Tau: Untangling Early Alzheimer's Detection--Dr. Lukasz Joachimiak

Tau, a protein, normally supports brain cells’ internal structure; Dr. Lukasz Joachimiak, of the University of Texas Southwestern Medical Center, is focused on what happens when it does not. His lab uses computational and experimental methods to determine how and why tau gets tangled and forms the toxic aggregates found with neurodegenerative diseases such as Alzheimer’s. The hope is to come up with ways of detecting Alzheimer's and treating it early, before the destruction of brain cells is underway. His cutting-edge research uses A.I.-powered computer simulations to come up with synthetic molecules that might prove effective in fighting brain diseases.

Transcript

Science Straight Up

Season 7, Episode 4

“Tau: Untangling Early Alzheimer’s Detection”

Dr. Lukasz Joachimiak, University of Texas Southwestern Medical Center

June 30, 2026

Moderators: Judy Muller and George Lewis

(THEME MUSIC UP AND THEN UNDER)

JUDY: From Telluride Science…this is Science Straight Up. I’m Judy Muller.

GEORGE: And I’m George Lewis. On this episode a new hope for early detection and treatment of Alzheimer’s Disease.

LUKASZ: So if we can detect this at 20 years of age, we may be able to treat people much, much earlier.

JUDY: Dr. Lukasz Joachimiakis a biochemist with the University of Texas Southwestern Medical Center.  It’s that time of year when Telluride Science gathers prominent researchers from all over the world for a series of workshops high up in the Colorado mountains.

GEORGE: Some of those researchers share their cutting-edge ideas with the community in what Telluride Science calls “town talks.” Dr Joachimiak spoke at the Telluride Mountain Village conference center.

LUKASZ: I think the future is..we really need to do this early. We have to diagnose people before they have disease, I think. All the studies so far are treating people way too late.

(recording of senior cognition exam)

DOCTOR: Doris, I just want to ask you some questions about your memory and we’ll be about twenty minutes to a half-hour so I can get an idea about how you’re thinking. Have you had any trouble with your memory?

PATIENT: No.

DOCTOR: No, it’s been pretty good, huh? Well, do you know what day it is today?

(pause)

DOCTOR: Monday, Tuesday, Wednesday, Thursday? (long pause)

GEORGE: About seven million people in this country are living with Alzheimer’s disease. A study by the University of Southern California estimates the societal cost of dementia at a staggering 818 billion dollars a year. And it’s only going to get worse as the population ages.

JUDY: So, what causes Alzheimer’s? For some time now, science has been studying amyloid plaques, buildups of proteins that interfere with brain cell function. These can cause another protein called Tau to get all tangled up into clumps called aggregates. When that happens, it causes brain cells to crumble, much like a building collapses when you remove the support beams.

LUKASZ: And so we think when tau tangles appear, this is what kills brain cells that then leads to the effect the clinical presentation of the disease.

GEORGE: Dr. Joachimiak and his colleagues are working on ways of detecting these tangled tau proteins early in the process to head off Alzheimer’s before those aggregates form and the destruction of brain cells gets underway. He says tests on animal subjects are hopeful so far and that the results could lead to very early tests for Alzheimer’s in humans…as early as the teenage years.

LUKASZ: So, it's really remarkable that in an animal model this happens really, really early, and so if we can detect this at 20 years of age, we may be able to treat people much, much earlier.

JUDY: He says there’s evidence that substances called “chaperones” can stop the tau proteins in brain cells from tangling and halt the disease process. His lab is working on designer molecules…artificial chaperones to do the job.

LUKASZ: We really need to do this early. We have to diagnose people before they have disease, I think. All the studies so far are treating people way too late, and so we need ways to diagnose disease based on confirmation, and then do this early, and we also need to be able to create treatments that can bind to these early misfolded states before the disease actually happens.

GEORGE: The goal: to create an injectable drug using gene therapy techniques that have proven effective against other diseases.  One of those employs harmless viruses to deliver the medicine.

LUKASZ: So the gene therapy that I think is probably the most promising for not just these diseases but other diseases is called adeno associated virus, and it's an injection of a virus that makes the protein but is not infectious, and so this has been approved for other diseases, and so I think it's safe, and if there's no other solutions to the problem, then this is what we have to do.

JUDY: Dr. Joachimiak says computer simulations, powered by A.I. are driving a revolution in designing molecules to fight disease.

LUKASZ: So one of the beautiful things now is that we can use computers, so you know we have large data sets, and so can train models, and then use this data to make better predictions about something. So, for example, we're using these new models to design molecules that can be specific for this form of tau tangle versus this one, and so then you can have a molecule that can essentially diagnose right a patient. So, I think it's actually a very exciting time to be in science.

GEORGE:  And it isn’t just Alzheimer’s. He says there are other diseases of the brain that may someday be treated with designer molecules.  Judy and I had a whole lot of questions for him.

JUDY: If my mother or father had Alzheimer's, they didn't, but if they did, is there a genetic link that, in other words, would you just say, "Oh, you should be so intervention should come early, or is there a genetic list? 

LUKASZ: So, not really, there's risk factors, so you can have so APOE, for example, is a protein where you have a specific form, and that puts you at higher risk to have to have disease, so there's several markers like this that can be at higher risk, but that doesn't guarantee you will or will not have disease. 

JUDY: What about ALS?

LUKASZ: ALS is a bit more complicated, because frontal timberal dementia is a disease where many different proteins cause the same disease, so ALS is sort of similar, so there's about four or five proteins are associated with ALS, and a lot of it is also sporadic, and so we don't know who will have disease, and ALS is even worse, because you essentially are trapped in your body, you can't move, you're cognitively fine, and you suffocate to death, so it's really, I mean, ALS is really devastating, the progression is really fast. So, I mean, I guess with Alzheimer's, you have a longer window. With ALS, it's, it's really terrifying. I think there is a football player that was recently diagnosed with ALS, and you know, he's an athlete, and so now he's wheelchair bound, and he was a running back that was one of the fastest people on the field, right? And so, it's terrifying.

JUDY: Brain diseases are terrifying, to especially those of us are getting on in years. You know, I can't remember somebody's name, and I immediately panic, but that's not the same thing you have been doing. This is really been a major discovery in the last 10 years or so, right.

LUKASZ: Yeah.

JUDY Do you remember a time when you thought, oh, this is really new. This is amazing. I'm doing this, and nobody else is, or not many of you.

LUKASZ: I feel like that every day. (laughter)

JUDY: Are there ever times in your lab I'm always imagining “eureka!”, you know? I just.. how excited are your.. 

LUKASZ: I think some of the tools that we've developed essentially enabled us to do things a little bit faster and earlier, and so then people sort of have to catch up to what we're doing afterwards, and so I think we're doing things that people haven't thought about, and I think sort of being at the forefront of science is like I think one of the sort of exciting things is because you have an idea, right, you're in the shower, you're running, and you have an idea, and then you actually get to go in the lab and do the right, the test that idea…

JUDY: You’re running and you think…aah! Chaperones!

LUKASZ: Yeah, yeah. Exactly. You think why? How does this work? (laughter)

GEORGE: At what point will you be able to start doing studies on human subjects?

LUKASZ: I think in the context of maybe five years, it's actually possible to create molecules that could, in principle, go into human trials.

GEORGE: You said you're using AI to help develop artificial molecules, is that is that expanding and growing at the exponential rate we see the rest of AI progressing.

(LUKASZ) Yeah, so it's a new field. So, you know, I did my PhD in a lab that sort of did this for the last, you know, 25-30 years. So, we've been doing this for many years, and then it was just sort of recognized. So, not everybody's doing it, but I've been doing it for a long time, so I feel comfortable doing it.

JUDY: Everybody’s doing it. (laughter) 

GEORGE: Can we back up, can we back up a little bit? What spurred your initial interest in science as a kid?

LUKASZ: So, my parents are scientists, so I was born in Poland, and I was sort of forced to move to the US as a kid because my parents got jobs in science, and so I've sort of at the dinner table we talked about science, so that's all I've really known, we've always sort of argued about things about science, so and that's sort of where the dialog actually in science is really important, because you essentially have a discussion about problems and how you think about something, and then convince other people to do it, and so the dialog, I think, is actually one of the beautiful features in science, where we can actually can communicate ideas and move something forward, and I think nowadays I think people can't do that anymore, which I think is sort of the pity, right? Essentially, we have to be able to communicate problems and solve them, and I think that's really missing in our current society. But we don't want to - we're not going to digress to that.

GEORGE: Well, I hope you're having a good time here until you're right, exchanging ideas with other scientists.

LUKASZ: Absolutely, yeah.

JUDY: Yeah, is anybody else doing this particular work?

LUKASZ: Not, not really. We're sort of, you know, so my department chair moved from, I guess, Washington University to create this department where we work towards a similar problem, but using different approaches, and so I think that's really inspired sort of, the synergy that you don't have in a classical department at a university, and so we've been actually doing some amazing things, because we have the right group of people to solve one problem using different methods that you don't have anywhere else in the world.

JUDY: Wow.

GEORGE: Well, I think we’re going to open it to questions from the audience. And just a reminder, please wait for the microphone to come to you.

MAN IN AUDIENCE: Apparently, 100% of the people that die from brain disease that played football as long as I did, from grade school through college post mortem or diagnosed with CTE, not 100% of them die from brain injury, of course, but my question is, is there is just a lottery, or is there anything I could be doing that would make a difference in not developing this disease.

LUKASZ: Yeah, so, so my son plays lacrosse, and you know it's, it's maybe a little bit less violent than football, but I sort of feel he's really good at it, and it's really difficult to say no to somebody who really wants to, you know, succeed in a sport that they're good at, and so you know, I don't really know what the answer to this is. You know, I don't think we should cancel sports. I think sports are a really good way to develop interaction with people, right, on teams, and I really don't know what the solution is to prevent this. You know, I think new technology and helmets has helped, I think. Better concussion protocols have helped, but I think ultimately, it's a repetitive, you know, hitting of the brain, and so if you hit, you know, a joint or an arm repetitively, right, you're going to have inflammation, bruises, and your body responds to it. So it's the exact same happening in your brain.

JUDY: But correct me if I'm wrong, but you are wondering now, after a lifetime, is there any intervention now that can help? Is that correct? Yeah.

LUKASZ: Yeah, I don't, I don't really know. I mean, for CTE, there's really nothing that I think you can do. I think the treatments for Alzheimer's are focused towards a protein that's specific to Alzheimer's, and not a tau. It's possible that you know some of these treatments that will reduce tau levels could help, but I don't really know if there's a very clear path in the short term for what to do. Probably still eat healthy, and exercise probably is going to help keep your brain active, but I don't know if there's really anything you can do to reverse it, I guess.

GEORGE One of our audience members disclosed he is living with early Alzheimer’s disease.

MAN IN AUDIENCE: I've been on disease modifying treatments for over four years now for mild cognitive impairment due to Alzheimer's disease, and what we have available now is some blood-based biomarkers that are now available to the public, and I think those are going to be quite beneficial in future detection, so if you could just comment a little bit about the current state of the blood-based biomarkers and their efficacy and use.

LUKASZ: Yes, so for Alzheimer's, there's sort of two markers that I think are important, so one of them is decrease of amyloid beta in the blood, and then the other one is the increase of a specific phoserine form of tau, so that ratio change is pretty diagnostic of having Alzheimer's disease. There's another marker called neurofilament light, which is a more general marker for degeneration in the brain, and so that may be something that's more general for diseases in the brain, rather than specific for Alzheimer's, but again, I think that the challenge is it's difficult to access the brain, right, and so one can, in principle, access, you know, the spine, the spinal cord, right, so the CSF, the spinal fluid, and so that's probably going to be the future, so if you can't access it in the right in the blood, I think trying to access this in the spinal cord is going to be the next step. It's a bit more invasive, but you know some of these treatments that deliver into the brain, you know this modification that reduces protein levels that is delivered through the spinal cord, and so that may be sort of the easiest, least invasive. It's better than accessing the brain directly through a little window, I guess, right. And so that's probably the next step, is trying to look at this in the spinal fluid.

QUESTION FROM AUDIENCE: I have a history of science question. I think I remember learning in college more than 60 years ago that the whole idea that proteins folded into three-dimensional shapes, and that that's how you explain nourishment, how you explain poisons, how you create antibiotics, but that whole idea originated in the 1930s which was still pretty recent when I was in college. Is that right?

LUKASZ: So Christian Anfinsen got the Nobel Prize, it's, I believe, in the 70s, for essentially showing that proteins fold through a very defined pathway into three-dimensional state, and the folding is controlled through a very specific step of interactions that get to that state. The challenge, so related, I guess, to brain diseases, a lot of these proteins that form these shapes, these clumps in the brain don't have a structure, so there are these really floppy noodles,  and so I think it sort of challenges how you think about the structure of proteins in a way.

JUDY: (NEW) Mark Kozak, the CEO of Telluride Science, chimed in with a question.

MARK: We had someone quite a long time ago talk, a scientist talk about neurodegenerative disease, and they had brought up something, some relationship between, or maybe it was a metaphor, like diabetes and neurological degeneration. Is there any connection between those two things?

LUKASZ: Yeah, so funny you say it. So my wife actually works on diabetes, and actually amyloids. So, in diabetes, you have a protein called amylin, which forms aggregates, and you can detect this in the blood, and so diabetes is also a protein misfolding. Disease, and so you can detect this, you know, so you can harvest, you know, a pancreas from a diabetes patient that had passed away, and it has these, these aggregates, and so we think you can reduce diabetes burden by reducing these aggregates, because the formation of these aggregates kills islet cells in the pancreas, and then, right, this causes diabetes. So, diabetes absolutely is an amyloid disease. I don't know if it's really established that everybody believes this, but the data is pretty strong, and so there's maybe a way to treat this, and you know, the benefit, I guess, is for this protein. This is just in the blood, right? So it's much easier to access. You don't have to go into the brain. So if you create a molecule that can bind this and clear this, that should be beneficial, and it'll be useful for millions of people. A very large population in the US has diabetes, so it's actually a very, very large problem.

MARK: So just to clarify, it's not that they're related, it's more that the mechanisms that happen are similar in both diseases.

LUKASZ: Correct.

JUDY: I know scientists hate to predict, but this is happening so rapidly, it seems. What is… look down the road? 

LUKASZ: What's the future?

JUDY: Yes, please tell us.

LUKASZ: So, my PhD advisor won the Nobel Prize a couple years ago, and he boldly proclaimed that we'll have designed molecules that will treat every single disease in the next 20 years.

JUDY: And how many years?

LUKASZ: 20 years.

JUDY: Whoa! (laughter) 

GEORGE: Hang on, honey! (laughter) 

LUKASZ: Whether he's right, I don't know.

JUDY: We have one more.

WOMAN IN AUDIENCE: When Judy said she forgot a name, and suddenly she panics, and we might have some other people in this audience that experience that as well, so can you talk a minute to distinguish if there is a distinction. What is the relationship with tau to the kind of forgetfulness that begins for some of us at a certain point, and does it indicate a beginning of something more, or is it a different thing?

LUKASZ: Yeah, I guess. I mean, there's sort of these episodes that people have, right? And so there's a moment where you don't remember. I mean, this happens to me, not that…

JUDY: it does?

LUKASZ: It does.

JUDY: Well, That's reassuring. 

LUKASZ: And then it takes a little bit longer to remember. And so I think the frequency of this sort of increases. I say, I think that's sort of maybe something to think about, right? And I don't know, this is something that's hard to see yourself, perhaps, right? Because if it happens, it's a frequency, you don't keep track of it, and then I don't know if other people can notice this, right? I think this is sort of the problem that it's inside of you, and I don't know if it's visible to other people, right? We noticed it among ourselves, yeah. yeah.

JUDY: I think it's about all the time we have, which is unfortunate, but I could go on. We want to thank our sponsors before we wrap it up, the Telluride Mountain Village Owners Association for giving us this space and Alpine Bank

GEORGE: And let's give a big hand to our speaker, Lukasz, for an enlightening and hopeful evening.  (applause)

(Theme music up and then under)

JUDY: Our talk was recorded before a live audience at the Telluride Mountain Village Conference Center and our engineer was Tuck Gillett.

GEORGE: Mark Kozak is CEO and Executive Director of Telluride Science and Cindy Fusting is CFO and Managing Director.

JUDY: Sarah Friedberg is Lodging and Operations Manager and Annie Carlson is in charge of donor relations.

GEORGE: If you’d like to donate to the cause, go to telluridescience-dot-O-R-G. Please tell your friends that’s where they can find our podcasts or on their podcast apps at “Science Straight Up.”

JUDY: And if you have questions or comments, you can email us… science straight up…all one big long word, science straight up at telluridescience-dot-O-R-G. I’m Judy Muller.

GEORGE: And I’m George Lewis, inviting you to join us next time on Science Straight Up.

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