Unraveling Alzheimer's: The Pathobiome Connection - Episode 353

Certain undetected infections, we call them stealth infections, even if they're incredibly common in certain people under certain circumstances, can be disease drivers that contribute to immunosenescence and indeed impact longevity, as well as the ability to live, you know, a healthy and enjoyable life.

Today I'm talking with Nikki Schultek. You're going to find this a really fascinating conversation. She's involved with a project called the Alzheimer's Pathobiome Initiative. And it has to do with the fact that a lot of chronic diseases, including Alzheimer's, heart disease, et cetera, have an infectious component to them. And she's been going down the rabbit hole in this regard. And the conversation we have is, I think, one of the most intellectually stimulating and somewhat far-ranging conversations we've had on the podcast. I think you're really going to enjoy the interaction back and forth. She's a wonderful— Wonderful guest. And, um, I think she and I are gonna end up doing some collaborations together, which you'll hear about as you, uh, listen to the podcast. So, uh, enjoy this. I think you'll really like it.

He went from saving hearts as a cardiologist to rewriting the entire aging playbook. Dr. Jeffrey Gladden believes 100 is the new 30, and he's got the science to back it up. This is the Gladden Longevity Podcast.

Welcome to the show.

Thank you for having me.

Yeah, I was excited when I saw the topic that you're going to speak— be speaking to us about, Alzheimer's and the pathobiome. And that's a really interesting topic. But before we get to that topic, I'm curious how you got to be interested in that topic. Tell us a little bit about how you got into all this.

Yeah, thank you for asking. So I got interested in broadly kind of understanding how infections or our immune responses to infections in the body can drive autoimmune states in general, really with particular interest on neurodegenerative disease and zeroing in on Alzheimer's over a course of time. But I kind of got recruited to it. I got really sick in my early 30s.

Mm-hmm.

I'm very thankful now to be in my mid-40s. So, it was like nearly 11 years ago.

Yeah.

And I contracted Lyme disease living in Connecticut, in the state where the disease is named, Lyme, Connecticut. And I was misdiagnosed for a year, which I actually consider myself fortunate. That's kind of short in the grand scheme of Lyme misdiagnoses. What the infection does is a number of things that are undesirable in certain people. It can impact your immune system broadly. And it also oftentimes, if you get a tick bite, which is one of the main routes of transmission, you may also get co-infections, other things that the ticks carry. It's sort of nature's dirty needle.

Yeah.

On top of that, I had had another factor in my case that I didn't realize was pertinent until I became unbelievably ill for an entire year with multisystem autoimmunity, was that I also likely harbored a chronic respiratory infection. a bacterium, actually not one, but 2 that are unbelievably common in the human population transmitted from inhaling when someone coughs on you. Some people, it can present like just a normal upper respiratory tract infection. In other people, it can become a full-blown pneumonia requiring hospitalization. And in many people, the infection is never cleared. It actually becomes chronic.

Wow.

This year of illness, where literally at points, I feared that I would not get to see my 3 and 5-year-old kids grow up. I was diagnosed with so many different conditions spanning from my GI tract, my heart, my joints, my brain. My physicians thought I could have multiple sclerosis. I do not.

Mm-hmm.

Although at the time it was interesting when I went to the neurologist, they said, we really can't tell you that you won't get lesions in your brain right now. You have a lot of symptoms that are very concerning and your MRI at this current point in time is clean. It was sort of just like this terrible Like looming feeling, lots of worry.

It's like this ax hanging over your head.

Yeah, literally. So, so this all happens to me in a year. I also developed a terrible bladder pain disorder called interstitial cystitis and terrible breathing problems, air hunger. My asthma that had been previously well controlled on steroids, inhaled steroids, basically became totally out of control. And I was immunosuppressed. So the, you know, I had a dozen specialists. I had previously worked in pharma and biotech, so I could navigate the healthcare system and I was advocating for myself. But what I noticed was everything was siloed. So I'd go see someone about a symptom in one part of the body, even though I had multi-system complex chronic illness, my physicians were thinking about their area of expertise.

That's right.

Hey, I have, you know, this all came on with joint pain, brain fog, fatigue, you know, air hunger was a new symptom. That's not typical for asthma. It's a different sensation than wheezing. What could this be? And they're like, I'm here to talk about your cystitis, or I'm here to talk about your arrhythmia. So we, so it went, I was the human hockey puck, I call it, like difficult cases like mine. 'Cause now after 11 years, you know, I fast forward, I became a collaboration architect and scientist to help bring people together globally studying more broadly, not just Lyme disease, not just this respiratory bacteria that initially introduced me to these concepts, but really to put some serious force behind a concept that is so logical. And it's that certain undetected infections, we call them stealth infections, Mm-hmm. Even if they're incredibly common in certain people under certain circumstances, can be disease drivers that contribute to immunosenescence and indeed impact longevity as well as the ability to live, you know, a healthy and enjoyable life. So yeah, my, my experience for that year with complex chronic illness, though, will likely continue the rest of my life. Like a lot of other patients that have later stage neurological Lyme diagnoses, where there are multiple co-infections involved, you know, there, it's very difficult to eradicate these organisms. So we really don't have wonderful solutions is the truth, you know, to a lot of these problems yet.

Right.

But the good news is that with enhanced advocacy and, you know, some of the efforts that research teams like ours and others around the world are, you know, basically grasping and launching forward, really a lot of spearheading by patients and people personally impacted, we're starting to see some serious momentum. You know, the concept of targeting diseases, and this probably resonates with you given your specialty and then your background, is waiting until the horses are already fully out of the barn is not a good solution.

Yeah.

Right? It's figuring out how to keep everything in in the first place. You know, What was the upstream event, for example, with Alzheimer's that led to the formation of a beta plaque or tau tangle? And that's really what the premise is behind our work is looking at one potential factor in the human exposome, or it's, you know, the word exposome, we use it a lot. It's everything that you come in contact with.

Mm-hmm.

And that can be a lot of toxins, mold, pathogens, certainly air pollution.

That's right. Well, it's, we've highlighted several different things here. You know, one is let's just talk about the medical system for a second because the audience has heard about this, but it's so disjointed. It's so reductionist in the way that it's constructed and the thinking that goes on inside of it that it's very difficult to get the solutions that people intuitively want to have, which is really a systems approach, a systems biology approach, right? That's one thing. Then, the other thing that you're bringing up is just the somewhat occult and very tricky nature of some of these infections that like to have a host to hang out in. And, they will either play with the immune system or kind of trick the immune system or do things to disguise themselves or activate the immune system in ways that if people have genetic predispositions and maybe some other things going on, can lead to a whole host of manifestations that are unrelated to the— directly unrelated to the infecting agent, but it's the immune system that now is out running kind of wild in the streets with, you know, in reaction to some of these things. So, it's really interesting not to try to unravel, right? And, to get to the bottom of it. To your point. So, yeah. Yeah.

I mean, it's sort of like a combination of the pathogens directly impacting and also the immune system running wild, like you said. So, so our research and others indicate that it's a bit of a combination and that it's different from patient to patient.

That's right.

So as you pointed out, like a systems-level approach to comprehensively looking at patients that have multi-system autoimmunity, for example, like when patients indicate to me, because I've shared story so widely. And I was treated with antimicrobial drugs for my Lyme disease and continue to, you know, have to take medications in order to stay well, unfortunately, due to the prolonged nature of my illness. Thankfully, I have specialists that know how to do that. The main issue is that many patients won't be identified as having a chronic infectious process. They'll be labeled as you know, various things, fibromyalgia, different types of arthritis. They'll, these patients will have tons of specialists. They'll be on multiple biologics, mostly aimed at disarming the immune system. And in those patients that don't really respond favorably to biologics, you name the condition, whether it's Crohn's, RA, you know, they really should be screened for stealth pathogens that can drive chronic inflammation. And result in some of the very processes that we call a disease when you look at blood work.

Yeah.

You know, one of the stunning examples of this being you're an interventional cardiologist is the bacteria that I was mentioning that is very strongly associated with asthma, Chlamydia pneumoniae. People have never heard of it, even though the majority of the population has come in contact with it by middle age. It is a really interesting bacteria because it has to live inside a human cell. It literally can't live outside the cell. It requires our energy and our lipids in order to survive. So essentially, it's like a little pirate.

Yeah.

It gets into the cell, it takes energy from the mitochondria, and many diseases of aging are linked with mitochondrial dysfunction or characterized by, as well as oxidative stress, uh, dyshomeostasis of metals and lipids, meaning all of these changes. And many of these changes are inducible by this particular pathogen. And so, I thought it would be cool to bring up a neat sort of connectivity between the study of that organism, which is a respiratory bacteria, right? Not the sexually transmitted chlamydia and the connection that was discovered with heart disease, atherosclerosis. Do you remember by any chance the trials that took place in the early 2000s with antibiotics?

Yes. Yeah. It was when people figured out that actually If you were looking at plaque, I think if you, there was a study done where they looked at plaque under a microscope and they found that, you know, at least half the plaques, you know, had active organisms in them. And a lot of the organisms were actually from the oral microbiome.

Yeah.

Right.

Yeah. So, so this, this was a really compelling field of study that died on the vine, unfortunately, because of poorly designed clinical trials, which were largely financially motivated the way the trials were designed.

Mm-hmm.

At the time when researchers were showing, oh, this chlamydia organism can be in the cells lining the vessels, right? Causing issues and utilizing lipids, causing foam cell production, right? Like it could, you could induce the hallmarks of the disease using animal models. You would repeatedly find organisms, like you said, oral pathogens, things like Porphyromonas gingivalis, but also this respiratory bacteria, chlamydia became an intense agent to study, and a lot of funding went to it from the NIH for a period of more than a decade. But then when the pharma companies came in and studied it, um, they attempted to treat it using a single therapy, um, which is a very tricky thing when you have a highly resistant organism by nature or an obligate intracellular bacteria.

Yeah.

Typically those require more extensive long-term multi-drug regimens. They did relatively short trials and they also looked at patients that were very, very sick. Many of the trials were for secondary prevention. So the people had already had events. And so they didn't, they didn't show any meaningful results with antibiotics. And basically the whole field dried up. But at the same time, and this is important history for our group, the Alzheimer's Pathobiome Initiative, Dr. Brian Balin at the Philadelphia College of Osteopathic Medicine with Dr. Alan Hudson from Wayne State in Detroit, had a really historic conversation about their curiosity, given the fact that this C. pneumoniae organism could get involved in atherosclerosis and infect immune cells and endothelial cells. Could it be in the brain and Alzheimer's? So this led to the very first publication in 1998, demonstrating using a multitude of different techniques, viable chlamydia organisms in postmortem brain specimens where the plaques are in Alzheimer's disease and relatively absent in the controls. So this was one of the first studies, the first study in the United States of America. Previously herpesviruses had been linked by Dr. Ruth Atsaki and others in the UK. But interestingly enough, the reason I wanted to talk about a little bit about heart disease and atherosclerosis is the Porphyromonas gingivalis organism that shows up in atherosclerosis is also being studied in relation to Alzheimer's disease. And the National Institute on Aging has given a $49 million grant to study a drug that would essentially target the virulence factor for the, the P. gingivalis. So it's something that at one time, the idea that organisms could be involved, microbes could be involved in Alzheimer's.

Yeah.

And really involved in any chronic disease. It's sort of been a hotly debated topic for a long time. But now more than ever, we're seeing that because it's so sensible, plausible, and, you know, from other areas of medicine, we know, you know, that these things can be drivers of inflammation. You know, it's—

Yeah. The way I think about it is that they're kind of accelerants. I don't know that they're the primary causes per se, because I know that there's underlying genetic predispositions for Alzheimer's and things like that. You've got Different pathways for amyloid processing, whether it's the alpha or beta pathways that it goes down. And there, you know, the ApoE4 plays a role there. You know, plasmalogens play a role, reverse cholesterol transport plays a role. And then, you know, many other lifestyle factors end up playing a role. But I do think that once you have a plaque, whether it's a in a coronary artery or in the brain. I think what happens is when you add the infectious agent in, now it's, you've got something that's actively stirring the pot, right? In terms of augmenting inflammation and augmenting the oxidative stress that comes from inflammation. So to me, it seems like it's, I'm sure it's pathogenic on some level, but it also seems to be an accelerant to an underlying process that somebody had a predisposition for. whether they'd been exposed to that pathogen or not, if that makes sense. So.

It does make sense. It's one way to look at the situation and, you know, many of the different things that you address. So the first thing I'll say is we can't uncouple genetics and the pathobiome. They're inextricably tied. One of the most powerful forces on human evolution have been pathogens that we've had to battle. And even ApoE4, which you know, people commonly refer to as the Alzheimer's gene. Having 2 copies drastically increases your risk of developing the disease, can be modifiable with lifestyle factors.

Yeah.

And we believe also prevention or treatment of certain infections. APOE4 enhances susceptibility of AD-associated pathogens, and these mechanistic models have already been done.

Mm-hmm.

As well as we now understand that the plaques, 2 of our different teammates within our consortium have Demonstrated that amyloid beta plaques are in fact antimicrobial in nature or antimicrobial responses. They're a part of the innate immune system and they are recruited in response to herpetic viruses and other infectious agents. So I actually think it— I have a slightly different view than you, slightly divergent, which is always a good thing in our book. That is the whole purpose of building a global consortium.

Sure.

Experts so that people can respectfully disagree with one another and debate these topics. But I think what we are finding in the work that has happened already, and as well as in the work that we're currently doing, is that the root of the inflammation itself is pathogenic. And then yes, certain other factors in your life can predispose you to risk to being basically affected in a negative way to things that may be commensal in somebody else's body. So, that's why we really liked the word pathobiome because it captures something that I think you're trying to grab the essence of with what you're saying, which is some people walk around and have Chlamydia pneumoniae or Porphyromonas gingivalis and they harbor it.

Yeah.

And, it is part of their commensal ecosystem and it may not be harming them, but at some point either in time Or never in a lifespan, there may be a tipping of the scales in which the immune system decides, okay, we've had enough, or you no longer have enough beneficial commensals, for example, in the gut. That's a great example of this, that you have a disproportionate number of the bad guys. And this can be, is an overlooked, I think our team thinks, factor in terms of longevity and aging. And, you know, it could be something where—

Right.

certain individuals have an enhanced susceptibility to the immune response and also to the burden of infection.

Yeah, no, I, I would agree with that. The other thing I would just say is that what I was positing earlier was really more of a thought, and I'm not, I'm not married to what I just said, but it seemed to me that it could be acting as an accelerant to some underlying predisposition because With ApoE4, we know that there was a survival benefit to ApoE4. Everybody was ApoE4 for, I don't know, 10,000, 20,000, 30,000 years ago. I forget the number because there was a survival benefit. And, what was the survival benefit? Well, they mounted a greater inflammatory response to whatever they were facing.

Malaria.

Right. Malaria, whatever else, tetanus or whatever else happened. So, So you now have something that was beneficial in one context, right? Where it's helping you to survive because you got an inflammatory response to kill off a bug that would've killed you otherwise. So that's helpful. Yep. But then later on when you get into a world where that's less the case, now it's, it's being activated by these other pathogens in a way that's accelerating another process, right? Or so it's, it's, it's a really interesting interplay between genetic survival timelines for survival. You know, like ApoE4 was good for short-term survival, but not so great for long-term survival, right? So, it just depends on what challenge the organism's trying to overcome in the moment. But back to your point, I do think that there's a really fascinating interplay between the gut, the commensals in the gut. What we've been excited about recently is we finally got ahold of anaerobic commensals that we can actually give as probiotics that actually have the ability to almost function like a fecal transplant for people, which has gotten very, very exciting, right? So that's kind of cool. And, and then I think, you know, one of the things that, one of the reasons I didn't go to an, into infectious diseases was because, you know, I trained in internal medicine before I went to cardiology, right?

Yeah.

But of course we have exposure to ID all the time, infectious disease all the time. And these are incredibly knowledgeable people. But it just seemed to me like there was just this morass of stuff that you could never quite get your arms around, right? And we're always trying a different antibiotic combination and, you know, then now you've got a co-infection. It just seemed like, oh my gosh, this is like a nest of stuff that I don't know. We, you know, cardiology seemed more straightforward. Back to where we are today. However, I think with the advent of AI and the ability to kind of deconstruct the rat's nest and look at it, I think it becomes infinitely more fascinating in terms of what we can actually do. So, absolutely.

Yeah. Yeah. There were, it's funny that you brought up FMT. So one of the, one of the brilliant innovators in, you know, the gastrointestinal space, the late Dr. Thomas Borody, had a ton of interesting patents and, you know, innovations. He was out of Australia in Sydney. He had— he was one of the early adopters of FMT and worked with teams here in the United States. But then he also became incredibly fascinated by the possibility of reversing atherosclerosis. So actually, you know, designed a clinical trial and gotten funding to study this issue.

Yeah.

Looking though with a much more aggressive antimicrobial regimen. But to your point about playing whack-a-mole with the bugs, In the long term, what I would love to see as a patient is better therapies, maybe enhancing the immune response, enhancing commensals that can be harmful to things that you don't want in your microbiome. You know, there are so many brilliant scientists and innovators in the world. And if people begin thinking about this as a facet, you know, with regard to longevity, with regard to chronic disease, begin thinking about the path—

Yeah.

biome, we'll start to see better solutions than, you know, what we currently have, which what we currently have has took me from being basically nonfunctional to, I get to sit here today, 11 years later chatting with you, which is a gift, but it's imperfect, right? It's not great long-term.

Yeah. It's a little messy still. You know, one of the things that I like about being able to use these commensal probiotics They're from a company called Designs for Health. There's one called Enterostipes, and there's another that's refrigerated, another one that's 5 commensals. But the thing I like about it is that, to your point there about getting microbes that actually drive other microbes out that you don't want to have, when you put these into the gut, what they've been able to show with their research is that it sort of changes the soil in the gut, so to speak, right? Because they're anaerobic. They're not sitting up where the air is passing over them. They're down in the, in the wall of the gut. And when they actually take hold and are doing well and healthy, then the bad bacteria that sit on the surface, like the weeds in the garden, naturally get pruned away. And, you know, as long as you're putting good food and other things to feed the good bacteria, you know, not sugar, now you, you're actually getting the garden to grow in a very healthy fashion. And I think I love solutions like this where we can actually change the soil, change the environment, if you will, internally to help it be in a very healthy place. I think coupling that concept with the idea of going in and killing off the bad guys that are actually harming us today, there's some mix of that, right? That's going to work. So, yeah.

Absolutely. Yeah. I mean, in my own case, like during the course of the year before I knew what was actually wrong with me, It was funny. I had always lived the way you should live. I never smoked. I was a runner, avid runner, weightlifter, yoga, healthy eating. I was intrigued by it from the age of 14. I picked up a Mediterranean cookbook that was sitting in my house and began cooking. I love to cook. When I fell ill, I leveled up the general health, right? But I couldn't like exercise or curcumin or you know, meditate or probiotic myself out of that one.

That's right.

It was, you know, totally degenerative in my case. And so the burden was— and I do have a copy of ApoE4, which is fascinating. And I have spent a lot of time, you know, researching it because it's been conserved, right? So it's not that it serves no purpose. It's, you know, like you pointed out, it helped us survive enteroviruses and the ancestors Withstood malaria, but it, it does do other things that may beget certain risk factors that, that are for those of us that now we live longer, right? We're living, human beings live longer. And so we were at one time, you know, the road was shorter. Now that the road is longer, maybe, you know, this, this active immune response can be damaging, you know, in the face of certain infections or a pathobio, you know, that you develop. But yeah, we've really felt that one of the solutions to kind of all of it is not to work in silos, but to build bridges between the different silos. So, working with clinicians, working with people that have one area of study that's completely distinct from the next person, people in immunology, we have experts in fungi, bacteria, viruses, neuroscientists, You know, people focused on peds, neuropathologists, biostatisticians, people looking at epidemiology. So, because essentially what I felt about it, and I felt the same way about my case, is that whether it's a complex disease or one complex patient, a team approach to looking at the problem is going to be a much better way of handling it because, you know, we're at a point where For a lot of chronic diseases, you know, with really healthy lifestyle, a lot of it could be avoided, right?

Mm-hmm.

Yeah. Plain and simple, just to keep the, to the facts, right? Like most people, you know, it's related to lifestyle. The majority of chronic illnesses can link back to, you know, not eating properly, not taking care of oneself. But in the case of people that already do that and then get devastating illnesses, You know, just discerning other disease mechanisms that are, you know, taking place in certain individuals and then having a precision approach. So we've really advocated for, in patients that have new onset memory issues or neuropsychiatric disease or neurological complaints, regardless of age, to have testing for various infections. And some of the strongly associated pathogens are, you know, Lyme bacteria, Borrelia burgdorferi, And some of the other tick-borne pathogens like babesiosis and Bartonella. And then of course, you know, herpesviruses, the good old cold sore, may not be so innocent as it appears. And then another important one appears to be Epstein-Barr virus with a very, very strong association with MS.

Mm-hmm.

You know, with military database study that revealed that in this very large cohort over an extended period of time, Essentially, if you didn't get Epstein-Barr virus, you didn't go on to develop MS. And that for many people, you know, they, some people will use the word causation, you know, Epstein-Barr causes MS and there are mechanistic studies highlighting that it could be a potential driver. But to your earlier point, there's likely to be like a complex array of things that occur that result in a tipping point. Including the genetics. So, you know, it's, we believe it's an important area of study, but we also believe that, you know, we have to really diversify how we examine chronic diseases where there's been little massive progress.

Yeah. Well, I applaud your thought process here and I align with your aspiration 1,000%. So one of the ways that we've come to think about this is to, and I'm going to push your, your construct a little bit further, which is that yes, it's important to have multiple specialists in the room, but we think that what's actually missing is a systems biology construct. Because when you get a lot of specialists together in a room, they still are working inside their own silo together. And in a systems biology approach, you actually create a construct where Particularly with AI, you can actually have all the different pieces. For us, there's a life energy circle, right? Which is the psychospiritual space, which is, as we know, a big driver when that's out of alignment, drives aging, disease, chronic illness, pain, all those things, right? So that's a big one. Then there's longevity itself, which is the hallmarks of aging. Then there's health, which is basically all the organ systems, subsystems. Then performance, which is how we stay fast, agile, strong, quick, balanced, et cetera. And then the environment we reside in, right? So when you have a system like that, then every disease will arise from within that system. And when you have a whole system, you may have specialists that come in at different points, but they're working inside of a system that's also pulling in other data because they're only aware of what they're aware of. And in a systems approach, you can actually bring in all the information and then get their input as well, but realize that, hey, well, we need somebody over here that actually can speak to us about something environmental or something psychological or something, you know, immunological or whatever it is, right? And so that's what we're working on now with, in the longevity space is, and the health space, human optimization space, if you will. is a systems biology approach to bring all this together and then leverage AI to help us actually understand where are the points for the highest leverage? Because that's really what we're after, sort of what I call the elegant solution, right? So we know there's Epstein-Barr, we know there's this, we know there's that, but where's the elegant solution, right? When we apply leverage here, here, and here, how do we actually coax the system back into health? So anyway, just to let you know. It's a little bit of an extrapolation from the concept of reaching out across disciplines to pull people together because it creates a construct everybody can come under and work together. So anyway, I don't know if that resonates.

Yeah, that's, you know, I think you would really resonate with how we do science within our consortium. So it's not like a typical consortium where everybody does their separate thing. We've been convening weekly for years.

Okay.

Some of the people, like a decade.

Yeah.

And we have data sharing, specimen sharing implemented, even a new enhanced sterility autopsy program. So we are working in a very integrated fashion, as you describe. And in our grant submissions, they're all team science grants, meaning it's never going to just be one investigator or 2 investigators. It'll be an entire team. And then I'm typically involved and some of our other leadership is involved to be sort of the hub.

Mm-hmm.

And to maintain that connectivity with the consortium. And that's actually one of our longer-term goals. Well, really short-term, but it can be long-term because it's aspirational. But we have an incredible research template and plan that we've begun to work. It involves multiple centers, different types of expertise, you know, with a main data core leveraging many of the things you mentioned. But obviously those are very expensive and costly, right? So we have identified various government mechanisms to support team science. and innovative research programs that take a systems biology approach. And we're finding, you know, still there are great challenges federally to get funding for this sort of thing.

Sure.

So, we've really relied very heavily on philanthropy funding to launch the program. But our desire is to be able to point to mechanistic pathways through which certain polymicrobial infections or infections alone, unlikely that they act alone, Yeah. Can be disease drivers, triggers, and/or worsening diseases in various patients with first emphasis on the brain. But, you know, the research platform is intended to be something that is a framework that's reusable. So in other words, the data core and then all of the different teams doing mechanistic studies, population studies, you know, various different detection methods for pathogens, the people looking at the immunology side of things, we are all basically convening as much as we can without having an institute. You know, would I love someone to come forward and say, wow, what a cool concept. You know, do you guys, would you want an institute? The answer is yes.

Yeah. Well, you've kind of created a virtual institute, but I realize the advantages of having something, you know, down the hall. Yeah, down the hall.

Exactly. Walk down the hall and talk to the team. Yeah.

But Yeah, it's very cool. You know, as I'm hearing you talk, I'm actually desirous. I'll use that word. I'm actually desirous of being able to take your data and plug it into the AI that we're developing because we're developing a systems biology AI in the longevity and health space. And the smarter that that is, the more elegant the solutions will be that come out. Right. And so we're looking at, when you think about the AI, it's a couple of interesting things. We're working to make it deterministic and also inferential.

Okay.

And so it's a combination of being able to put in things that we know to be true and keeping it to basically color inside the lines, but then to be able to see relationships across things And work towards, you know, what I call the elegant solution again. So I think you're working in a space where by definition you are curating and cultivating data that fits perfectly into a systems biology approach because that's actually what you're doing is your own systems biology approach. So it'd be really interesting to see what could come of that because we're looking at it through additional lenses that most doctors aren't, right? From the longevity side, the hallmarks of aging, probably we have full omics inside this, right? Genomics, metabolomics, proteomics, all of it, right? So, we have massive amounts of things to leverage against this that could really accelerate, you know, what we all learn, quite honestly, and how we help people. So, that would be pretty interesting.

Yeah, we've seen some really great collaborative efforts taking place around, for just to take Alzheimer's for a second, just to pick one field where consortia are formed and they'll be using omics approaches, a variety of them, and leveraging neuroimaging and biomarkers and tracking lifestyle.

Right.

One of the things that's frequently And pretty, I mean, always across the board omitted is any kind of nod to the microbiome or the pathobiome. You're starting a little bit more with the microbiome.

Yep.

Which I think is a related but sort of distinct subject, right? When we talk about pathological organisms, it's very different than the idea of, you know, a resident microbial community, which sort of has just a neutral or even beneficial tone to it. But yeah, absolutely. I mean, it sounds like what you're developing is really fantastic and could be highly applicable to, you know, serve as, you know, something that data like teams like ours and others, you know, as, as that accumulates mechanistically pointing in various directions, highlighting certain genetic traits, you know, highlighting certain pathogenic states that, that are taking place in certain people. For example, one thing we're really curious about is 2/3 of Alzheimer's cases are women.

Interesting.

And for MS, actually, both are infection-associated chronic diseases. And so we're deeply curious about the changes that take place through a woman's lifespan hormonally and how those may play into susceptibility to neurodegenerative processes and/or vulnerability to pathogens or As you said, the immune system, you know, mounting a defense against something that is inappropriate and harmful.

Yeah, I think, I think, I think it's a really fascinating field, right? You know, when you think about aging and you think about women aging, men have their own issues, of course, but when you think about women aging and you think about how important estrogen is for the brain, You know, there was a really interesting study that was done by Kaiser Permanente a while ago now where they looked at 500,000 women. It was kind of a retrospective study.

Yeah.

They looked at 500,000 women and they looked at women that got any form of hormone replacement. And by that, it could have been they got testosterone for a month, they got estrogen for 2 weeks, they got, you know, estrogen, progesterone, testosterone for 6 years. They got whatever, right? And what they showed was that there was a 50% reduction in, in dementia in the group that got any form of hormone replacement therapy, which is, I thought was fascinating because, oh my gosh, I mean, if you just got testosterone for 2 weeks, really that's going to have any kind of impact, or you got estrogen for 3 months or whatever, right? Unopposed estrogen, which we know is potentially dangerous. So I think, I think it's an interesting piece of it, but when you think about it, There's, you know, the hormones, they basically create a lot more robustness in the tissues. They also are immune modulating in many respects when they're balanced, right?

Yeah.

So, the combination of immune modulation, tissue resilience and robustness, you know, the many factors that go into play here, and then you bring in the pathogens and all this, you can see it's just this incredibly complex morass. But I think For the first time, we're actually going to have enough compute power to actually get our arms around it and be able to say, oh, okay, here are the— here in this individual, that's what I'm thinking about for the individual. In this individual, here are the 8 or 9 factors that are the most critical. If we correct those, this should steer the ship, right? So, absolutely.

And that's really one of the, you know, that's what you mentioned about estrogen is something we've really zeroed in on because In females with estrogen depletion, you know, some of the barriers become more permeable in a bad way because membranes, the gut barrier. But a lot of people don't really think about the blood-brain barrier. And I don't think it's been studied really effectively, you know, to look at is there enhanced permeability of the shield that's supposed to protect the brain if you're also seeing increases in translocation of gut bacteria. With depleted estrogen, you're seeing enhanced UTIs, urinary tract infections, vaginal yeast infections, and then tissue thin. So, it's very fascinating, understudied. And so, we're very privileged to be able to help work on that and get to that space of research in the context of aging in females as it pertains to neurodegeneration and Alzheimer's.

Yeah.

Because I do believe there's something there as you're pointing out. It's just likely to be, it's going to need to be precise, precise approaches, right? That take a lot of factors into account. And as you mentioned, AI, what an incredible tool to help us do that.

Yeah. I'm so excited about it really. You know, I think the other thing to think about is to bring in the functional medicine physicians and the true longevity physician. Everybody's a longevity doctor now, but bring in the actual people that are, you know, working at the, the root cause of the root cause kind of area. Yes. And the functional medicine approaches, which may not have as many studies behind them, and many times have many studies that just aren't, you know, widely referenced. But there's a lot of information there that when it's aggregated together, I don't think we're that far away. I, I've told people 2 years ago, I thought we were going to crack aging in 3 years, and I still think we're on on course to crack it in the next 12 months. And the reason I say that is because, you know, kind of the work that you're doing, the way that AI is really facilitating this rapid integration of information that can be very precise. And I think if we get a little bit of quantum computing on top of it to ask the optimization questions, we're not far away from actually being able to crack it. And so, if you can crack the code on aging, then I think you can really crack the code on health. And health optimization, diseases start to fall like dominoes also, I think. So pretty interesting.

Absolutely. And some of the diseases that we study also manifest in childhood. So we are also examining, while we're called the Alzheimer's Pathobiome Initiative, we are looking at the whole human lifespan because we acknowledge that some of the neurodegenerative neuropsychiatric diseases that get diagnosed early Um, bear a lot of similarities, um, whether you're talking about symptomatology or, uh, biomarkers from blood or CSF, uh, neuroimaging studies, and even brain specimens, postmortem brain specimens. So one of the things that our team is digging into are, uh, cases of PANS and PANDAS.

Yep.

Um, these are the pediatric neuroimmune disorders linked with infection as a trigger. Or a continual simmering pot, um, either in tonsils in the case of PANDAS, uh, or it can even be, you know, from a tick bite, something like Lyme disease or COVID, um, SARS-CoV-2 can be a trigger. But these disorders bear some striking similarities to neurodegenerative disease associated with advanced age.

Mm-hmm.

And so, okay, well, if neuroinflammation is present, if, uh, autoimmunity is a factor, Enhanced blood-brain barrier permeability, mood alterations, sleep alterations, urinary, you know, so there's so many different things. And so we're stepping outside the bounds of specialties, but also across the lifespan.

That's right.

And it's, you know, due to really external inspiration, honestly, Dr. Gladden, it's like my own experience with complex chronic illness, but then also talking to patients around the world and a lot of patients can become extremely knowledgeable. Like we're talking—

Very knowledgeable.

They can become thought leaders.

That's right. Yeah.

And so those of us that have had to take the pain and turn it into a solution because there wasn't one, because we feared we'd lose our lives or our ability to thrive and be with our families, those things can really accelerate and inform research and also things like what you're doing. And it's interesting, there There have been points in time where obviously with all of the sophisticated diagnostic approaches that we have now to evaluate patients, something that gets lost is at times, especially in the context of people that have chronic Lyme disease that drift from one doctor to the next, is just that patient-physician connection. Like the person across from you listening to your story, piecing together the clues And digging a little bit deeper, you know, because a complete blood count on somebody with chronic Lyme looks pretty unremarkable oftentimes. And so, you know, that next level of curiosity, that next level of interpersonal connectedness at the soul level between a practitioner and their patient has to come back into the space because the more sophisticated we get, the more disconnected we can become.

Yeah, no, that's, that's, I mean, I think you're bringing out something about the healing connection, really, the therapeutic connection, the therapeutic relationship, the therapeutic trust and construct that goes between, you know, somebody that needs help and somebody that wants to provide help. Yeah, you're never going to move away from that. You know, I also keep in mind the fact that while the body can be exposed to a million different insults, maybe 10 million different insults, It only has a finite number of responses.

Yeah.

Right? And so, right, it only has a finite number of responses. So if we can actually understand the way in which these external, you know, agents or whatever are, how they're triggering the finite number of internal responses, which is typically inflammation, oxidative stress, you know, leaky gut. I mean, it's really fairly finite, right? Um, then we should actually be able to, um, have some interventions that actually go in and stop these things. Right. And so, so you're, it's 2 prongs. One, you're stopping the reaction to what happened, and 2, you're clearing whatever the, the insult was that came in. Right. So you have 2, 2 sides to that. Right. Yeah.

So do you want to know the reason, one of the reasons why I believe that the amyloid Clearing antibodies are not demonstrating a whole lot of efficacy.

Sure.

It's that it's there for a reason. It's not to say it's not problematic. It is. But what happens, even if you took away the amyloid and from the research that's already been published, if you have a confluence of organisms that by nature of being alive, they have to steal energy from your mitochondria. They have to dysregulate metals, lipids. They have to drive oxidative stress as a part of their whole thing, right? They cause the release of heat shock proteins and cytokines. You haven't actually handled— you've taken the batteries out of the smoke detector while the fire is raging. So, you know, the drug situation has undoubtedly delayed progress because, you know, and I, I worked in pharma and biotech. I'm not against drug development. We need innovation. We need people that are actually creating solutions to the problems. We need better testing for infections is one great example. We need better precise treatments, things like phage therapy that could potentially have promise to be more widespread use someday.

Right.

But until somebody really develops a solution around these problems. And it may not have to be a therapeutic solution, could be preventative or something else. I think the economic thrust is missing and the economic thrust also informs and exerts pressure on the federal thrust for funding.

Yep. I'm just going to say something for your audience. A phage is basically a virus, so you can use a virus to go kill other things, right? Just so if that slipped past you, we use something called EcoPhage actually to kill off things in the gut. It'll go in and kill off all the bad stuff, right? So, we're familiar with Yusufage, but that's an interesting thing. I think to your point about economic incentives is one of the biggest problems in medicine, right? Because chronic disease, it makes more money than curing disease on some level, right?

Yeah.

And so, there's lots of financial incentives that I think are misaligned with health. It would be nice if we could get those straightened out. But in the meantime, I'm not going to try to change systems that are, I just want to find the answers that we need to find and then let those speak for themselves. Right. So that's absolutely, yeah.

We're right there with you. Exactly. We're not focused on, you know, what hasn't been done or, you know, like looking in the rearview mirror, we're trying to look ahead and say, well, what can we do in the context of the funding we have with the information we have with the resources we Yeah. And one of the things we felt is so important is collaboration and doing so in a very intentional manner, not just consortia that show up every once in a while. And yeah, we're on an email distribution list together, but true collaboration, you know, saying, hey, I ran this specimen of the same region. Did you, what did you find? Here's what I found. And then, oh, I didn't pick that up. You know, so this whole idea of rigor and reproducibility in science, which Dr. Jay Bhattacharya, the new director of the NIH speaks about all the time. That's exactly what we are doing with the Alzheimer's Pathobiome Initiative. We're leveraging preexisting testing that is, you know, some of them perhaps not even commercially available, but are in academic labs looking at the most reliable ways of detecting neuropathogens that can become very problematic and that in and of themselves can trigger disease pathology.

Yep. No, I think that's right. I think it's good to look outside the allopathic model or even the osteopathic model, right? And look at there, I mean, there's a lot of wisdom in traditional medicine practices, you know, Ayurvedic medicine, Chinese medicine, things like that. They've been dealing with this stuff a long time. What goes on in Japan? I mean, I'm really, I'm agnostic to where the solution comes from. I really don't care where it comes from. I just care that it works. So.

I agree. I have to admit, like ages ago, you know, because right out of college I worked for Pfizer and, you know, I think that the allopathic medical community sort of looks down upon some of the more traditional, longer standing, even, you know, leveraged by humans for so much longer than our modern medical machine. But during, you know, my own chronic illness journey, learning, you know, with the working with a functional doctor, a naturopath, as a part of my team, you know, there is, it's a big world and there are abundant solutions and ideas. And I'm like you, I feel like, boy, if the, if the solution could be, you know, tucked away hiding, I mean, I was pretty excited. There was this seaweed extract derivative by a company called Shanghai Green Valley Pharma.

Hmm.

They went and got approval in China. I do not know where they stand as far as US approval, but they were giving it for patients with, I believe, mild to moderate Alzheimer's disease.

Hmm.

proposed mechanism was modification of the gut microbiome.

Okay.

But as you said, there are so many natural compounds that have themselves evolved defenses against pathogens and have anti-inflammatory properties too. So yeah, it's once we grasp, as you're saying, that you keep going back to like the systems biology way of thinking. And if we can actually do it, which is challenging because people tend to form factions and groups, right? And then kind of hang out with that group.

Tribal, right?

Yeah. Not that it's a bad thing, but I think we need to be sort of talking to one another because we have big problems that deserve faster solutions and more accessible, right? Because a lot of what we are talking about, the precise approaches that even I've had the benefit of receiving, they're out-of-pocket expenses, right? They're not, these things are not covered by insurance. And so the current model really is to go after sick people and they're already sick. But in the future, if reimbursement would allow for longer precision medicine visits, you know, like my Lyme disease specialist spent 4 hours with me the first visit. Can't really do that within the bounds of insurance.

No, you can't. It's a combination of insurance and the healthcare system won't allow it, those 2 together, right? So I think a lot of the solutions are going to come out of the alternative approaches because people are able to take more time. I think the incentives are aligned around Not how do we make a drug that we can make a billion dollars off of, but how do we actually find a solution that's going to work? I think there's, I think in some sense there's more intellectual integrity in, in some of those areas than there could be when someone's really aligned with a, you know, with a financial bottom line, so to speak. And I realize drug discovery is expensive and I understand all that and I understand there's lots of reasons for it. There's also a lot of AI stuff now that's coming along to really, you know, rapidly speed up drug discovery also. Like I've been looking at some stuff where, you know, they, they spent, I forget how many months trying to find 4 molecules that could do something. They ran AI for 3 minutes, it came up with 1,500. You know, it's just like, it's crazy, right? So I mean, the, the rate of innovation, this is why I say aging will be cracked in a year because the rate of innovation is—

Yeah.

Right. High five, right?

I would like, I would like you to be right. I mean, this would be very good. I'd be thrilled.

Yeah. But the rate of innovation is so beyond exponential that it's almost hard to comprehend. So that's why I think if, but I love the idea of trying to collaborate with you on this in some way, shape, or form.

We are always, you know, right at our website, alzpi.org. We, right there, it says, you know, there's always a link to reach out. You and I obviously are connected now. Yeah. We're always keen to collaborate with other people that have open minds, a deep curiosity, and a desire to see change like within a lifetime, right?

Yeah.

I think there's so much that can be harnessed. And we wrote a paper in the last year with a team, the gentleman who helped to co-found Viome, the gut microbiome testing company, Momo Vucic. We wrote a paper that we essentially called attention to the chronic disease epidemic needing a Manhattan Project style approach and not to build a bomb, but to leverage the existing solutions that are there. And I think that's a lot of what you're saying and what your concepts are hitting on is that we already have tools that can help us address the various issues that we are aware. And you made this point before that I wanted to really agree with, which was that the biological mechanisms are finite, right?

Mm-hmm.

So engaging in various inflammatory pathways, like Even if, for example, we're able to say, okay, this certain set of pathogens in this particular individual that has ApoE4, for example, and then other genetic traits will result in increases in IL-7. And so where you could begin to paint a picture, and then once the machine learning or AI is involved, you can then start to draw inferences if you have large datasets, right? Like if you accumulate enough information about enough people. So I think it's just a very exciting time. And I love your timeline of a year. I feel like I'm going to hang my hat on that. I like it.

Yeah.

Good.

All right. Well, we'll reconvene next August. So. It sounds good. Okay. Beautiful. Well, Nikki, it's been such a pleasure chatting with you. I really appreciate you taking the time. Thank you.

And I appreciate you, Dr. Gladden. Thanks for, you know, it was very informative. I learned a lot from you about what you all are doing and look forward to continuing to talk.

Yeah. Beautiful. All right. Well, thank you.

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