Alzheimer’s Neuroscience • McCance Center / Rudy Tanzi
Stop the Wildfire Early
Can we stop Alzheimer’s before it starts?
Dr. Rudy Tanzi – Harvard Medical School professor, Director of the McCance Center for Brain Health, and one of the pioneers of Alzheimer’s genetics – joins UnNatural Selection to explore how decades of discovery are changing our approach to one of humanity’s most feared diseases.
Tanzi explains why the field is moving from treating symptoms to early prediction, early detection, and ultimately prevention—and how genetics, biomarkers, human brain models, and drug discovery are converging to make that possible.
But beneath the science is a broader lesson about innovation: find the causal mechanism, move upstream, use extreme signals to reveal hidden structure, and place multiple bets where the potential payoff is asymmetric.
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Nic (05:10.997)
Rudy, welcome to UnNatural Selection.
Rudy Tanzi (05:15.843)
Thank you, happy to be here.
Nic (05:17.769)
It's it's an honor having you here. the the work that you've done is extraordinary and inspiring. And before we get to that, I always start with the same question just to give you a chance to give some context and level set for the sake of the listeners. And so through the course of your career, Rudy, could you give us a sense of what need or impact drives your work?
Rudy Tanzi (05:43.843)
Well, I've been working on the puzzle of Alzheimer's disease at Mass General Hospital from when I was even going back to when I was a before I was a student at Harvard Medical School, when I was working as a research assistant with Jim Gasella and we were the together the first ones to find a disease gene of any type using genetics. It was like I say, Jim Gasella's idea and my hands and
And he's only five years older than me, where we were couple of kids testing the first genetic linkage markers to find the Huntington's gene. And well, 1982 I said I'd like to have my own project in anticipation of my doctorate thesis at at Harvard. So I started working on Alzheimer's in eighty-two, did the first genetic linkage studies there. and I gone from genetics to model systems to drug screening.
To drug invention. And the drug that my late colleague and I invented is widely believed by the field now to be our greatest hope for a small molecule that will someday be used to prevent the disease in a system of early detection, early prevention, with the goal of eradicating Alzheimer's by nipping it in the bud at the time that the first pathology might show up.
So it never gets to the point of symptoms. so you know, Alzheimer's is one of the worst diseases you can have. If you ask people what disease they fear most, surprisingly it number one answer is Alzheimer's disease, because it robs you of yourself. It you know, you spend your whole life in building your neural network and and storing up memories and experiences that define who you are and your loved ones, and then it rips rips that away.
Nic (07:26.445)
Interesting. Mm-hmm.
Rudy Tanzi (07:40.591)
It's a insidious thief. So I see it as probably one of the most unmet medical needs in the world. And I've spent now, well, four over f about forty five years almost studying this disease. And what I'm happy about is that everything in that those last four or five decades has come into fruition right now, meaning that my clinical trials are all starting right now. and it took this long to come up with the drugs that we're trying and
And and patience.
Nic (08:11.521)
That's extraordinary. So it's it's it's really great. I and and I've known people that have suffered from it. It truly is a terrible disease. you know, you just it's it's terrible for the families and for the victims. They both suffer in different ways. And it's it's really exciting and encouraging to hear that such progress is being made. For a while, a lot of the big pharma companies were divesting from neurological disease.
And so is there a resurgence in in interest in in these fields?
Rudy Tanzi (08:42.69)
I think there's a realization about the approach, which is the first problem is we do not diagnose neurodegenerative diseases like Alzheimer's and Parkinson's disease until there are symptoms. Well, the symptoms show up decades after the first pathology. And it's only when that initiating pathology, usually misfolded proteins,
Cause enough damage to lead to a vicious cycle of neuroinflammation that you lose enough neurons and synapses in the part of the brain where the disease was initiated to then have a movement disorder like Parkinson's disease or a memory and learning disorder like Alzheimer's. So the way we diagnose Alzheimer's disease today would be the equivalent of not diagnosing heart disease until you almost have congestive heart failure.
and at that point, it's too take it's too late to just watch your cholesterol or take Lipitor and manage your cholesterol. And we had to come to the same realization about Alzheimer's disease, that amyloid was controversial as the cause in a completely analogous way in the early days to cholesterol was controversial as the cause of heart disease. How we got to cholesterol, early onset, familial disease.
Fully penetrant gene mutations that guarantee disease by 50 or 60 years old. Brown and Goldstein, the LDL receptor mutations that guaranteed heart disease at an early age and it implicated cholesterol. The work I did here, Mass General, finding the first V familiar early onset Alzheimer's genes, and I say finding meaning we were a team. We I like to see we co-discovered, I co-discovered those genes with others, including at other institutions.
But the first three early onset familial Alzheimer genes all said the same thing. Amyloid is what causes this disease. And the reason why pharma companies dropped out is because they were trying to hit amyloid when a person already had the diagnosis of the disease. So I like to say it's like if amyloid was the match, the lights to fire, and the first brush fires are the tangles, the tau tangles that start killing neurons.
Rudy Tanzi (11:05.218)
You don't get the disease in terms of symptoms until you get the wildfire of neuroinflammation. So here's a patient diagnosed with the disease, the wildfire is blazing. And we're going in there in the early days trying to just blow out the match, the amyloid. Similar to giving a person who needs a coronary bypass lipator and saying, Here you go, good luck. And so I think pharma companies had to realize that amyloid does cause this disease.
The faster you make amyloid, the sooner you get this disease. But it's something you have to treat 10, 20, or even 30 years before symptoms, the way we manage cholesterol to avoid heart disease. Now, with that realization, with the FDA on board saying, yeah, we'll take a shot at that, that let's hit that early pathology and see if we can prevent this disease. Now companies are coming back to this. But that's why they were leaving.
Nic (12:01.389)
Interesting. I do we have a clear sense of what causes Alzheimer's? I've heard everything stories from I I've even heard it's like type three diabetes. It's so some kind of
Rudy Tanzi (12:12.459)
Yeah, I know. No. That was that was for that was just for headlines. Yeah, no. what causes Alzheimer's disease is amyloid. It's amyloid deposition. And I say causes because it triggers the disease. I mean the COVID virus, you know, can cause cell death. I mean can cause death of an individual in the early days.
Nic (12:18.294)
Okay.
Rudy Tanzi (12:39.127)
But you didn't die from the virus. The virus set off a cascade of events, eventually leading to enough inflammation and tissue damage in the lungs that you died. Amyloid is initiating this disease. HIV causes AIDS, but you die of cop using carposarcoma. So in this case, amyloid is what triggers the disease. And all of the gene, the early onset genes, even the most common risk factor, APOE4.
All say amyloid. Beginning in the early 2000s, using GWAS, genome-wide association studies, to get to the rest of the genes and early f going from early to late onset disease, we found the first one here in my lab, and that was CD33. CD33, we had no idea what it was. It's a gene in the microglial cells that ends up controlling both amyloid removal and inflammation.
And now we know of over 120 Alzheimer's genes from GWAS, and two-thirds of them are microglial genes that control, whether microglial cells are going to clear your amyloid, which the new Alzheimer drugs help to facilitate, or whether they're going to go into a pro-inflammatory state and cause neuroinflammation. They're the true Dr. Jekyll and Mr. Hyde cells. They can be your best friends helping to clear your amyloid.
By phagocytosis uptake and clearance. But if they're exhausted and overwhelmed or they get the wrong signals from dying neurons that they assume must be due to an infection, microglial cells don't discern cell death. They don't try to figure out what's causing it. They first assume it's an infection, even if it's not there, and they say, wipe out this part of the brain. That's inflammation. So two-thirds of the late onset Alzheimer's genes all control microglial activity on that.
spectrum of housekeeper cleaning up amyloid versus converting into killer causing neuroinflammation. so what causes the disease, well what triggers it is amyloid. The faster you make amyloid over your lifetime, the sooner you get this disease. Down syndrome patients, which got me into this disease because I was studying chromosome 21 originally, trying to build a map of that chromosome way, way back 40 years ago, 45 years ago.
Rudy Tanzi (15:06.533)
they have an extra copy of the APP gene, the gene I isolated from my doctoral thesis at Harvard, the amyloid precursor protein. and so they make more amyloid from day one, and they get amyloid deposition in their brain at the rate at the same level as an Alzheimer's patient by middle age. And then that cascade keeps going out to tangles and neuroinflammation. So the controversies over about amyloid.
Nic (15:25.399)
Well
Rudy Tanzi (15:34.943)
Anybody who still thinks there's a controversy needs to pick up scientific papers and read rather than just think what they want. It's that simple. saying amyloid doesn't cause Alzheimer's disease now is like saying cholesterol doesn't lead to heart disease. And it's it's like I said earlier, it's perfectly analogous. You can't just treat cholesterol after you need a coronary bypass. You had to do that before. You can't just treat amyloid when you have a full diagnosis of this disease.
And the brain's already deteriorated to the point of dysfunction. We have to back it all up to secondary, someday primary prevention, early detection, early prediction based on genetics and biomarkers, and treat early before that that cascade begins.
Nic (16:23.967)
Yeah. No, I I I'm a huge fan of prevention. It's the whole basis of the program that I co founded with Dr. Green, who we both know very well. And you you mentioned about a hundred and twenty markers for Alzheimer's. It's at this point, what's her level of confidence in be able to being able to predict whether somebody will get Alzheimer's or not? Is it I know it's probabilistic, but is it a multi multi omics
Problem where you have the markers and you may or may not get it depending on your lifestyle and your exercise and all that, or is it mainly genetics?
Rudy Tanzi (16:59.713)
Yeah. So we have 120 loci with multiple genetic variants at each locus. So it's a little bit more than just a marker. We know the gene. In most cases, we know the genes. And but here's the thing is if it's early onset for middle Alzheimer's disease, like the first three genes we found in the 80s and 90s, those gene mutations guarantee the disease by 60 years old. So that's fully penetrant, 100% predictable.
Fortunately, that's only 1.5% of Alzheimer's disease. And then you get to ApoE4, which is the most common late-onset genetic risk factor. And APOE4 is present in a good 25% of the population. But if you look at Alzheimer's patients, it's in 50 to 60% of them.
So, but ApoE4 does not guarantee the disease. having two copies of ApoE4, which is about 10% of patients, pretty much guarantees you're gonna have amyloid at some point in your your life. One copy does not say you're gonna live long enough to have amyloid in your life. So ApoE4 is not fully penetrant. and if you take the late onset risk factors, you know, 120 other genes.
And you add up their effect on risk using a polygenic risk score, it's still really not greater than ApoE alone. E4 is the biggest gene. so we kind of gave up trying to come up with a really definitive polygenic risk score because if you look at the effect and area under the curve, ApoE4 kind of is equivalent or
maybe a little below looking at all of these different markers and SNPs and other loci put together. So what we what we're doing now in my lab and other labs are starting to do this too is we're trying to find all the gene variants and and SNPs that offset APOE4 risk or either exacerbate it or mitigate it. We think it's more valuable that let's APOE4 is the big daddy, let's
Rudy Tanzi (19:26.898)
Use that, but let's find all the other variants that either increase or decrease risk significantly given the inheritance of E4. Because if otherwise you take all those 120 other Alzheimer's loci from GWAS and say, let's combine those together with ApoE4 for a polygenic risk score, the prediction isn't much greater than Apo E4 alone. It's it's so such an amazingly prevalent you know, such a huge effect size genetically.
And that's why Rob by Bob Green, you know, your buddy and our buddy spent so much time working on E four and predictability and getting doing the most pioneering work on whether patients, whether folks who have E4 wanna really know or not. I mean he he was the first to do that.
Nic (20:12.629)
And so so so again, given this probabilistic nature and and where you're focusing on is upstream on the prevention side, what are the kind of indications that tell you whether somebody should be the an intervention should be applied towards somebody that has susceptibility? Is it having one of these genetic markers what you know, or or is it other physiological symptoms or is that a combination of them? How do you know?
Rudy Tanzi (20:40.618)
Yeah. Sure. Yeah, so let's so I like to use the term early prediction, early detection, early intervention. Early prediction being genetics family history. So if you have very strong genetic susceptibility, like Down syndrome, the early onset familial Alzheimer genes that we co discovered.
Nic (20:41.175)
Put this person on a treatment.
Rudy Tanzi (21:08.572)
Which is APP gene, the presinal one gene, the presalin II gene, all co-discovered here at Mass General. actually the APP gene I isolated at children's hospital because I was in a Down syndrome lab working when I was a student. so those three genes with a hundred, you know, now five hundred mutations in those three genes, 1.5% of all Alzheimer's guarantee the disease. So if you in so if you're born with one of those, you don't wait for biomarkers to say you've begun pathology.
You know you're going to get it. You start as early as possible. And I'll get to what the drug I think is going to be in a moment. Same thing with Down syndrome. Now, in ApoE, the most common late onset, biggest risk factor there, ApoE4. I would say if you have two copies of ApoE4, you know, your risk is increased. It's, you know, it's it's about 3.7 fold over, as you know, just a common ApoE3 variant.
Nic (21:39.917)
Mm-hmm.
Rudy Tanzi (22:07.409)
and there you may not begin primary prevention. So we so for Down syndrome, early onset, familial Alzheimer's, primary prevention, you don't wait to see pathology beginning. You know you're gonna get it. Right. For one copy of ApoE4, you know, if you had something super safe, democratized, is very affordable, sure you might try it. The way I the way you take a statin for heart disease. But it's still
Nic (22:19.287)
Mm-hmm.
Rudy Tanzi (22:34.496)
you know, questionable as to when and how we're going to have that type of treatment. Now, if you have two ApoE4s, and you know, that's not as common and it's, you know, you know, the the E4 variant is the minor allele of the of the of the of of ApoE. there I would say if you have two E4s, then latest studies say you're probably gonna live long enough given
lifespan right now to have Alzheimer's pathology. You may not have symptoms of Alzheimer's disease because the pathology didn't translate enough to that cascade of cell death and synapse loss to get symptoms, but you're going to have amyloid in your life, with very few exceptions. Very few. So there you might think about primary prevention rather than secondary prevention, should you have a safe enough and affordable enough drug.
Nic (23:09.29)
Mm-hmm.
Rudy Tanzi (23:34.084)
so that's that's so I think right now, so if you think about it, when I started in this field, we had nothing. Then we waited for you to get the disease and have cognitive impairment, and there were drugs like Aricept and Reminil followed by Namenda that basically treated the symptoms. Let's make the most of those neurons you have to improve your cognition, treating symptoms, but we're not really hitting the progression of the disease. And then
Nic (23:39.917)
Mm-hmm.
Rudy Tanzi (24:04.312)
there were all the failures of amyloid drugs because we were making the mistake of trying to treat amyloid when somebody already had full-blown disease, which as I said earlier, it's like a wildfire is blazing and you're trying to blow out a match. The match started 22 years ago. And that's why a lot of companies like Pfizer left the space. And then we came to the realization that there's a compromise. And it's very similar to how statins came around for cholesterol, because what happened was
Nic (24:17.887)
Mm-hmm. Yeah.
Rudy Tanzi (24:33.407)
We knew that antibodies could be used, immunotherapies, like the now-approved Lakembi and Kasumla, to basically get microglial cells to eat more amyloid. That's what those antibodies do. The antibodies to amyloid, the antibody gets into the brain, a little bit of it. The antibody binds to the amyloid. Then the IgG domain of the antibody binds to a receptor on microglia called the FC gamma receptor.
And that gets the microbial cells to go and clear the amyloid and get rid of it. And if and in the early studies, going all the way back to Bapenusimab and the earliest antibodies, they were treating late-stage patients. They were removing the amyloid, but there was so much inflammation and cell death and synapse loss ongoing that you could blow out all the matches you want. The fire was blazing. And then finally, there was Azi working with BioGend that said.
Nic (25:22.841)
interesting.
Rudy Tanzi (25:30.569)
Let's, you know, let's push it back to the earliest stage of the disease. The fire is just beginning. It might still make a difference if we blow out the rest of the matches. Let's take the earliest stage of Alzheimer's. And after their phase two, doing a lot of modeling, they said, here's how big and how long the trial has to be. If we take the earliest stage of Alzheimer's and start getting rid of amyloid and see if we can do something to cognition.
Nic (25:34.029)
Mm-hmm.
Nic (25:42.625)
Mm-hmm.
Rudy Tanzi (26:00.416)
So they had to use 1,800 patients for 18 months. You know, I don't know, it costs a billion dollars, very expensive trial, right? And what they found was that by getting rid of the amyloid at that earliest turning point, going from pathology to the first mild cognitive impairment symptoms, that after 18 months, those who got rid of the amyloid with the antibody, immunotherapy, went downhill 25% more slowly.
Nic (26:30.837)
Wow.
Rudy Tanzi (26:30.847)
Basically, in skiing terms, you took them off the blue slope and you put them on like a tougher green slope, not fully green. Okay. So that's that's that's how those drugs got approved, because there was a significant effect on cognition. You didn't make them better, you didn't keep them even, you just went downhill more slowly. And the FDA said, Well, that's better than nothing, right? At least we can do something for them. So now
Nic (26:38.933)
Nic (26:50.146)
Mm-hmm.
Nic (26:56.333)
Mm-hmm.
Rudy Tanzi (26:59.717)
With the FDA coming around to that idea that hitting that pathology early is a good idea, then many others have now are now trying to do the same. So what is that? That's still treatment, but it's right on the border of secondary prevention. Now you might say to me, well, if we have things that can remove amyloid, like immunotherapies, why don't we use them for secondary prevention? How about all those people? We have biomarkers now, like.
Nic (27:27.693)
Mm-hmm.
Rudy Tanzi (27:27.851)
PTau 217 blood biomarker that can very effectively tell you if you have plaques and tangles in your brain. And if you tested everyone in the US, most estimates say 30 million people would find out that have P-Tau 217 positive positivity in their blood, meaning they started plaques and tangles already, because these are older people. And why not give them all the antibody now and just give it to the amyloid? Well, the antibody has issues. It can cause edema and swelling.
Nic (27:47.981)
This for a tenth.
Rudy Tanzi (27:57.14)
It can cause microhemorrhage. You have to have MRIs to make sure you don't have edema in microhemorrhage. Fortunately, that's 99% reversible, but you have to keep track of it. So it becomes a very expensive treatment over 50,000 per patient. And that's why, you know, CMS, let's go to Dr. Oz and say, hey, 30 million people need this immunotherapy, and it's gonna cost 50,000 per person. Uh-huh. Where's where's that gonna come from? So but in a perfect world.
Nic (28:06.167)
Mm-hmm.
Rudy Tanzi (28:27.657)
If that immunotherapy was perfectly safe and cheap, then 30, then you everyone over 40 or 50 could be tested for P tau 217. 30 million people would find out they don't have Alzheimer's yet, but they're on their way with increased risk if they live long enough, and you nip it in the bud. unfortunately, the antibodies are not safe enough and and and affordable enough to do that. So that brings up my drug.
And the drug that my late colleague Steve Wagner, who died during COVID and I invented 25 years ago, called a gamma secretase modulator, not inhibitor. Okay, gamma secretase modulator. So companies early on, when we realized the two enzymes that clip the amyloid precursor protein to release the A-beta peptide that makes amyloid, beta-secretase first.
Gamma secretase second. Normally the clip is alpha secretase, which clips right in the middle of A beta, you don't make amyloid, right? That's the most common clip. So folks first at Lilly tried to make gamma secretase inhibitors. And we and many others said, but wait a minute, gamma secretase is an essential enzyme for the whole body. It's after you have a membrane protein get clipped and shed, you leave behind a stub, that's the stub removal. You can't just
Nic (29:56.557)
Mm-hmm.
Rudy Tanzi (29:57.161)
Stop that, you're gonna get into trouble. And sure enough, that trial was a disaster in terms of safety. And so at that around that time, my colleague Steve Ryder and I in about 2001 invented a drug that we call the gamma secretase modulator. And it was first inspired by some work on NSAIDs, where it was shown that so many NSAIDs like therboprofen, ibuprofen, didn't inhibit gamma secretase.
But they modulated where gamma secretase would cleave. And but they weren't very powerful. The first NSAIDs, they weren't powerful enough, they didn't get into the brain very well. So my colleague Steve Wagner and I started started a little company back then called Neurogenetics. And we screened, we did a high-throughput screen and said, let's find drugs that very simply reverse what the familial Alzheimer's disease mutations do.
Nic (30:27.944)
interesting.
Mm-hmm.
Rudy Tanzi (30:52.116)
Well, all the familial Alzheimer mutations and APP, presenol one, presinolone two, all 500 something of those, except for five of them, do the same thing. They increase the longer A beta peptide that's 42 amino acids long, versus the more common one that's 40 amino acids long. So he said, let's just find a drug that basically reverses the ratio. Instead of 42 to 40 going higher.
Like these rare early onset mutations do, let's find drugs that make the ratio go the other way. And it turned out that those drugs act like the NSAIDs, and excuse the PUM, but NSAIDs on steroids. That was bad pun. so so we had now the first next generation drugs that would modulate the production of A beta by gamma secretase, but not inhibit gamma secretase.
Nic (31:46.785)
I see. Yeah, I see. Yeah.
Rudy Tanzi (31:48.709)
and that's called the gamma secretase modulator. And it's taken 25 years and about 70 million dollars of development, both in the original companies that went bust to the neurotherapeutics blueprint from the NIH to me starting another company for disclosure in 2022, Active Pharmaceuticals, that licensed all the intellectual property on these original next generation gamma secretase modulators. And finally, just when I
Would love to retire. that clinical trial is beginning. So the clinical trial, the phase one is beginning now on the first next generation gamma secretase modulator after 25 years. Now I say first, now technically Roche, they made a gamma secretase modulator with similar scaffold and structure to ours, but by intellectual property an independent molecule. And we're cheering them on because.
You know, their structure, their scaffold is similar enough to ours that if they look safe and they work well, it bodes well for ours, which was the original Gamma Surteus modulator. And they're doing really well. Roche is, of course, a big they yeah, yeah, they did phase one. I think they're in phase two now, but they showed it safe. They showed that they decreased 42. They showed that while decreasing 42, the 40 went up a little bit, the 40 stayed around the same.
Nic (33:00.309)
Are they past f phase one already?
Rudy Tanzi (33:16.242)
And 38, the small A beta 38 that actually prevents plaques from forming went up. And that's exactly what we predict our gamma sequence modulator should do. And they even tested patients in with the early onset pre presinullah mutations down at Columbia, the the famous kindred down there, and they took young people who carried the presinullah mutation that guaranteed they were going to get Alzheimer's.
Nic (33:22.331)
wow.
Rudy Tanzi (33:45.205)
didn't have pathology yet, and showed even on that those pe those presentiliar mutation carriers, 42 went down and 38 went up. Which means that not only might this drug be a statin for Alzheimer's disease, right? But a godsend for that poor 1.5% of patients who are born with a mutation that's a life sentence that guarantees you the disease. Because for them, you start taking this drug as early as you can safely, and it reverses that ratio.
of 42 to 40 back the other way. Visionally how Steve Wagner and I envisaged it envisaged it when we started that screen 25 years ago. So the hope is that the gamma secretase modulator, which Roche or ours, I don't care whose it is, we just want it to happen. but you know ours is just going into phase one. We're a little biotech company, not a big pharma company, so it took a little while. but the hope would be that that drug will someday be used in everyone who carries
The early onset familial mutation that guarantees the disease, gives them a new lease on life. But for the average person, maybe Apo E4 double carriers would start taking it no matter what early on. Like I said, E4 single carriers are kind of transitional. But everyone's going to have the ability at some point to have a blood test. And there's more good news coming, right? So it was the P tau 217 originally told us if you have plaques and tangles in your brain.
Nic (34:55.041)
Mm-hmm.
Rudy Tanzi (35:13.17)
And the more plaques and tangles you have, then the higher the P tau 217 goes. Now, P tau 217 is seeing a tangle, but it detects tangles specifically induced by amyloid, amyloid-induced tangles, versus you know, bangs to the head type of tangles like playing football and getting CTE. So P tau 217 tells you not only whether you have plaques and tangles, but the magnitude of pathology.
Nic (35:28.23)
Mm. Mm-hmm.
Rudy Tanzi (35:42.42)
But now in a new paper from Mass General from Risa Sperling's group and Rachel Buckley, they showed that you can have a higher PTau 217 with no symptoms in even pre-pathology, and it it predicts that you're on your way. So that means we're moving back to primary prevention, right? If we can if you can have a PTau 217 test.
That before a PET scan sees any plaque or tangle, says you're on your way, think about it. You it's like me getting my cholesterol test when I was in my twenties, because my dad died with heart disease when he was 45. So you can have a younger person, you know, get the P tau 217 test before the cascade has begun in the brain, the tangles haven't formed yet. You don't have that whole propagation beginning yet, and nip it in the bud with primary prevention. But you need a safe, affordable drug.
Nic (36:10.647)
Mm-hmm.
Mm-hmm.
Nic (36:19.349)
Exactly.
Mm-hmm.
Rudy Tanzi (36:38.886)
Enter the gamma secretase modulator. So that's my dream. Just like we manage cholesterol early in life and take a statin if we have to, like I do, the gamma secretase modulator will be the statin that we take someday, not just for secondary prevention, but for primary prevention. And I think it's going to be sooner than we think because things are moving fast.
Nic (37:01.399)
Well, I was gonna say, I mean, you know, given that there's really nothing out there like this, assuming we see positive results in phase two and phase three, this could be definitely something that gets accelerated approval at some point, given the amount of people that suffer from these diseases.
Rudy Tanzi (37:16.488)
Yeah, but you just put your finger on it. What is the outcome we need to see? Because if the FDA wants to see that a gamma secretase modulator that turns off the A beta 42 and turns up to 38 makes patients cognitively better? Nope, not gonna happen. If they want to see that that drug gets rid of amyloid in someone who already has amyloid.
Like the immunotherapies, Lakembi, Casuna, probably not going to happen. Think of it like a kitchen sink filling with water, and the brain is filling, is filling with amyloid. And you may not even have symptoms yet, or maybe you're just at that cusp of symptoms. And the antibodies, casoonla, lecembi, come like rotor rooter and unclog the drain and let the amyloid out. You see, the amyloid disappears. We're just turning off the tap. We're turning off the tap.
of the bad A beta 42. So if you do that and someone already has amyloid, you know, even in an early stage patient, right, after 18 months, we're not going to have removed amyloid. So we're going to have to have very sophisticated, careful discussions with the FDA to say, this is like a statin. We're turning off the bad guy. We're turning up the good guys. We can show mice that this works.
And if this drug we show is turning down 42 and turning up 38, the way Roche already showed for their gamma secretase modulator, and I'm optimistic we'll show for ours, based on the similarities, then let us have a shot. This this disease is huge. It's gonna wipe out CMS. This disease can single-handedly wipe out Medicare, Medicaid. Take a shot on goal. It's cheap, safe, affordable, little white pill, let people take it.
And and let's see if we can let's see if we can slow down amyloid deposition by turning off the tap before the sink even starts accumulating water. Because once once the brain has amyloid deposition, even a small amount, that's triggering tangles. And tangles propagate and spread. They don't stop. That's why I call them brush fires. They keep going. And eventually they're going to trigger neuroinflammation, the wildfire. So you want to get in there early on and turn off that tap.
Nic (39:22.646)
No, it's
Rudy Tanzi (39:42.203)
And it's gonna have to be a matter of a leap of faith and trust that that's a good thing to do when we discuss this with the FDA later on, or Rose discusses it with the FDA.
Nic (39:51.232)
It's i given that these clinical trials run years, right? It could take ten years for a drug to go through the entire process and get back out to the market. Are there things that people could do right now where they have a family history? Maybe they have the the genes that we're talking about here. Are there things that people could be doing right now to slow down the progression or somehow mitigate the the in some cases inevitable outcome or maybe the probabilities of getting something like this?
before these drugs actually get out to market.
Rudy Tanzi (40:21.703)
Yeah, for sure. Yeah. So I I just I would just say that given where Roche is already and we're going to phase one, I think we're going to show that we can hit the A beta production the right way within a few years. And then it's gonna really be up to discussions to the FDA. So it could be much sooner than than 10 years, I'm hoping, you know, within not even five years. But in the meantime, yes, what can we do? So I also so besides directing
The genetics and aging research unit, which is where I am now, 11 labs, including my lab, basic science of Alzheimer's disease from genetics to we created the first organoid of Alzheimer's. We our organoid does in six weeks, but it takes 22 years in a human brain to go from pathology to cell death and enough cell death to get Alzheimer's. So but I also direct the McCant Center for Brain Health, which is where we are doing our clinical trials.
but our mantra there when in terms of advice for people about lifestyle is SHIELD. I came up with an acronym SHILD. it's been around for almost 10 years now. And some have taken that acronym and turned it into calling it the six pillars of brain help, but SHIELD was actually the first version of it. And S is for sleep. So if you get seven to eight hours of sleep, you allow the lymphatic system of the brain to clear ammo amyloid while you're sleeping.
H is for handling stress. Cortisol is a killer. So, you know, managing expectations or just trying to relax, take on a meditation practice, H, handling stress. I is interacting with others. Loneliness is a very untalked-about risk factor for Alzheimer's disease. If you don't have social stimulation, it's not good for the brain. in some cases, it's if hearing is impaired, that can that can cause social isolation.
You don't even realize you're undergoing sitting at the table, not hearing what people are saying. So I is interaction. E is exercise. We and others have shown that exercise induces neurogenesis, birth of new neurons in the hippocampus, one of the main regions affected in the brain by Alzheimer's disease. Exercise also induces a muscle hormone or myocine called irisin, which was discovered by Bruce Spiegelman at Dana Faber.
Rudy Tanzi (42:47.219)
But we showed that when you exercise, the irisin gets into the brain and binds to astrocytes. And just like when you sleep, it gets them to release an enzyme called neprolycin that breaks down the amyloid enzymatically. Another way to get rid of it. So exercise double, doubly good. Get rid of amyloid and neurogenesis. L is learning new things because at the end of the day, the more synapses you have, the more you can lose before you get into trouble. So
Learning new things, and this goes along with social interaction, I as well. You're building more synapses. So it's like money in the bank, synaptic reserve. So as your brain starts being attacked by inflammation, you have more synaptic redundancy to keep you from undergoing cognitive impairment. And the last one is most important that's D for diet. And we've learned unequivocally, what's good for the gut is good for the brain. We've always heard what's good for the heart is good for the brain. So, you know, you want to take care of your
Your blood pressure and BMI and you know stay cardiovascular fit. That's the other thing you can do, is just wash your vitals and your numbers. But on the other hand, your gut microbiome, and we've shown this in multiple papers now, controls amyloid removal in the brain. So if you give mice a high fiber plant-based diet, you can basically dramatically reduce amyloid in the brain.
So does this translate to humans? So D is diet, Mediterranean diet, heart healthy, gut-healthy diet, as much plant-based fiber as you can get, even if you're not a vegetarian like me, you know, every day trying to get your good dose of your vegetables, your your fruits, your seeds, your nuts, your whole grains. So we did a trial with Dean Ornish, who's famous for his cardio diet. and it was a small trial. It's only 50 patients, 25.
were on a lifestyle intervention that mimicked SHIELD. most importantly they had the people who were on the lifestyle intervention had plant-based diet meals and snacks delivered to their home that D Dean and his wife designed vegan meals. And so that was the most compliant enforceable part of the lifestyle invention. The rest was make sure you sleep, exercise
Rudy Tanzi (45:12.53)
go have these lectures to go to, interaction with others in the group, et cetera. but the D was enforceable. And it turned out that that trial, although it was small, 25 plus 25, 25 on the intervention, 25 plus C1, that they had a level of cognitive improvement by the same measures that were used in the immunotherapy trials for the Kenbian Casuna, what's called CDR Sum of the Boxes.
Nic (45:12.577)
Mm-hmm.
Rudy Tanzi (45:42.524)
The FDA required the toughest cognitive test there is. And in this case, they slowed down their cognitive decline, actually even more than the immunotherapies. And if you looked at one measure of this, what's called sum of the boxes, the CDR global score, overall they improved. They actually got better. Now it's only fifty people. You know, it's too small a trial. but great start and and
Nic (45:59.02)
Yeah.
Nic (46:06.177)
Well, yeah.
Rudy Tanzi (46:11.164)
Dean's doing a larger trial now of a hundred and fifty people to see if that holds up.
Nic (46:15.327)
Is this related to the McCann's brain care score? I interviewed Jonathan Roseand last year and I believe he was working on some kind of a brain so it was a like ten or twelve point inter
Rudy Tanzi (46:29.22)
Yeah, yeah. So so Jonathan and I created the McCann's Braincast Score when in the beginning Jonathan was one of the co-directors of the McCann Center and co-founder with me of the McCann Center together with Greg Vic Young. So Jonathan's moved on now to his just running his own lab. He's not part of the center anymore, but it's called the McCann's braincast score because the McCant Center that I now direct developed it and now Jonathan is is
Nic (46:48.281)
I see, okay.
Rudy Tanzi (46:57.69)
improving it and keeps enhancing it. So now it's in Jonathan's hands. So Jonathan Rosant is running the Global Brain Care Coalition based on a brain care score. But when we developed that brain care score originally in the early days of the center, now about seven, eight years ago, we decided you needed to keep track of your vitals and your numbers, your blood pressure, your A1C, your your your cholesterol at BMI, etc.
And then the other part of it was shield, right? How much do you sleep? Are you exercising? Purpose in life. you know, are you are you learning new things, your social interactions, your diet? So the brain cast scroll is was your vitals plus aspects of shield. And now Jonathan keeps making it, keeps improving it now to make it easier and easier for people to do. And he's running that effort now separate from the McCann Center. But we our center first developed.
Nic (47:43.895)
I see.
Rudy Tanzi (47:57.158)
Pink score.
Nic (47:57.902)
Yeah, okay. And I know that, you know, and I I could talk about Alzheimer's you know, for the rest of the time, but I know that you do a lot of work on aging as well, right? I mean, you run the aging and genomics center. are there things that you we're learning about aging and the biology behind that that are worth sharing with a population in terms of how it might actually affect human lifespans?
Rudy Tanzi (48:23.848)
Well, yeah, that I mean, the the the genetics and aging research unit where I am now is mainly focused on Alzheimer's disease. When we named it 30 years ago, we were also interested in aging and longevity and more general aspects of aging. But the aging and brain health with aging aspect now moved to the McCann Center. And and there we're doing clinical trials on repurposed drugs and natural products that
Nic (48:43.831)
I see.
Rudy Tanzi (48:53.936)
Are meant to curb age-related brain pathology, which is mainly Alzheimer's pathology for the most part. So when we invented these these first mini-brain organoid models of Alzheimer's, going back to our first paper in Nature in 2014, it made drug screening, you know, a hundred times faster, a hundred times cheaper than a mice. I mean, think about it. In mice, you had to do one at a time for a year. Now we have a 96-12 plate. You do 100 drugs at a time.
The past 10 years we've screened every known approved drug, four or five thousand natural products, and determined which ones stop the amyloid, which ones prevent the amyloid from causing tangles, which ones keep the tangles from spreading, which ones stop the microglial cells from causing neuroinflammation, which ones, like Lakembi and Casuna, the two Alzheimer's approved drugs, get the microglial cells to eat more amyloid. And so we've come up with that all of these bins of known drugs.
and natural products that do this. And now we're putting together in combinations that hit multiple pathologies at once. Right now it's two a combination of two ingredients at once. And we already started our first clinical trial at the McCant Center with our first natural product combination. But I have about three dozen combinations that work to clear more amyloids, stop inflammation, and prevent tangles with known approved drugs and natural products.
And we got a nice donation from an anonymous foundation to do many more of these trials. And we're now we also just applied to Upper H with the help of Chris Coburn, who made the introduction, to get money to do even more of these trials. And the idea is that if we can take but a dozen shots on goal with these combinations that are meant to blow out the match, clear more amyloid.
And stuff keep the wildfire from starting, stop the neuroinflammation. If we get one of them to hit, then we are going to have that safe, affordable combination that can be an actionable item when you have your blood test. So in in a perfect world, if we can tell everyone if their P tau two seventeen is high and give them something dirt cheap and safe to help prevent it.
Rudy Tanzi (51:16.741)
That's the that's the goal of the trials we're doing at the McCann Center right now. So there so that's how Jonathan and I kind of split it up. He's doing the brain care score and that work, getting the word out to the whole planet about how to keep your brain healthy and what to keep track of. And we decided to focus on these clinical trials of repurposed known drugs and natural products to nip the disease in the bud in a safe, affordable way that could be democratized. Now I'll add one more thing in that you may have heard there's a act, a bipartisan act.
under consideration right now in Congress called ASAP, the Alzheimer's Screening and Prevention Act. The idea is to get widespread screening for something like P Tau two seventeen. But if you're gonna do that, you want it to be actionable so you can, you know, you don't want to just say, yeah, yes, sir, you have plaques entangles, good luck. You know, or try try try SHIELD or take the brain care score. You know, so we want to come up with something they can take that's real, like a medicine that
Nic (52:04.779)
Yeah. Good luck with that.
Rudy Tanzi (52:14.94)
that's safe and affordable enough to use across millions of people who might find out they're positive. So all of this is gelling and dovetailing right now.
Nic (52:23.437)
And and so what's the trajectory for ASAP? Is it something that's gonna be voted on soon? Because you presumably these two things need to converge at some right? You've got the clinical trials.
Rudy Tanzi (52:33.297)
Yeah. I I I think it will be voted on soon, but I've been in deep discussions with CMS. all I mean, all the part we even had a we even had a panel I helped put together with the head of FDA, actually the head of the NIH, the head of Opera H FDA, head of neurology for FDA, Dr. Oz, head of CMS, all got together.
to discuss how to do this. And we all agreed, if you're going to do a blood test for a biomarker, you know it works, make sure the blood test is high quality and reliable. And right now the cost of having a very reliable PTAW 217 test might be too high to give to everybody on CMS. So you have to work on that. And if you're going to give that test, make sure you tell them there's something they can do about it.
Besides brain care score and sh and shield and lifestyle. And that's why there's a huge effort right now to come up with safe and affordable options for early prevention. And that that when we're relying, you know, we're we're vote we're betting on repurposed drugs and natural products. But this is all while we're waiting for our gamma secretase modulator, the real drug, because once the gamma secretase modulator works, whether it's ours or roaches, then it's like, okay.
I'll I'll try to live a life that ma that that manages my cholesterol, but I'm taking lipitor just in case. That will be the lipator for Alzheimer's disease. But in the meantime, we're doing everything we can with lifestyle and repurpose drugs and natural products to try to come up with something for early prevention, given that it's a big push toward early detection right now.
Nic (54:06.464)
one hundred percent. I mean then they come, yeah.
Nic (54:17.771)
Yeah, I mean you you talk about the the holy grail there with like early testing and detection coupled with preventive therapeutic that can help you mitigate and avoid the disease entirely. this is something that I know a lot of people are gonna be incredibly excited. and of course a lot of people don't have access to this information because it's published in science and nature and your typical person doesn't read those magazines, and even if they did, they're they're hard to comprehend. So
Sharing this information in a way that lay people would be able to understand is really exciting. And you know, for for the last question, Rudy, it it it's a hard one in general. I almost feel it's almost impossible to answer it in your shoes because you've discovered and you've been responsible for so many incredible discoveries in science over the years, especially when it comes to Alzheimer's. But the the question that I'd like to ask to close is a zoom out question.
Rudy Tanzi (55:01.53)
Yeah.
Rudy Tanzi (55:09.914)
Yeah.
Nic (55:12.481)
So let's say that you can you find yourself at some point in the future where you can look back on your entire body of work. what would be the best case scenario that would make you feel like you've achieved the full impact that you were capable of? What discoveries, changes and how understanding of aging and Alzheimer's that would give you the biggest sense of fulfillment over the things that you've accomplished, either to date or things that you're still working on?
Rudy Tanzi (55:20.305)
Yeah.
Rudy Tanzi (55:28.303)
And then
Rudy Tanzi (55:39.525)
Yeah, I would go back to I think my my entire career in in this disease has been summarized now by a goal of early prediction using genetics. So you know what you're up against, early detection using biomarkers, early intervention. And if what I want to look back at is someday there we'll be using genetics to predict your a priori risk and when you should start.
A preventative drug, combine that with early detection so that you don't start too late, just in case the pathology is going to begin soon, like the P Tau two seventeen that says you're on your way. and third would be the gamma secretase modulator, or maybe some of these other repurposed drugs and natural product combinations, so that we give something that people something they can do about it, where they find out they're at high risk, they find out maybe.
The biomarkers say they're just beginning the disease and they can nip it in the bud. So my goal is to look back and say we eradicated, eradicated Alzheimer's disease with early prediction, early detection, early intervention. and you know, and it's gonna be a combination of things we're gonna have to use to do that. But we're on our way. That some of them are already in trials. the best, I think the best bets are already in trials right now. So this is where we we're in a
an a a golden age of where where the last forty years have come to fruition and we're finding in clinical trials where the rubber meets the road.
Nic (57:16.205)
That's extraordinary. Well, this has been an honor to to get to know you, to hear your story, obviously for having you on the show. And thank you so much for your time, Rudy, and I really look forward to seeing you hopefully at the World Medical Innovation Forum next month.
Rudy Tanzi (57:31.803)
I'll be there. Look forward to meeting there. Thank you. Thanks for having me.
