But the bottom line is that most of us who have been in this field like myself, 40 years, amyloid comes early. And amyloid does its job early. And by the time you have even earlier signs of dementia or mild cognitive impairment, amyloid is already peaked, plateaued, and if anything, even has to go down a little bit.
RUDY TANZI: You have to hit it on the way up a decade two, maybe three decades before. So that's where these antibodies and the amyloid that Lilly and Biogen and others are making is going to be useful. The question is, can you make it cheap enough to use it for secondary prevention?
MALORYE BRANCA: Also, can you detect it early enough?
RUDY TANZI: Yes, you can. We have C2N in Wash U, Randy Bateman's company with Dave Holtzman. They have a IP mass spec, relatively expensive Abeta test for the blood, but it mirrors pretty well what's happening in the brain. So I could see the future being that at some age, you get a blood test to see how your amyloid is. If the results look alarming, you might check further with a PET scan.
RUDY TANZI: And then the doctors decide OK, for your age, you're in the upper 90 percentile for amyloid. You need the antibody. We got to perform liposuction on your amyloid. We've got to suck it out of the brain. OK. So you're going to get the antibody. Then after that, we're going to keep the amyloid low with the equivalent of a statin for amyloid.
RUDY TANZI: Maybe it's going to be my gamma secretase modulator since the small molecules will last man standing even though we're academia, we were funded by the NIH blueprint. Based-inhibitors are not safe. Gamma secretase inhibitors are not safe. We always bet on gamma secretase modulators that Steve Wagner, my colleague and I for 20 years. And we're finally going to go into phase 1 over the coming year.
RUDY TANZI: So I think we're going to win that battle. But you might get on a cheap little white pill like gamma secretase modulator after the antibody does its work, maintain, check a year or two later to see how you're doing with the blood test. If it looks like you're OK, great. It doesn't, let's do another scan. So we're going to monitor amyloid buildup. And if your amyloid is high, we're going to check your tauopathy, your tangles, things like phosphate tau 217 or 181 or 231.
RUDY TANZI: And if that looks high, you're going to go get a tauopathy imaging test. And it may be that if it's so bad, you might need immunotherapy to stop tau propagation. So a lot of companies now are using antibodies to stop the spreading of propagation of tau, but they're now disappointed that doesn't make patients better. It doesn't make patients better because it's part of the initiating pathology.
RUDY TANZI: The tangle is just a brush fire that's lit by the match of amyloid or the bang to the head. You have to hit that decades before.
MALORYE BRANCA: Do we know what time?
RUDY TANZI: Well, companies have to realize that these initiating events happen anywhere from one to two to three decades before symptoms. And they have to stop just following each other like lemmings off the cliff. OK. Saying, oh, someone is starting doing tau propagation antibodies. We have to do that too. Think for yourself.
RUDY TANZI: Look at the overall data, read some papers, look at the brain imaging data, look at what's happening. Don't try to treat a pathology that happened two decades ago to get the cascade going now that somebody has full-blown dementia. In a full-blown dementia case, look at what's happening. It's rampant neuroinflammation causing synaptic damage and cell death. You have to put that fire out, or you have to protect against that fire.
RUDY TANZI: So the first example of success in protecting against a fire was a company I started just seven years ago called Amylyx, A-M-Y-L-Y-X. I own equity in the company. I'm a co-founder. But seven years ago, two kids from Brown University, they were kids, undergrads, came to see me for a science project. And we talked about ideas about how to protect neurons against neuroinflammation, protecting cell death at the level of mitochondria and the endoplasmic reticulum, the ER.
RUDY TANZI: We did some early experiments. And I was amazed that these two drugs that we were testing, one to prevent mitochondrial apoptosis, the other to prevent ER-driven apoptosis. We put them together, and you could put a hydrogen peroxide on neurons in our dish, kill them all, and these two drugs together, not alone, save 90% to 95% of them. So we decided to go for ALS first, because it's a quicker route to trial.
RUDY TANZI: And it's a very devastating disease unmet medical need. So we did a phase 2 ALS trial, 150 patients, and it worked. We did it at Mass General. My chief, Merit Cudkowicz, ran the trial at the Healey Center. We published the trial in the New England Journal of Medicine, successful trial. And now, this little company, Amylyx, is looking at probable-- I wouldn't say guarantee, but it's looking very good for approval in Canada, Europe, and the US hopefully over the coming year or so.
MALORYE BRANCA: And that's for ALS.
RUDY TANZI: I don't want to make any formal statements on behalf of the company. But at this stage, they're saying that they have a chance for approval now for ALS. And you can try this in-- now, they're trying to get Alzheimer's and other diseases. First time, yeah--
MALORYE BRANCA: When we talk about Alzheimer's, are we talking about a range of diseases or are we talking about one condition?
RUDY TANZI: The disease is heterogeneous in many ways. How do you initiate the disease? In some folks, they're making normal amounts of Abeta amyloid and tangles like the general population. But they have genes that ramp up their neuroinflammatory response when that time comes. Others have genes that just ramp up the amyloid early on. Others, like we just recently found in our newest genetic study, have genes that make synapses more vulnerable to amyloid and neuroinflammation from the whole genome GWAS.
RUDY TANZI: So there's many different routes to get there. But in the end, it's neural inflammation that takes you out. If you want to treat a patient who's symptomatic, no matter how you got there, you have to stop neuroinflammation or protect against it--
MALORYE BRANCA: But if you're treating a patient--
RUDY TANZI: --along the way--
MALORYE BRANCA: --pre-symptomatic, if you are trying to prevent the disease, you need different range of drugs?
RUDY TANZI: Exactly, Malorye So it's a pre-symptomatic early intervention stage. That's where heterogeneity comes in. So in some folks, it may be more important to stop amyloid. In some folks, it may be more important to stop the tau pathology from spreading. My guess is if you have drugs that safely promote amyloid clearance by microglia like a little white powder that does what [INAUDIBLE] does for 100 times less money, or when you have a drug that stops the tangles some spreading, any drugs to stop initiating pathologies-- I think despite the heterogeneity,s we're seeing heterogeneity in how the tangles spread, the type of tau phosphorylation, despite that heterogeneity, if you have drugs that promote the clearance of amyloid that's initiating or hit the amyloid production like gamma secretase modulators, or drugs to stop the tangles from spreading, they're going to be useful in everyone despite the early heterogeneity.
MALORYE BRANCA: But you're seeing this as an anti-cholesterol, but it's something that people will take. They'll be deemed at risk. They'll take a preventative medicine and that will reduce their risk.
RUDY TANZI: That's right. Yeah. I see it exactly analogously to checking your cholesterol when you're young and taking care of your cholesterol levels decades before you might get heart disease. That's how we put a big hit on heart disease. And remember, no one believed Brown and Goldstein when they first showed this one family, early onset hyperlipidemia, and they said, it's the LDL receptor mutation, maybe cholesterol has something to do with heart diease, they got the same criticism that we got when I discovered and others discovered the familial Alzheimer genes.
RUDY TANZI: And we said, it's amyloid. And this controversy and the media loves it. They love to whip up the controversy and make scientists look like stupid kids fighting with each other. But the smart scientists don't do that. They don't look at whether something's involved. They look at when it's involved. That's the mindset change we need.
RUDY TANZI: Not whether, when. And when tells you when to hit that pathology, whether it's secondary prevention pre-symptomatically versus what you have to do in a patient who is suffering right now, we have to hit neuroinflammation or protect neurons from oxidative stress. You have to always look at the [? potential ?] order of things and then determine when to hit. And this is something that pharma has not done well.
MALORYE BRANCA: No. They really follow each other. What are the next big questions? Your paper was a revelation in terms of steps forward and our understanding of Alzheimer's disease. But what are the outstanding questions? What are the next things that we need to solve?
RUDY TANZI: Well, I think when you look at-- thanks for your words about the paper. I think it was a unique study to use. It was the first study to use whole genome sequencing as input for GWAS, where you're capturing all the rare variants. And we were surprised as anything to see instead of hitting amyloid genes or neuroinflammation genes like we've seen in the past from the early studies in the 80s and 90s on getting to amyloid to the GWAS studies, it's that neuroinflammation to finally see synaptic genes.
RUDY TANZI: I think what these groups of genes tell you what are the best targets for either preventing the disease or treating the disease? So if you're going to hit all the first four genes we found in the 80s and s say, amyloid, so you can try to stop amyloid production safely. I think our gamma secretase modulators that don't block gamma secretase but that allosteric modulators of the gamma secretase docking site, so you make small Abetas rather than longer Abetas that are less prone to form amyloid.
RUDY TANZI: We shift from longer Abeta to shorter Abeta. We don't just hit gamma secretase with a sledgehammer like Lilly did and got in trouble. But beta secretase hit it with a sledgehammer. You can't. These enzymes are too important. Instead of hitting with the sledgehammer, you have to tweak them with the jeweler's screwdriver. That's what we're doing with the gamma secretase modulator.
RUDY TANZI: And then you have drugs that can promote microglial clearance of amyloid. That's what Aduhelm does. But we have many drugs from our drug screens and from Alzheimer's in a Dish model, the brain organoid model, where we could do what Aduhelm does with cheap little white powders and nutraceuticals just as well. And we're testing that in mice now to see if those could become a replacement that's cheap enough that you could use it for secondary prevention in 38 million people.
RUDY TANZI: That's our goal. That's how we're going to prevent the disease. But in terms of treating the disease, I like for example what Denali, and Alector, and AbbVie are doing. They're targeting the main neuroinflammation genes like CD33, trying to turn it off with an antibody. For disclosure, I do have-- I'm the inventor on the issued patents for CD33 gene therapy and immunotherapy.
RUDY TANZI: So I have to disclose that. But I like what the idea of activating TREM2. That's something that using Christian Haas' antibody to activate TREM2. So I think now that there are some companies who are ahead of the curve like AbbVie doing the deal with Alector on CD33 and TREM2. Denali doing CD33 and TREM2. I don't know how much of big, big pharma are doing it other than them, but that's the way forward for treating patients is that you have to learn from the neuroinflammation genes.
RUDY TANZI: Then finally, these new genes we found from whole genome sequencing based GWAS, the synaptic genes would tell us how we might provide resiliency to synaptic [INAUDIBLE] Because at the end of the day, no matter how you get there in Alzheimer's, the degree of dementia correlates with the degree of synapse loss. So that's why I tell everybody when I write my books on the side, build up your synaptic reserve with the same rigor and vigor as you build up your financial reserves.
RUDY TANZI: Because the more synapses you make, the more you can lose before you lose it. Because you want to build up those synapses, because they're going to get hit as you get older. But suppose with these new genes we found from the whole genome sequencing GWAS, we can learn exactly what the target to provide resiliency and synapses to make them less likely to die in the face of amyloid, tangles, and neuroinflammation.
RUDY TANZI: So I think have to look at-- the genetics is always telling us the targets. But importantly, the genetics also tells you when you have to hit that target. And the earlier the onset of the genetics, the more you're into secondary prevention area. The later the onset of the genetics in terms of age of onset, the more you're into treating patients right now.
RUDY TANZI: It's a rule of thumb that people forget.
MALORYE BRANCA: What kind of barriers does this raise? Are people going to volunteer for these trials?
RUDY TANZI: Oh, yeah. So I'm a co-director of the McCance Center for Brain Health at Mass General Hospital. We're doing trials right now on supplements, nutraceuticals that we find work in our Alzheimer's in a Dish model. We created these 3D [? nueroculture ?] models. For the first time, we could show--
MALORYE BRANCA: The organoids?
RUDY TANZI: --the organoid. It's more of a 3D culture, because it doesn't have the same development as an organoid. It's more amenable to drug screen. We call them 3D cultures you can call them organoids. But we get a plaque in four weeks. These are stem cell-based neurons. They have to be mature neurons. IPS drive neurons do not work in this model. They're too immature.
RUDY TANZI: We have to use either the human embryonic stem cell line derived neurons or direct fibroblasts to neuron neurons. IPS derived neurons don't work. So we put the Alzheimer's genes in these neurons. You get amyloid plaques in four weeks, wait about a week you get full-blown tangles, [INAUDIBLE] some endogenous tau. We could show for the first time what mice did not show us. Amyloid directly induces tangles.
RUDY TANZI: We have to be honest, the most referenced paper in our field, the amyloid cascade hypothesis, was a hand hand-waving argument for why mice didn't get tangles. We now know mice don't get tangles after you put amyloid genes in the brain, because they can't make tangles. They have the wrong isoforms of tau. You need 50-50 3 BP, four BP tau like the adult human brain to get a tangle.
RUDY TANZI: They don't have it. So people said, OK, well, we're going to speculate from amyloid to tangles as 10 arrows. And it takes so long, the mice don't live long enough, thus, the amyloid cascade hypothesis. Most referenced paper in the field. All mainly driven by a hand-waving argument to explain away why amyloid looks like the cause of disease.
RUDY TANZI: All the genetic says this, but the mice won't get tangles. Well, now, we know they can't make tangles. You do it in a dish model, amyloid makes tangles directly. And then if you add in microglial cells on the side, you can see they get recruited once neurons start dying with plaques and tangles, and microglial cells come in. They start eating synapses and axons. They activate the astrocytes.
RUDY TANZI: The astrocytes [INAUDIBLE] synapses. The whole thing is modeled in a dish in five weeks. So this has made drug screening, supplement screening, nutraceuticals, natural products screening 100 times faster, 100 times cheaper. You can't--
MALORYE BRANCA: Do you have volunteers who are taking these drugs?
RUDY TANZI: Well, we have. Right now, we're at the stage where we spent five years and many millions of dollars. Cure Alzheimer's Fund and the NIH funded this [INAUDIBLE] Cure Alzheimer's Fund the best research foundation really on the planet for Alzheimer's in terms of high-impact research. And they funded this. And now, we have like over 100 approved drugs and natural products, we've identified to either stop the amyloid production safely, induce microglial clearance of amyloid like Aduhelm, stop amyloid from inducing tangles.
RUDY TANZI: Forty different drugs would do that. The amyloid is there, but you don't get tangles downstream. We can prevent that. Then we have about 40 drugs that prevent the reactive astrocytes and microglia that cause--
MALORYE BRANCA: These are all in development?
RUDY TANZI: These are all identified in the dish model. And now, we put together a task force with Cure Alzheimer's Fund to pick out which of the drugs and natural products are safest and most efficacious to stop platform clinical trials. So we're talking to, for example, Howard Feldman at UCSD and the National Alzheimer's clinical trials. We're setting up our own thing at Mass General. We already started one of the trials on one of the natural nutraceuticals at the McCance Center.
RUDY TANZI: One of this is already ongoing. So we're making that shift now into saying now that we can screen for approved drugs and natural products using these dish models so quickly, and we can target exactly what pathology we want and pick out combinations. That what we did with Amylyx. Amylyx, it's very likely over the next year going to get approved for ALS and they're doing an Alzheimer's trial now.
RUDY TANZI: It was picking two drugs, one drug, one natural product, one protected mitochondria, one protected ER. There was a taurine analog called [INAUDIBLE] that protected mitochondria. It was a short chain fatty acid phenylybutyrate to protect the ER from the unfolded protein response. And then those two drugs together led to a successful ALS trial and protected neurons against oxidative stress and neuroinflammation.
RUDY TANZI: So now, we're trying to repeat that saying, let's see if we can hit amyloid that way, tangles that way, amyloid induced tauopathy, tangles spreading, microglial activation, the ability of microglial cells to activate astrocytes, neuroprotection. But now, it's 100 times faster, 100 times cheaper, because we have these dish models. And we don't have to depend on mouse models, which were unreliable to begin with.
MALORYE BRANCA: Well, yeah, that sounds like a huge hurdle that you've overcome. Is there anything else that you see in your way between now and taking these to the final finish line?
RUDY TANZI: Money. Look, it's hard to get companies to fund repurposing trials. If you're going to repurpose a drug, or add it, or do a combination of a repurposed drug and an actual product, you have to start a small company that then generates intellectual property around that combination like Amylyx did. But big pharma won't come in until you do that combination. You get the idea that it's efficacious.
RUDY TANZI: So that's what Amylyx already did. So we're on our own to-- so luckily, we have folks like the Cure Alzheimer's Fund, the NIH, other philanthropic donors, who are helping to find these early platform trials. And if you get the right combination, yeah, then you launched a biotech company around it. You get the IP around it. Then you get pharma interest.
RUDY TANZI: But it has to start organically. But that's where we're at. We have our list. We're checking it twice. We're going to go-- not go on to pilot--
MALORYE BRANCA: Are you doing any more genetic studies?
RUDY TANZI: We're always doing genetics. I've never stopped doing genetics since finding the first SNPs in 1980 out of college. And we're doing more whole genome sequencing. In fact, we just analyzed 30,000 whole genome sequences, both common SNPs and rare SNPs. And we just identified five or six more genes that reach genome wide significance that we're going to write up for publication very soon. So it's important to keep that pipeline of genetics coming in, because those are the targets you have to hit.
RUDY TANZI: But pharma has to get it through their heads that a target tells you not just what to hit, but when to hit it.
MALORYE BRANCA: Exactly.
RUDY TANZI: You can't just wait for-- the elephant in the room here, Malorye, is with Alzheimer's and neurodegenerative diseases. We wait until the brain degenerates to the point of dysfunction before we treat it. So we're reactive. Imagine if we did that with diabetes. We said, we're going to wait until you lose half of your [? eye, ?] your beta cells, and your pancreas. And then we're going to treat you.
RUDY TANZI: Well, imagine if we did that with heart disease. We're going to wait to see when your heart doesn't-- starts to get clogged up and doesn't work very well. Then we're going to try to treat you. And that sounds absurd. But that's what we do in Alzheimer's. So that's why we started this McCance Center to be proactive. Early detection, what are the indicators of brain health? I started a company called REACT Neuro, where we have a modified VR device that does a VR neuropscyh exam, eye scanning, and voice analysis.
RUDY TANZI: So it can predict Alzheimer's or brain health issues decades before problems. We're hoping that this device that takes two minutes to do the brain health exam will be in every single doctor's office someday. That when you go for your physical every year, at the end, you get your mental. You get two minutes of-- think about it, your doctor gets from the neck up.
RUDY TANZI: Like Patrick Kennedy says, there's no checkup from the neck up. They get from the neck up and they look at the holes in your head, mouth, nostrils, eyes, ears. OK, you're fine. Isn't there something up here under my skull? Yeah, we don't do that. So we want to change that. We want to get to the point where you see early changes in the brain, early detection just like we do for the heart, the pancreas, or the lungs.
RUDY TANZI: Early detection, early intervention. And use the right drug at the right time. So that's the goal. And we just hope pharma will adopt this mentality and stop just being reactive and chasing the next big drug that fails and works with us to do this. That's my hope.
MALORYE BRANCA: Well, that's fascinating. I have to say thank you first of all, the body of your work and for the time that you've spent with us today. And I will circle back with you with some fact checks. I'm sure that it was just fascinating talking to you again Thank you so much.
RUDY TANZI: Well, thank you for having me, Malorye. I enjoyed the conversation.
MALORYE BRANCA: Take care.
RUDY TANZI: Thank you. [MUSIC PLAYING]
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