Most of us hope to live a long, healthy life, but reaching our later years without our mental faculties or the ability to live independently is a “hollow victory,” says Dr. Eric Verdin, president and CEO of the Buck Institute for Research on Aging. Impediments can include the onset of Alzheimer’s disease, dementia, and other neurodegenerative diseases.
Dr. Verdin moderated a discussion that included Dr. Li Gan, Director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine, Dr. Claire Clelland, John D French Alzheimer’s Foundation Endowed Chair, Assistant Professor of Neurology at the University of California, San Francisco, and Dr. David Jones, Director of the Mayo Clinic’s Neurology Artificial Intelligence Program. They spoke about discoveries and novel therapies in this field during the DOC 2025 session, “Neurodegenerative Diseases: State of the Science and What You Can Do Now.” The Faculty identified avenues that may aid not only in early detection and treatment of neurodegenerative diseases, including Alzheimer’s, but potentially, one day, in their prevention.
At the Mayo Clinic, Dr. Jones and his colleagues are using artificial intelligence (AI) to aid in the discovery and potential treatment of diseases and conditions related to dementia. Jones notes, as an example, that Alzheimer’s disease is not a single entity, but can have multiple forms, he says. He points to his and his team’s work on StateViewer, an AI tool they developed that mines symptoms and scans of patients’ brains to locate patterns mirroring previously diagnosed cases. The tool identified that 11 percent of those diagnosed with Alzheimer’s instead had a condition called normal pressure hydrocephalus, which is “100 percent treatable,” he says.
To Jones, these findings — and the AI tool that located them — represent the next era in brain health, with “expert brain care universal for all.”
For Dr. Clelland, the next frontier in neurodegenerative research lies with human testing. Her team works with CRISPR editing, a tool that edits genes with precision at the molecular level in human DNA. They’ve focused on genes including C9orf72, a leading genetic cause for frontotemporal dementia (FTD), and APOE4, which increases the risk for dementia. Today, Clelland is working to stem the onset of cognitive loss from neurodegeneration through therapeutic deliveries. That requires “discovery research in human tissue,” she says. Clelland believes this avenue can be done safely, would boost the eventual effectiveness of human clinical trials, while also reducing their cost. Even more critically, this approach would “…hopefully be a roadmap to cure other monogenic diseases over time,” she says.
Dr. Gan’s work is steeped in the area of resilience. In particular, she focuses on the way one genetic carrier may develop Alzheimer’s as another, whose brain carries trademarked signs, including amyloid, can remain free of tau tangles, the protein that leads to cognitive decline. The answer, Gan and her team found, lies in genetic coding, specifically the “Christchurch mutation.” Using CRISPR technology, like Clelland, Gan’s lab found that the mutation helped steer inflammatory responses in cells. Removing the mutation drove a strong inflammatory response, while keeping it left the cells “much more subdued,” she says. Diving deeper, they found that the driver of this response was a protein called cGAS, “a very ancient alarm system,” she says. Today, they’re inhibiting cGAS to help dampen inflammatory responses and potentially halt the development of tau.
You can hear more from these three researchers at the forefront of neurodegenerative science today in our video or read our lightly edited transcript below.
TRANSCRIPT:
Dr. Eric Verdin
We have an exciting panel. I just wanted to give a couple of words of introduction in terms of, having a panel on Alzheimer’s and longevity without cognition is a hollow victory. We all recognize that living old, without all of our faculty, the ability to interact and to understand and to have memory and independance are really, as I mentioned, hollow victory.
One of the reasons that that this topic is so essential is that in a conference that focuses on aging, our risk of Alzheimer’s doubles every five years of age 65. So just make the calculus. If you get to 80, it’s actually, eightfold higher than it was at 65. And it keeps going on every five years.
Interestingly, also the biology of Alzheimer’s tells us that it starts in decades before you actually become symptomatic. So which actually offers a true preventive, window. The field has, there’s been a lot of discussion in terms of why we do not have, a solution for Alzheimer’s. And as you heard yesterday, I think there was really exciting talk saying that heart disease is something that should not exist. We have all the knowledge to actually stop it, eradicate it. We’re far from this, in terms of Alzheimer’s. Even though the effort has been commensurate, there’s been an enormous amount of resources. I won’t go into the details of why we are here today, but there’s a lot of excitement in the field right now with the three people who are on stage today in terms of new directions and really reassessing, of what have we done and why, where should we go in the future so that we can actually maybe ten years, 20 years from now, make the same declaration that was made about heart disease.
Some of the things that have changed are blood based biomarkers that are coming online that can actually assess or maybe detect who’s at risk. New emerging technologies, and some novel therapies that are coming. One thing that should be clear to me, it should be clear to you as a disease is multifactorial and heterogeneous. And so what we call Alzheimer’s might actually be a whole collection of disease.
It’s been a lot of focus, almost not exclusive, but I think too much focus on a beta amyloid and tau in the past 20 years. Which doesn’t mean that they’re not playing a role, but they’re not playing the only role. And there’s a lot of exciting work going on, on neuroinflammation, on vascular disease, on metabolism and insulin resistance. And people are actually calling, Alzheimer’s type three diabetes and sleep and hearing and the list goes on. Clearly single targets one won’t be enough. And I think there was a talk yesterday that I hope you appreciate it for what it’s trying to do. This was Dean Ornish talking about lifestyle intervention by themselves actually can already move the needle.
Prevention is really critical. And so all of the lifestyle factors that we’ve talked about, I think are going to be important in the future. So what the field is shifting from identifying people at the moment where they’ve already lost a significant fraction of their neurons and are becoming symptomatic to really early detection and prevention and treatment.
That being said, we have some really key people here in the field who are going to help us to navigate and understand where the field is. So I’m going to, first ask, Claire Clelland from UCSF, a neurologist scientist whose work spans patient care and cutting edge gene therapy for neurodegenerative disease. Claire leads the lab that uses, CRISPR patients, Iasb, induced pluripotent cells. A novel CNS delivery platform to tackle genetic dementia like frontotemporal dementia and other dementia. ALS and Alzheimer’s. And she also brings, interestingly, a deep commitment, to equity in neuroscience, which is something that I think concerns all of us. And in mentoring the next generation. Claire, welcome.
Dr. Claire Clelland
I’m going to talk today about brain health, aging and what I think is the fastest path to curing dementia, which is through genetics. So I share the mission that many of you have in this room that we can cure neurodegenerative diseases, which is a disease, really, of aging. And I’m going to talk a bit today about preventative measures, the roles of genetics in clinic and research and gene therapy.
Dementia is really a disease of aging. So there are rare cases of dementia that afflict folks in their 20s, 30s and 40s that are caused by single gene mutation. But, but as we age, our risk of dementia goes up. And folks over 90 years old, 40% of them have dementia. I want a level set on the definition of dementia as an irreversible, progressive loss of cognitive function due to neurodegeneration.
So due to death of brain cells, there is currently no credible evidence that we can reverse Alzheimer’s disease. But the state in 2025 for folks who are cognitively normal is prevention. There’s a lot of risk factors on this slide, that we’ve heard about during the course of the two days here. But if I could highlight two that, I think if you had to put your money on, you should put your money on, it would be exercise.
You already know the benefits of exercise and tight blood pressure control. There is good data from clinical trials that reducing your blood pressure. And I’m in tight less than 120 over 80. That second number diastolic number is likely to drop in the future, especially for folks over 65. This is what you can do to reduce your risk of dementia.
I’m going to tell you a little bit about genetics. We are focused on genetics because I think this is where major medical breakthroughs are coming, is in the genetics space. And I’m going to make a case for why you should care about, rare diseases and rare forms of dementia. So there are rare causes of dementia. I mentioned that earlier in the picture.
Here is Lindy Jacobs in the center with her mother, Allison, who suffers from, a rare form of mutation T so one letter change in the 300 billion letters of your genome is the difference between health and disease, life and death. This family has dementia running in their family. Her grandmother died of dementia. She watched her mother die of dementia.
She herself is a gene carrier. There’s a beautiful article by Virginia Hughes in the New York Times. If you want to learn more about this subject that was published on Christmas Day last year. So there are rare forms of dementia that tell us a lot about the causes of dementia. This is nature’s experiment nature. Nature’s done this experiment.
These are inroads into pure cases of dementia and the path to treating it there. There’s also genetics that are common that affect many of us. A quarter of a quarter of the world’s population carries at least one copy of the APOE4, which increases your risk of dementia. Two copies of that gene increase your risk by 8 to 10 fold, which means 60% of people by 85 that are APOE4 carriers will get dementia.
This is the vision for the gene therapy. So folks will come to clinic. They will get gene sequence. We heard earlier. And I agree with this probably by birth most people will be sequenced in the future. From that sequencing we’ll identify causative mutations depicted in red. But we will also get information about their surrounding single nucleotide polymorphisms.
These are normal differences between your two gene copies. So the copy you got from mom and the copy you got from dad. And we can target those using CRISPR, which is a technology that allows us to selectively target the genome for changes. We in my lab use that technology to cut out those mutations from the genome. And then the cell repairs that DNA cut, removing the mutation from the genome.
We selectively target mutations or the allele so that we can observe as much of the normal gene function as possible. We recognize that we don’t know everything about every genes function in the in the body, and that genes are doing good things that promote health. And so I want to give you an an overview of where we are currently, on CRISPR discovery and optimization for our lead target seen in C9orf72, which is a leading genetic cause of both FTD and ALS, and we’ve essentially cured that disease.
In addition, patient stem cells and stem cell drive neurons we’re testing. And in mice currently we have other indications for genetic causes of FTD, Alzheimer’s disease and genes we’re targeting in Parkinson’s disease. So the CRISPR part in a dish is essentially done. But we do not yet have a therapy for humans. And why is that? Because the CRISPR gene targeting is only one half of the therapy.
The other half is delivery. We have to be able to get this technology into patients brains and spinal cords, and that is the major roadblock in the entire world right now. So, this challenge of delivery for CNS, therapeutics is compounded by, I think the way that we currently road drug discovery programs, the current model of the traditional model of drug discovery was really built for small molecule molecules, and it is failing in the current age of humanized biologic therapies.
I think our drug discovery pipeline is essentially built to find failures, and I know that is controversial to say, but I say that because it mostly finds failures. So clinical trials mostly find things that don’t work in humans. Why is it. So the traditional pipeline you need to look at the specifics is that you test a whole bunch of things in cells or mice in your lab.
You find a few things that you carry on to further animal testing and enabling studies. And the first time that that therapy is ever tried in a human has clinical trial where patients are hoping for a benefit, and where we often find that the therapies don’t work. If the clinical trial pipeline and the drug discovery pipeline is mostly finding failures and human, brain delivery is an exceptional challenge, then what is the path forward?
We know from animal studies that particularly for CNS delivery, the animal studies do not predict what works in humans. So we know this from the AV literature. We know this from other delivery modalities. The human brain is bigger than animal brains. But it’s not just a bigger brain. I drew the human brain, non-human primate brain or rat brain to scale.
I couldn’t put a mouse brain on this slide because it’s too small. But the species specificity problem is a real problem for human therapeutics, particularly the amazing humanized work that many folks are doing now. We want to revolutionize this platform of drug discovery with the most rational, logical next step, which is that we need to do discovery research in human tissue.
How can you do that safely? We have built a platform at UCSF in collaboration with Neil Single, who is a critical care physician scientist, to use brain dead subjects to do some scary research. So these are folks who are dead from by neurologic criteria. They’re usually in the ICU. So they still have blood perfusion. But they are clinically dead.
This is the typical source of organ donation. But there are folks who can’t be organ donors. And there’s families who want to make meaning out of that death. They can participate. Those family members can consent for their, deceased loved ones to participate in our study. And we can test hundreds to thousands of CNS targeted particles in a single brain dead cadaver across all modalities.
HIV is lipid nanoparticles, viral particles, peptides. And we’ve opened this, but we haven’t done this platform yet as we’ve just spent a few years building it. We’ve opened it up to the best particle makers in the country, and we are ready to solve the CNS delivery challenge. What that looks like in a dish. These barcodes are genetic barcodes, but we also put functional tags on them.
We put an mRNA in these barcodes that the cell has to translate into a protein that turns the cell green. So we can see where all those particles went. And then we can use sequencing to identify the composition of that particle and what route of administration it used to get to the to the organs and cell types of interest.
The new pipeline would look something like this. We would test first in human tissue. We would find candidates that we already know will work in humans. Right at the outside of testing. We take those lead candidates back to animal models for toxicity testing. And by the time that that that candidate gets to clinical trials, we have hopefully decreased the time it takes to do discovery research, to human translation and increase the effectiveness of clinical trials, which would ultimately reduce reduce the cost of clinical trials.
We are hoping to develop first and class genome therapies for neurodegenerative diseases. We’re starting with the leading genetic cause of FTD and ALS. But we want to rapidly translate that to more to genetic cases that affect millions of folks around the country. We use novel strategies to remove the mutations, while preserving as much of the normal gene function as we can.
And really, the innovation is screening and human platforms. I didn’t have time to talk about the bioinformatics and biomarker discovery that goes along with this work, so that way it can be ready for clinical trials, and hopefully be a roadmap, to cure other monogenic diseases over time. Thank you.
Verdin
Thank you very much. Our next speaker is, Dr. Li Gan, a friend, a collaborator from my Gladstone UCSF days. So we’ve both moved on to different organizations. She’s now, the director of the Appel Alzheimer’s Institute at Cornell. Li’s group has helped to establish the importance of, post-translational modification of tau, including acetylation and she’s uncovered how immune and glial dysfunction accelerates Alzheimer’s disease. She’s also deeply engaged in the biomarker world, and translational strategy. Li, we’re glad to have you.
Dr. Li Gan
Thanks very much. It is really a pleasure to be here. In the past, a day and a half, I’ve been deeply inspired by the talks and also the conversations. So today I will talk about how to enhance resilience. I wanted to start with a very uplifting story, of Donna Algeria. So she lived in a small village in Colombia along with her extended, relatives.
They carry a very aggressive, early onset Alzheimer’s, mutation. So many of her relatives, develop, severe dementia in their 40s. But Donna, Algeria has no symptom until, even late into the 70s. So what is, happening in the rain? So this, when we looked at, her brain using imaging. And the field is astonished. How do I do? How come the. It’s not showing up? So, when. Oops. So we just have to, imagine it. So I don’t know why it’s not showing up. In my advance. It, So the field was really astounded, when we looked into their brain so consistent ways, this mutation, which lead to increased amyloid plaque deposition.
Donna Maria, Donna Algeria, as a brain is full of amyloid, it’s actually more amyloid than her symptomatic relatives. But her brain is really, lacking another pathological hallmark, which is tau tangles. So what is tall? Tau is, the protein that aggregates in the neurons and can spread, damaging neuronal function, but also spread from one neuron to another and lead to cognitive decline. And this is the reason. Donna Olivia is free of, the symptom.
This relationship between amyloid and tal is, replicated also in the general Alzheimer population. So if you look at this slide, you would appreciate that the culprit of memory loss is tau, not amyloid. So this is a Pet scan, patients that, looking at their amyloid deposition as well at healthy position and along with a cognitive decline.
You can see from the, light blue, if the patient only positive to amyloid plaques, they have very, very little decline over the six period of time. But if the, patients had also positive for the healthy position, as you can see for those other two, a darker, the darker, traces that they had much more severe decline of cognition.
This tells us that it is very important to, to, stop the Tau toxicity. So this also can explain why the current anti amyloid therapy is not able to stop memory loss. Even though it was, even the patients are treated at very early stage. So, my lab in the past 50 years has been trying to understand how to enhance resilience and resistance against all.
As Eric mentioned, that my lab has develop strategies to enhance Tau clearance using both small molecule cures as well as monoclonal antibodies. But what I will tell you today is about our work in, understanding how the resilience appeal carried by Donna and Olivia that can help us develop more effective drugs. So it turns out some are really carry a mutation that is very rare.
We call it the Christchurch mutation. The April year Leo and this rare nature’s gift, I call it, shielded her from her brain from the tau buildup and memory loss. So how to study it? We wanted to study the mechanism so we can turn this nature’s gift into a small molecule. Appeals. So we used, CRISPR screen, or CRISPR editing, as Claire mentioned, in her talk to recreate the Christchurch mutation, both in the animal model mouse models as well as, IPSC, derived stem cells.
We then turned the stem cells into, immune cells, which are microglia, and then look at the molecular signatures that is generated or altered by this, resilience early. So this is a cartoon. And the, the paper is published, and showing that, how this Christchurch alter the response of immune cells to tau.
In the absence of the Christchurch mutation, you can see that the cells respond to that healthy position with, inflammatory. It was a very strong, in fact an inflammatory response at including antiviral response, in particular the interferon response. But if you have this Christchurch resonance mutation, then the cells have a much more subdued, response to these tau proteins and that reduce the immune stress.
How did this happen? So, the research allows us by going into deep into the immune cells. And we discovered that the key protein that drives this difference is a protein called cGAS. And you heard it from the Q and A yesterday. cGAS is a very ancient alarm system.So it senses a double strand DNA in the cytosol where it shouldn’t be.
As a response triggers antiviral, response because the cells established in DNA in the cytosol as virus. So then it started to launch this antiviral response using that and, interferon response. But the double strand DNA could also come from nucleus, as shown in this slide, especially in the form of, chromatin fragments. When the genomic T genome becomes unstable. You have a jumpy DNA. It could also come from mitochondria, which is where we found what tau protein triggers. We found that when immune cells of exposed to tau aggregates that the micro mitochondria become damaged, it becomes leaky. So the mitochondrial DNA, which orange from bacteria now leak into the cytosol, triggers suggesting activation. So the interferon response will become rampant even though there is no infection.
This is how our brain is damaged. In response to these, to the hyper active alarm system. So how do we turn this, discovery into a therapy? So because we now cGAS is a core of the problem, we developed, small molecule inhibitors at this brain penetrant and then use it to treat the mouse model mouse that carry, having the Tau build up what we found is astonishing.
We found that the cGAS inhibitor can actually mimic the Christchurch mutation effects in the form of molecule signatures in the form of dampened inflammatory response, as well as in the form of reduced tau spread. So, you heard probably from the QnA yesterday, were very also excited about the link of cGAS with this exceptional longevity of naked mole rats.
Naked mole rats, as you probably heard from yesterday, live ten times longer than their rodent relatives. So the mutations or the differences of the naked mole rat cGAS is a four amino acid that lead to dampened interferon response to the W 28, but promoted the DNA repair mechanism. So we’re already, excited about this discovery and hoping we can harness this difference of naked mole rat cGAS and a small molecules to actually mimic, this, in the new function of cGAS.
Take home message not amyloid, but tau and inflammation as a drivers of a cognitive decline. And we have to be able to target that beyond amyloid therapy. And one of the ways to do it, we heard today or we heard from that today, which I was very inspired, is to strengthen our mitochondria and reduce our stress.
We also are seeking for partnership to further develop this first in class, brain permeable, cGAS inhibitors so we can actually stop tau from build up and build the resilience. Thank you.
Verdin
Thank you. I think we’re going to have a lot of exciting things to discuss, as I can see, as we moving further forward. Finally, we have Dr. David Jones, from the Mayo Clinic and neurologist who is bridging clinical care and cutting edge. I, David Leeds, mayor’s neurology. I initiative works on network based biomarkers, diagnostic models for Alzheimer’s and related disorders and has contributed to, I understand ING of this executive Alzheimer’s and early onset forms. David, we’re excited to have you.
Dr. David Jones
Thank you. It’s a pleasure to be here. The word dementia in, if you translate that into the original Latin is being without a mind. Now, I don’t want to lose my mind. You don’t want to lose your mind. It’s horrendous to watch our loved ones lose a piece of their minds. This is what we are missing in the current field of Alzheimer’s disease. We don’t. The mechanisms of the mind are what we’re missing. And how do they relate to the disease? That’s what we need to sort out. And that means, I believe that if we solve dementia, we will solve intelligence. And if we solve intelligence, it will help us solve dementia. These are synergistic problems. And when we overlap them, we can.
Where you’re stuck in one field, you can go to the other. And you can synergistically creatively go back and forth. And we can finally start to make progress both on intelligence and on dementia. So one, every three seconds someone in the world develops dementia. There’s obviously a horrendous financial cost, but, there’s this is devastating for human beings.
And by 20, 50, 130 million human beings, and we don’t want, the individuals lost in this, every single patient dementia happens to them in a unique way. For them, an average is really don’t count. There’s many different quote unquote causes. So we need to get to the bottom of this at an individual level.
When a patient comes to see me, I think about them, not the 139,000,000 in 2050. The problem is we can’t measure the mind. We’re terrible at it. We don’t understand it. How do we even begin to approach this? Cardiology is able to make advances with a lot more numbers that relate directly to the physiology that we care about, which is the heart needs to pump.
The brain needs to think, how do we measure this? We just have metaphors. We talk about proteins. Proteins don’t think so how do they relate to us? Thinking and having intelligence. So the breakthrough that we are working on is we look at brain energy. Those mitochondria need fuel. They need glucose. There’s a scan that’s been around for about almost 50 years. FDG, Pet, widely available, just isn’t used. But we’re understanding it’s telling us it’s a good biomarker of mental function in all neurodegenerative diseases. And so we are able to simplify the information. The FDG, Pet scan color, code it into a small number of dimensions. Now, each one of these dots you see here is a patient and it’s color coded by, which areas of their brain are not working.
If they’re close together, they’re similar to one another. And so you see these different dementia syndromes clustering like Lewy body disease post your cortical atrophy your vision is gone. Typical Alzheimer’s disease, semantic dementia. You no longer have semantic information limbic predominant or late disease taking away memories in late life. Behavior problems. Behavioral frontotemporal dementia. So all of the mind is laid out there in that heterogeneity.
We put this into a diagnostic tool, that, really understands this functional organization of the brain. And so when a patient comes in, this dot in the middle represents the patient. This is the patient’s brain. Blue is where it’s not working. We find matches, matches I’ve seen at Mayo Clinic in the past. And I know what happened to those patients.
I kind of call that brain like mine. It’s like, yes, I’ve seen about 20 patients have a brain that looks just like yours. What happened to them? What was their diagnosis? How did we treat them? Those areas in blue are, the problem. We like to explore these things in detail, really looking closely and make sure, these things are lining up with their clinical symptoms, the way they’re losing their intelligence.
Here’s some matches, as I get further away, these are other patients we’ve seen that’s informing the advice I’m going to be giving you. And so here is a different plot, same sort of thing. Each dot is a patient, and how close together they are, how similar their brains are. And you can see if you could describe the whole field of neuro behavioral neurology in one slide.
This kind of does it because you get visual symptoms. Maybe you get executive symptoms. Maybe you get language symptoms. Some people can’t speak behavior symptoms, semantic knowledge memory. Some people fall. They lose the ability to manipulate their mouth. Lewy body disease. You have hallucinations. They’re all here on one slide. And then the proteins associated with those conditions are there too but this is what we’re use to, to, well, this I didn’t project right.
But, what we did was I looked at 15,000 scans at Mayo Clinic and ran the tool. And what we found was, you know, it’s not all Alzheimer’s disease. There’s different forms of Alzheimer’s disease. We found 11% had this condition called normal pressure hydrocephalus. What is that? That causes dementia symptoms, and it’s 100% treatable. So why would you want that and not know it?
We recently had to do a randomized, placebo controlled trial published in New England Journal to prove doctors should be doing this. Just published last month. This condition has been around for 75 years. Why do we have to do this? Trial people are nihilistic about getting the diagnosis right. These patients shouldn’t be missed. They need to be treated.
Here’s just a clear kind of patient example. My new patient has given us, permission to share his story. But it took him several years going to see neurologist after neurologist across the country to try and get a diagnosis. Every doctor he saw. I know you have dementia. It’s one of these. I don’t know what it is, but I can tell you there’s no treatment.
That’s not an acceptable answer. If somebody tells you there’s no treatment, you want to know what’s the diagnosis? That’s how you know there’s no treatment. You don’t even know the diagnosis. How do you know there’s no treatment? He came to see us and we could say, well, here’s all these different possible ways you could get dementia. Which one did it to you? He landed right there. That’s the non degenerative cause and that’s surgically reversible. So we did surgery that week. And now he says I can enjoy time with my family again. I can go out with my friends. I can even go down do my own taxes. These are moments that I thought I’d last forever. So how many of cases like this are acceptable to miss?
How many have to exist before we say we should catch all of them? Let’s say one. We need to catch all of them. And so this tool we’re using now, it’s been, rolled out enterprise wide at Mayo Clinic for about four months on this investigational use. And it’s very quick, wide adoption. And people have logged on to this application about 2000 times, and there’s about 70 plus users and growing, it increases diagnostic accuracy.
Reading these brain scans by 3 to 5 times reduces reading time by 50%. Has a lot of integration with our EMR, and it’s built on Google Cloud architecture. And, there’s these static reports and there’s these dynamic reports. Hey, this is new technology. It’s helping us right now, today in clinical practice. And we’re just getting started. And so just as an example, this is a study, where we, we gave the radiologist instead of 14 different types of dementia.
We said three picked three different categories. It’s either post your cortical atrophy, Lewy body disease or something else. This is all autopsy confirmed cases. The tool itself is about 87% accurate in this data set. The for readers about 70%. This is a trainee who’s almost at random chance. But then you give them all the tool and they all become better than expert level.
That’s what we want. We want to democratize this stuff. We want to digitize my knowledge and understanding, put it in a tool, and you don’t fly to the Mayo Clinic anymore. You get this done where you are because there’s millions of people who need access to this. And so here’s, Nathan Young. He’s a community neurologist in a community practice, and he says FDG pet with state here is a game changer in practice. And very practical for cases in the community practice, sort of knowledge sharing and expertise helps us set us apart. It’s a great for patient care. The state we are no longer need to bug David to help you read scans. It’s like having an expert work with you. In each case, I put a little error there because he does not bug me.
I love this, this is my expertise. But they don’t need me as much, which is great. It’s why we made the tool. I’m not going to go into details about this, but I think design, designing your technology within the environment that’s going to be used to help you sharpen it, make sure it’s right and iterate quickly and really make friends with your information technologies to do this right. Then you can bottle it up, maybe in like our cloud platform, give people access to it after, you know, it works. So key takeaways I think there is a new era for brain health coming. I think we should be seeking precision and dementia diagnosis. I think AI transforms neurologic expertise into scalable precision, and with the right partnerships, we can make expert brain care universal all. So thank you very much for your attention.
Verdin
Thank you all for your presentation. I think, it’s hard not to have a hope by hearing all the progress that’s being made. I want to start with you Claire and start with you and ask you, gene therapy, for Alzheimer’s. Seems like at least seems to me like something very far out. The work that you’re doing is really addressing the major problem of all gene therapy, which is delivery. I just wanted to I’d like to ask you to give us a sense of how far are we from actually bringing this, discovering the proper vector. How would this be administered? Do you really think that, gene therapy for Alzheimer’s is going to become reality? Reality and how soon?
Clelland
Yeah, I really believe it. So I devoted my life to training for 20 years to pursue this work. I think we are at the starting line, but it’s going to go faster than we, think. So I get asked this question almost every time that I give a talk, and I do not have a timeline because it all depends on delivery. It’s how fast we can get that answer to delivery. If we can get that answer quickly, then we can go very quickly to the clinic, because all the other components of gene therapy are already in place.
I think we as our traditional models of testing in mice and going through this pipeline, we were potentially decades off. I think if we can turn that on its head and really solve the human delivery challenge, we will accelerate not only gene therapy for dementia, but essentially gene therapy across the entire body, because this kind of humanized testing will give an answer not only for the brain and spinal cord, but will give an answer for every viable organ in the body.
So it could be very fast, and it really depends on if we can we can do these large scale community efforts.
Verdin
This is maybe a bit of a technical question, but quite often, when you think about delivery, there’s an issue of reaching every single cell. If it’s going to be, knocking out something that’s toxic, is the field thinking more of dominant positive, in terms of what you’re going to be administering and which means that you can only target a limited number of cells which are going to be having a global effect. Can you give us a sense of how the field is moving it?
Clelland
Yeah. So that’s a, complex question with a lot of moving parts. My approach is that we want broad CNS distribution. So there’s in any dementia, there’s not just one focal part of the brain involved. There’s a lot of parts of the brain that are involved. So we want broad CNS coverage. We are cell type agnostic. So people often say like what cell types do you need to hit? We don’t know how all the cell types are interacting to cause disease. There’s good evidence it’s not just one cell type. So we want to hit broadly the key cell types at least neurons, astrocytes, microglia if possible.
But I think the answer to the question about how many cells you need to hit or how much affect you need to have for it to be effective for patients. Really, the answer lies in our gene carrier patients who have the gene for mutation they develop normally through development, live into adulthood, with the consequence of that gene mutation already in their genome.
And do fine something with aging pushes them over the edge into disease. And if we can just push them back into their homeostasis, I think they can handle the effect of some of that mutation. So that gives me hope that it’s not 100% efficacy that we need. We’re somewhere in the range of just getting people back into their homeostasis.
Verdin
I’m going to do something that probably is going to make you feel uncomfortable, but I know the audience wants to hear it. How soon if you had to make a bet hub? Five years, ten years, 20 years?
Clelland
if we could get the funding to do our human discovery platform and brain dead patients, I think we could have an answer in 1 to 2 years on the delivery platform. Then I think we can go from there very rapidly to look like so. But I won’t I won’t answer the question. Depends. It depends on, you know, the resources and the innovation that happens in this space.
Verdin
But it’s coming.
Clelland
It’s coming. Yeah. This is a solvable problem. This is an engineering challenge. This is not figuring out what to do. We know what to do. It’s figure out how to do it. And that’s a very different space, we’ve been in dementia for a very long time .
Verdin
Li, your lab is taking a completely different approach, which is the use of small molecules, which, you know, many of them actually penetrates a blood brain barrier.
You’re not you don’t have an issue of delivery. The issue of cGAS activation has emerged not only in the brain, but also in the whole organism in terms of aging. The question has been what activates cGAS during aging? One of the things that you mentioned is mitochondrial dysfunction. So mitochondria are ancestral bacteria that live in our cytoplasm. When the bacteria do not function well, they release their DNA. And the cell recognizes this as an infection, which is actually remarkable. That’s what you described. But there’s another mechanism which I think I’ve heard actually more often mentioned in the terms of aging, which is, retrotransposon activation. Maybe I’ll just say a word about this.
Our genome is made out of about 50% of silenced old viruses, which is kind of crazy. Over the billions of years of evolution, we’ve been infected. These viruses are in our genome and they’re silenced. And as we age, these viruses get reactivated. And one of the theory is that they actually activate again cGAS. So has that been explored in the context of Alzheimer’s?
Gan
Yes. Absolutely. One of the things, for the sake of time, I did not describe the retrotransposons. In fact, Tau accumulation in neurons is already known to reactivate those retrotransposons. So there are multiple ways that she gets activated. By mitochondrion dysfunction, I mean, I we heard the talk about the stress would there be to mitochondria dysfunction. I think the increase of those inflammation was even very short, acute stress could be explained by the activation of cGAS pathway. Of course, in the chronic condition, when you have tau accumulate in the neurons, you actually push, making the genome to be activated.
So you have the retrotransposons, to be activated. And that is already been shown both in the Drosophila model as well as in the human neurons. I think both roads could lead to this simmering of activation of cGAS and that is in what the system is chronically, devoting resources to fight against infection, that’s not there. So essentially it’s a phantom infection. The body or the, the cells are trying to fight against. That is why the compromising of the neurons function.
In our published work, we actually have identified the specific mechanisms, a specific transcription factors that get compromised by this simmering inflammation because of those you because of the fight against phantom infection. So, you’re right.
Verdin
On the other hand, I mean, this system has evolved to protect us against infection. So what happens when someone is on a cGAS inhibitor? Are they becoming prone to infection, which is by itself another problem. How does one how do you envisage this to actually be.
Gan
I think evolutionary it’s actually quite interesting when you talk about thinking about cGAS pathway. The activity of cGAS in the human is, more than ten times lower than in the mouse. When you talk about naked mole rat, it’s even lower than human. So I think the theory that evolution cGAS as a detection of infection is no longer its major function. And because, evolutionary we have developed many pathways to fight against infection. And cGAS has become anciently obsolete. In all, animal work, we find that deleting cGAS completely the mice are completely fine. There’s no symptom. They’re completely fertile. And they live longer. I think the and also in terms of the safety window, just reducing half of cGAS in our mouse models was sufficient to confer protection. I think the window of cGAS inhibition is pretty, large in terms of safety concerns.
Verdin
David. I think speaking about, prevention, it seems to me that diagnosis or visualization is really the key. So can you speak to how soon are these technologies coming? Who should get a brain scan? Is this something that you would recommend in the whole population on a regular basis, or how should we think about what’s up, what’s happening in the future. Recognizing that quite often when people become symptomatic, it’s the diseases that are already pretty advanced. Y
Jones
I usually start this by saying one, I’m not giving up on patients and I’m giving up patients with symptoms and developing new technologies to, provide them care and reverse every cause of symptoms that I can. As we do that, we’ll get better at understanding the mechanisms of the mind. Then we can have a rational strategy for monitoring the mind in pre-clinical stages. Right now, we don’t have a rational strategy for that. We have protein measurements and things in brain scans of proteins, that misses the mark. As we have a rational strategy for measuring the mind. Then I think you’ll see new, options for doing that.
We’ve got a paper under review now, which, we did, a crude functional measure of the mind, functional MRI, resting state, functional MRI in asymptomatic individuals. It predicts at the group level, not at the individual level when you’re going to get amyloid in your brain. So as those sorts of technologies, develop, which requires the field to advance, in this way, you’ll be able to use these functional measures of the mind as we age to do what we want for keeping people healthy. As you intervene, you want a biomarker that has shown a response, that’s related to the physiology of interest, which is your intelligence.
Verdin
We’re going to move to some other questions.
Audience Member
Thank you for this great discussion and for these presentations I wanted to ask Li, you know, in cancer immunotherapy, we’re trying to cultivate cGAS in order to enhance the anti-tumor immunity. And this happens by creating double stranded DNA breaks. One of the questions is whether as part of the etiology for Alzheimer’s, there’s a DNA repair deficit that’s acquired or part of aging or a result of a toxin or from oxidative stress in the brain, that’s damaging the genome.
Gan
CGAS Sting agonist has been developed trying to do to be developed to improve the immune oncology for cGAS-STING has not really made much success as far as I know. I think the activation of the sporadic cases in the 80s comes from what you have said, you know, the stress of mitochondria, as well as the beta transpose, the, the, the DNA damage due to oxidative stress. And that will lead to these snips of DNA that a self-made colonized that set on the shelf DNA that floating around, and that being recognized as virus and engage the hyper activation of the immune response. And that is damaging, to the brain. So I think those are floating around DNA, which can be used to trigger, enhancer and cancer, immunologic responses to cure, to kill, cancer cells could be damaging in the, chronic neurodegenerative conditions.
Audience Member
Thank you all for the work you’re doing. Long Covid is very common. We see many patients and, of course they experience fatigue as well as cognitive changes in other symptoms. Is there any evidence that cGAS activation may be playing a role there?
Gan
Actually there was a very, extensive epidemiological studies published in neuron a few years ago, Medium to Long Covid, showing that people who have been hospitalized for severe infection, has much higher risk of developing new degenerative dementia.
We actually have mined Long Covid, human brain single nuclei. We find that in the long Covid brains have significantly enhanced the interferon response. We actually have published in Nature Neuroscience 2023. One of the concerns we have is because of the large population have been, infected with Covid virus, I mean, billions and billions of people, there could be a delay of a tsunami, for neurodegenerative diseases, including Alzheimer’s with a 10 to 15 years from now, because of the exposure to virus, as well as what you mentioned, the non-COVID.
Verdin
I would like to finish by asking, one question to each of you, what are the two things that you would or that you do or that you would recommend that we all do to prevent our own risk of Alzheimer’s independently of what our genotypes are. What do you think are the key things that people, if they had to take two message home, what would they be for you, Claire?
Clelland
Exercise to clear those proteins that we talked about from the brain and getting that blood pressure on under tight control to preserve any stress on the brain. That’s the two biggest factors. But I think there’s evidence for.
Jones
Exercise, sleep, mindfulness. This is about how you use your brain. What’s in your brain. The information processing it’s doing, being in the present moment is very healthy for this physiology. We’re worried about.
Gan
Be positive. Be optimistic.
Verdin
Thank you to all of you for this. Thank you.