The Peter Attia Drive - #236 ‒ Neurodegenerative disease: pathology, screening, and prevention | Kellyann Niotis, M.D.

Episode Date: January 2, 2023

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Kellyann Niotis is a neurologist specializing in risk reduction strategies for the prevention or slowing of neurodegenerative disorders. In this episode, Kellyann provides an overview of the various diseases associated with neurodegeneration, including, but not limited to, Alzheimer’s disease, Lewy body dementia, and Parkinson’s disease. She goes in-depth on Parkinson’s disease, explaining its pathology, role in movement capacity, very early warning signs, and the role of anxiety and sleep. Similarly, she provides an in-depth discussion of Alzheimer’s disease, including the latest in screening, genetics, and tools/strategies for prevention. She ties the discussion together by explaining the differences and commonalities among the various diseases of neurodegeneration and the potential causative triggers, and she highlights the importance of early screening, cognitive testing, and taking the proper steps to lowering the risk of disease. We discuss: Kellyann’s background, training, and interest in the brain [2:30]; A primer on neurodegeneration: different types, prevalences, interventions, and more [5:30]; Overview of Parkinson’s disease and neuromuscular disorders including ALS [16:00]; Parkinson’s disease: early signs, diagnosis, genetics, causative triggers, and more [17:30]; Interventions to delay or avoid Parkinson’s disease, and the role of sleep and anxiety [31:15]; The challenge of standardizing early interventions for Parkinson’s disease without a clear biomarker [39:45]; Alzheimer’s disease: pathophysiology and the role of the amyloid and tau proteins [47:45]; Can PET scans be informative for diagnosing Alzheimer’s disease? [51:15]; Tau accumulation in the brain, tau scans, serum biomarkers, and possible early detection of Alzheimer’s disease pathology [57:00]; Cognitive testing explained [1:03:30]; The challenge of identifying the stage of the disease and why drugs have not shown efficacy [1:14:45]; The association between hearing loss and dementia [1:17:45]; The relationship between oral health and neurodegenerative diseases [1:21:30]; Genetic risk for Alzheimer’s disease [1:24:45]; What one’s mitochondrial haplotype can reveal about their risk of neurodegenerative disease [1:32:30]; The positive impact of exercise on brain health [1:37:00]; High blood pressure as a risk factor [1:40:00]; Why women are disproportionately affected by Alzheimer’s disease [1:44:15]; Final takeaways: the future of understanding neurodegenerative disease and further reducing risk [1:46:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, I'll focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of the space to the next level. At the end of this episode, I'll explain

what those benefits are, or if you want to learn more now, head over to peteratia MD dot com forward slash subscribe. Now without further delay, here's today's episode. I guess this week is Dr. Kellyanne Neodis. Kellyanne is the first fellowship trained preventative neurologist who specializes in risk reduction strategies for patients seeking to prevent or slow neurodegenerative disorders, including Alzheimer's disease, Lewyody dementia, and Parkinson's disease. Kellyanne previously managed the country's first Alzheimer's prevention clinic at Wild Cornell Medical College

and New York Presbyterian Hospital, where she followed in the footsteps of one of her mentors, Richard Isaacson. Kellyanne is currently a full-time neurologist in our practice early medical, where she leads the preventative program with respect to neurodegenerative disease. In this episode, we focus on a deep understanding of neurodegeneration and the various diseases associated with it ranging from Alzheimer's disease,

which of course most people think of first and foremost, but also talking significantly about Parkinson's disease and Lewy body dementia. As we talk about Parkinson's disease, we get into everything from its pathology, the role in movement, capacity, anxiety, and sleep, as well as other warning signs, tools for prevention and possible future biomarkers. When it comes to Alzheimer's disease, we also discuss its pathology, specifically the role of cognitive testing, and the role of visual and auditory issues. This is something that I think is becoming more clear today than it was even three years ago when we first had podcasts on this topic. Talk about oral health, exercise, hypertension, and why women may be at higher risk for Alzheimer's disease. In other words,

we know that women are at a 2x increase risk. The question, of course, is why. So, without further delay, please enjoy my conversation with Dr. Kellyanne Diodes. For the delay, please enjoy my conversation with Dr. Kellyanne Beotis. All right, Kellyanne, great to be sitting down with you and talking about all things neurodegenerative disease. This is something I've been looking forward to for a while. Maybe just to begin, kind of give us a bit of a sense of your background and how this has become of interest to you. Did you always know you wanted to become a doctor? So, thanks for having me. I'm super excited to be on the show finally. So it's an interesting question.

I'm gonna say I always wanted to be a doctor, sparing the fact that when I was younger, I thought maybe I'd be a singer or a mermaid or something crazy like that. I love scuba diving, so I had a large fantasy. Actually, that's your point. Mermaid can combine the love for scuba diving with singing. It's like it really is the perfect career.

It was the perfect career for me, but no, I was always a nerd. Actually, I don't know if I'm allowed to say this, but in high school, the quarterback of the football team joked and said that I was a waste of pretty because I never went to any parties and all I did was study. I was obsessed with biology and obsessed with chemistry and was a bookworm pretty much. And did the brain always interest you? I found that interesting, you know, a subset of people when they go to medical school already know what they're going to do.

Many people do not. Were you that person who went interviewing for medical school knew you wanted to do neurology? No, not at all actually. So I'm a first generation American. My dad and mom Bolton give me a lot of coaching when I was growing up, but one thing that they taught me was whatever you're gonna do, just love it because you're gonna do it for the rest of your life. And when I was in medical school, I just loved learning. So I loved every single subject. But when I got into the clinical rotations,

I found myself a little disappointed in them because I wasn't interested in the algorithms of the disease and the actual treatments that were being offered. And when I was thinking about things like prevention or exercise or diet, I pretty much just got shunned. So when I was thinking about specialties, I thought about what could I read for the rest of my life and be fascinated by and that was pretty much the brain for me. Now, a lot of people will say neurology

is a pretty depressing specialty because a lot of the patients you're caring for have conditions that can't really be reversed. At least in my med school neurology was not a core rotation. We were not required to do it. So I assume that was the same for you and you did it as an elective? Yes, I did it as an elective. And it is so depressing. Most of these diseases, almost a whole of them, we don't have effective treatments for sparing things like migraines and MS now, but Cleoblastoma, terrible disease, terrible treatment options, not much has changed in the field.

And when you think about things like neurodegenerative disease, which is ultimately what I went into, the diseases are devastating for both the patients and their families. Now, you did your neurology residency at Cornell, which is how you met our mutual friend, Richard Isaacson, and that's, of course, how we became connected. And then you did a fellowship at Mount Sinai in movement, disorder specifically. I want to take a step back and make sure people, including myself, understand the breadth of this field called neurodegeneration. So, when you look at the actuarial statistics of mortality, neurodegeneration accounts for the third leading cause of death.

So, you have all of the diseases that are lumped under ASCVD, atherosclerotic cardiovascular and cerebral vascular disease. That's number one. Cancer is number two, and then neurodegenerative disease is number three. And those three basically account for, sorry, there's one other. Actually, no, no, those are the top three. And I think they account for 70% of death, quite a sobering thought. Now within neurodegenerative disease, you have a lot of different types of pathology, some of which we've spent a lot of time on this podcast talking about. We've talked a lot about Alzheimer's disease. We're going to talk about that again today. But

what I want to do today is be more broad. Because in getting to know you, I've come to understand that there are some of these diseases that affect men more than women, and we have a far better sense of how to discriminate between these diseases than affect men more than women, and we have a far better sense of how to discriminate between these diseases than I used to think we did. I used to think that, you know, for example, Alzheimer's disease and Louis body dementia could only be distinguished on an autopsy. They couldn't be distinguished clinically. I used to never think about Parkinson's disease in the same way that I would think about, say, a cognitive disease. And I really, until recently, never understood the differences in the patterns of where

the disease occurred in the brain and how that translated to deficits. Now, the other day, you explained to me in a way that I thought was so elegant, looking at the different parts of the brain. Maybe you could sort of rehash some of that for folks. Let's take a step back and talk about dementia, which is an unbroloterm, and then a further step back, which is neurodegeneration, which encompasses dementia's and other processes like Parkinson's disease. So when we think about neurodegeneration, everyone thinks about Alzheimer's disease because it's the most prevalent and chances are you know

somebody who was affected by this disease. But the other diseases that we're going to talk about today are also very common, and you've probably never heard of them, but you should, because there's a reasonable likelihood that they will affect you at some point in your life or a loved one. So when we think about dementia, what falls under that umbrella, we have Alzheimer's disease, we have vascular dementia, we have Louis body dementia, frontal temporal dementia, what falls under that umbrella, we have Alzheimer's disease, we have vascular dementia, we have Lewy body dementia, frontal temporal dementia, but when we think about neurodegeneration as a more broad term, we start thinking about diseases like Parkinson's disease, hunting tins disease, ALS, and then more rare diseases like progressive, super nuclear palsy, multiple

system atrophy, cortical basilar degeneration. So taking a step back in terms of understanding what these diseases are and what symptoms people may present at, I like to look at it as what part of the brain is this affecting. So neurodegeneration means death of the brain cells. Where is that death happening? So for things like frontotemporal dementia or vascular dementia, you're talking about the frontal lobe

primarily, and the frontal lobe is involved in processes such as planning events, problem solving, speed of processing. These are all executive lobe functions. When we think about Alzheimer's disease, we're thinking about the temporal lobe. That's where the degeneration is mainly happening. And that's mainly a memory problem, but it's also a language problem. The language center is in the temporal lobe. For diseases like Louis body, we're thinking about the parietal and occipital lobe. The parietal

occipital lobe are involved with visual spatial processing. So you get symptoms like issues with depth perception, issues following plotlines of movies or following plotlines of books. Patients will have to reread passages over again to really fully comprehend what's happening. And hallucinations is something that you can see later in the disease course. And is the difficulty with depth perception part of what feeds into the movement disorder that we see that kind of differentiates Louis body from AD? Yeah, I really think so. And it's interesting and we'll talk about this later. So maybe we'll stickie note it for now. But visual impairment is a risk factor for neurodegenerative diseases. And how does that relate to how we can prevent these diseases? Well, it's possible that the visual processing

is needed to reinforce the neuronal circuitry. And what I mean by that is our brain needs sensory input. It needs sensory stimulation. When we don't have that, those neuronal circuits aren't getting exercised for lack of a better term, and they're more likely to atrophy. So if you don't use it, you lose it. And in relation to your question, yes, I think that that visual processing is why you have the depth perception issues that you see in lube body. So I definitely will make a note of that because I want to come back to not just the visual part, but the auditory part as well. Yes. I want to go back to something you mentioned at the outset. You talk about how vascular dementia overlaps with frontal dementia. What is it about that? When I

think of vascular dementia, in my mind, I'm thinking of small vessel disease that's similar to atherosclerotic disease, basically some form of ischemia. Why is that unique to the frontal cortex? And why is that not something that the rest of the brain is just as sensitive to? So I actually think vascular dementia and Alzheimer's dementia are the ones that overlap more. And the reason I say that is because it's very difficult to discern clinically the difference between Alzheimer's and vascular dementia, we classically will say yes, the speed of processing issues are more prevalent in vascular dementia versus Alzheimer's disease. It's more of a memory issue. But when we're looking at metabolic changes in the brain,

we see that the frontal lobe is hypo metabolic in terms of glucose utilization in front of temporal dementia and in vascular dementia. And why is that? It's hard to know exactly, but it may have something to do with the vascular term of the brain and what areas of the brain are more sensitive to glucose, metabolism, cholesterol, metabolism, and vascular risk factors. Yeah, it's very interesting because there is such a high association with

diabetes in this condition, but my recollection is that the brain doesn't require insulin the way the rest of the body does to facilitate glucose transport into neurons. In other words, insulin resistance per se should not be an issue in the brain proper. But of course, I've seen experimental data that look at intranasal insulin injections that temporarily alleviate some of the symptoms associated with this type of dementia, suggesting that maybe insulin resistance is playing a role paradoxically. And of course, you always have to wonder if the metabolic syndrome that is associated with types of diabetes in that entire spectrum is simply a marker of the underlying vascular problems as well. So this is an area that Kelly and I really find myself confused. In the end, it might not matter that much from a preventative strategy, but nevertheless,

it creates a little bit of confusion in terms of mechanism of action, at least in my naive mind. It's really interesting clinically when you look at data. So we do cognitive testing on a ton of patients. So we get to look at this in real time and we get to compare it to serum biomarkers. So thinking about high cholesterol, meaning high ApoB, when we see ApoB in patients, we often do see reduced speed of processing and clinically we see that if you correct things like the ApoB, you see improvement in speed of processing. Can we about the time course there? It can happen rather quickly over a

course of six months, but it's dependent on the person. That's kind of amazing. I mean, obviously, we take this approach with patients, but a lot of our patients that are in our practice don't really have the MCI that you are seeing in your clinic. The patients that you enriched to care of at Cornell were obviously far more advanced. Is there a point at which you just didn't see any improvement in symptoms regardless of intervention? Like I said, everyone's different. And there are a lot of different factors that could influence something like executive function and speed of processing. I think what's most helpful is looking at individual and putting their lab values and an understanding of what

their risk factors are next to each other, because if you see somebody who, for example, does have out of control cholesterol and you're looking at their executive function in tasks like generating words that start with F or A or S, that's a really popular test that gives us clues into, is the vascular risk factor affecting this person's cognition. If you see that, the chance that you intervene on their cholesterol and they have a notable outcome in the next 6, 12, 18 months is pretty high, but it depends on the person. And it also depends on what other factors are playing a role. For example, sleep.

Sleep is huge. And I can't emphasize enough how important sleep is to speed of processing. If you are getting shit, crap, sleep, sorry, you really aren't going to see high speed of processing. You really have to be sleeping in order to process information. So I want to put a pin in that as well, because I do want to come back to sleep staging. We've obviously separately and previously talked a lot about REM sleep disruption and the implications for that. So I want to come back to sleep. But let's go back to kind of this broader sense of what's going on.

So you have these three areas of the brain that can be impacted, that can lead to various types of dementia. And each of them seems horrible in their own right. Ironically, Alzheimer's seems the least horrible in that it's mostly a deficit of memory and language relative to robbing you of executive function processing speed in the front of the brain and movement disorders and visual disorders in the back of the brain. But to be sure, these are all awful conditions. Let's talk a little bit about the things

that we think about more with the Shrek 2 movement. So Parkinson's disease, and obviously the perhaps the worst disease of them all ALS. ALS and Parkinson's disease are very different because ALS is more of a peripheral nerve problem. Parkinson's disease is more of a central problem, more related to Louis body.

ALS is really rare, only about 18,000 people in the US have ALS, unlike Parkinson's disease, which is much more common, a million people in the US have Parkinson's disease, and the incidence of Parkinson's disease is actually doubled in the last 25 years. It's the fastest growing neurological condition. And just for comparison, how many people in the United States carry a diagnosis of Alzheimer's disease? About six million. So six million to one million to 18,000. Yep, and for Louis body, it's about 1.4 million. So less common than Alzheimer's disease, but still.

That's actually pretty common. That's 25% of it. Right, but still very common. So still reasonable likelihood that someone listening to this podcast today is going to be affected by one of these diseases, ALS less so. But the interesting thing about ALS is that there's a connection between ALS and frontal temporal dementia. So there are certain genetic risk factors. One is C9 orf. That's what I say C9ORF, it puts people at risk for both ALS and frontotemporal dementia. So some family members will have the frontotemporal dementia and other family members will have ALS. We don't know what turns one person to develop the more peripheral

nerve problem versus the more central nerve problem, but it's an interesting connection that you'll see. Now Parkinson's, again, I didn't realize it was quite that prevalent. So is it a different disease when it occurs in young people than when it occurs in older people, or is it basically the same disease and it just has a variable time of onset? So we, in my opinion, aren't very good at the way we're diagnosing these diseases. So we're using a clinical diagnosis to say somebody has Parkinson's disease. So you need to have resting tremor, bradykinesia, which is slow movements, rigidity, which is stiffness of

the muscles, end or postural instability. So falling, not being steady on your feet. That is a really rudimentary way of looking at the disease. Yes, it's saying that there's something going on in the brain that you're losing dopamine neurons, but really these diseases are starting way, way, way before those symptoms are actually presenting. So if you look at people who have REM sleep behavior disorder, which is acting out your dreams.

So punching, kicking, screaming in your sleep, that is over 90% positive predictive value that you will go on to develop either Parkinson's or Louis body like disease. And that starts 20 to 30 years before a tremor muscle muscle stiffness, or postural instability will ever present. Wait, that's going to be a little scary to some people because I think a lot of us think, I move around a lot in my sleep, but how is this diagnosis made? Is it relying on a spouse or someone in the bed with you or is it something they can only be done with polysomnography? So the gold standard is polysmography, but you actually don't need polysmography to diagnose it and in fact one simple question has a greater than 90 percent sensitivity and specificity for picking up REM sleep behavior disorder, which is

does your bed partner note that you are punching kicking or moving a lot in your sleep? And when we're saying moving a lot, we're not just talking about tossing and turning, we're talking about it's clear that this person is having some sort of dream and they are acting that out in their sleep. It's different than just the tossing. And to be clear, are you saying that if that exists, so if someone in their 30s is experiencing that, there's roughly a 90% chance they're going

to go on to develop Parkinson's disease or Lewybody dementia. Correct. And it's a terrifying fact. It is a terrifying fact. But the way that I think about it is knowing that is like picking up breast cancer when it's localized to the breast tissue, the way that we're doing it now, we're picking up Parkinson's disease by the time we get the diagnosis of Parkinson's disease. So by the time someone has tremor rigidity, brain cancer. Yeah, it's like diagnosing metastatic breast cancer.

Yes, 50% of the dopamine producing brain cells are already gone. Okay, so let's actually tell people a little bit about what's going on in Parkinson's disease. So let's explain what dopamine is in the basal ganglia and all these things so that people understand how that happens. And let's spend three minutes on just the med school explanation because I think it's important to understand you have to understand a little bit about the anatomy and the neurobiology of this to understand the prevention stuff that we're going to want to talk about. So what's happening in Parkinson's disease? Virtumentary Medical School 101. What is happening in Parkinson's disease?

So dopamine producing brain cells, so dopamine, allergic cells live in a part of the brain called the substantioneigra, pars compacta, which is a center that controls movement in the body. These cells are dark colored, and in Parkinson's disease, these cells start to die. You need dopamine. So these cells produce dopamine. You need dopamine to move, but you also need dopamine for a slew of other neurological processes, including mood regulation.

So if you don't have adequate dopamine, you often suffer from anxiety and depression. Do we have any sense of what leads to the loss of those cells? So what are the risk factors for Parkinson's disease? Is what you're asking? Yeah, or even just more pathologically, like for example, has it been ruled out that it's autoimmune? Is there any reason to believe that the immune system is attacking those cells and destroying them? Does it seem to be unaffected by anything else? Is it programmed cell death, presumably not?

Is it inflammatory environment that destroys those dopamine-producing cells? Do we have some sense of what it is mechanistically that's doing this? So the immune system and inflammation seem to play a large role here, but it may be more related to the mitochondria and the lysosome function. So autophagy and removing damaged organelles seems to play a really big role in these diseases. Which seems to be a common thread

across all of neurodegeneration. We've talked about this on a previous podcast with Eileen White, got it's probably been two and a half years ago. But one of the surest ways to impart neurodegener disease onto a mouse is to knock out the genes responsible for autophagy. They'll basically all succumb to neurodegeneration. I want to say it's something as absurd as at four months of age. Now, four months for a mouse, right?

That's the equivalent of, I don't know, probably 15 or 20 years old for a human, maybe less. And to think that if the only thing you've done is knock out a topology, you might argue, well, they would have gotten other diseases later on, but that the very first thing that they get and the thing that ultimately kills them as neurodegeneration probably speaks to the importance of this process in homeostasis within the brain. Absolutely. And I mean, we don't have perfect models for Parkinson's disease because the models that we use are either models that are induced by toxic exposures or genetic models,

which there's no one's eyes fits all. I think this disease is just so broad and can present in many different ways and can have many different ideologies. But if you look at the genetic models for the disease, really one of the main genes is called GBA. And what happens is that enzyme gets stuck, the glucosorebricides, enzyme gets stuck in the endoplasmic reticulum and it can't break down glucose fengocene. So you're not getting these chemicals broken down where they should be. They start building up, and when

they start building up, the lysosome can't get to these substances to break them down appropriately. So the lysosomal function is really impaired. And once you start impairing the lysosomal function, then the mitochondria becomes affected. Then you start triggering a whole slew of inflammatory cytokines, and the process just is a vicious cycle. Two questions, then. You can take them in whichever order you like. Do we have a sense of what are the causative triggers, not just associated? What are the causative triggers, not just associated with a causative triggers of Parkinson's disease. We should talk about the same for Louis body, of course, as well, but let's just focus on one.

Secondly, if you're talking to that person who's 40 years old, who is having the sleep disturbances that we now think have a high likelihood of predicting the beginning of this damage. What do you do? This is touching on so many points. So if you want to first start with what is triggering the disease, well, we don't have the perfect answer, but we know certain things do trigger it or seem to play a role. So pesticide exposure seems to play a role. Solventic. Which pesticides do we know? Yeah, so it's paracquot and road and own, which road and known is not used in the US anymore, but paracquot is still used in the US. So we see a higher prevalence of Parkinson's disease and people who live in more rural places in the US

and if you look at epidemiological studies on where as Parkinson's disease Distributed in the US you'll see there is a quote Parkinson's disease belt and it really runs through the Midwest Of course the USDA and the FDA would never acknowledge this because They would have to say that this is just noise and that there's no data there. They would have banned this pesticide. So what is it that you think that they don't see in those data or how are they explaining that away as a confounder for something else? You know, I don't think I have a very good answer to that.

I don't know why they don't acknowledge that these studies are real and these associations are pretty profound. There's clearly just like there's a stroke belt in the South. There's a Parkinson's disease belt in the Midwest. What are these pesticides used for? Agricultural. Any foods in particular? I don't know. Okay. And you probably don't know if there's substitutes that could be used that are slightly higher costs that are less toxic. I'm't know. Okay. And you probably don't know if there's substitutes that could be used that is like the higher costs that are less toxic. I'm not sure. Are these pesticides in greater use today?

What explains the fact that you said earlier Parkinson's is the fastest growing neurodegenerative condition in the U.S.? Yeah. Great question. And there have been a lot of theories hypothesizing why the prevalence of Parkinson's disease will grow in the future. And one of them, which makes me laugh a little bit, is smoking. So smoking is, quote, protective against Parkinson's disease. It's like one of those weird things that you read about and you're like, oh, wait, why?

Just like I think inflammatory bowel disease also smoking is, quote, protective against it. And they're saying, well, less people are smoking now. So maybe that's what's driving the disease. But I don't really buy into that because I don't really think smoking is offering that much protection to your brain. And it's doing so many other terrible things for your brain and body that it's just not something to ever consider when we're thinking about ways to optimize

our health. I actually think it has a lot to do with the movements that were going through day-to-day and how much screen time we're spending every day, but we can touch more on that later. So you think it's a loss of movement capacity, basically? Exactly. And just like we were talking about, or I think Richard talked about it in his podcast, the idea of cognitive reserve, building as much cognitive reserve as possible, well, you want the same with your body. You want to build up as much movement reserve as possible,

because if you don't use it, you lose it. And the less you move, the more likely you are to develop one of these neurodegenerative movement processes, I believe. How many of those cases of Parkinson's disease percent-wise, do we think of a clear genetic predisposition? And you mentioned one gene already. We were going to talk a lot about the genes around Alzheimer's disease. What is the genetic landscape look like here? So right now we say 10% of organs and diseases related to a clear genetic ideology.

GBA is one gene, LARC2, LRRK2 is another one. And both of these genes are tested in 23 and me only one variant of each, so it's not a perfect test. So it's negative for you, doesn't really mean you don't have a variant in one of these genes. But those are the most common. There are other less.

And are these more like ApoE4 where they are risk factors, but they're not fully penetrant in the way that hunting tenses. Yes, exactly. So if you have one of these genes, it depends on a lot of factors, especially ancestry. So Ashkenazi, Jewish people with Ashkenazi, Jewish ancestry have a higher risk that these genes will express. But we're looking at penetrants of around 30% but for a large two, it can be much higher up to 80%. Some studies quote actually a hundred percent depending on how long you live, but I don't know if I believe it. So that's 10% 10% yeah. Whereas in Alzheimer's disease two thirds of cases have E4 at least one copy of E4.

So you could say E4 is playing a bigger role there potentially. Yeah, I would say that our understanding of Parkinson's disease is so far behind our understanding of Alzheimer's disease and our understanding of the genetic architecture of it is so far behind. I would say that we're probably at least 10 years behind the field of Alzheimer's disease and we will identify more genetic risk factors for this disease. I have no doubt about it because the number of patients

that I've seen that have a clear family history and multiple family members and testing for every known gene that we could has just turned up nothing, there's clearly something there that we are missing. Again, we see this also with breast cancer. We see women in whom breast cancer runs in the family up and down sideways, and they test negative for every known gene associated. But you've got to tell that woman your daughter's at risk, even though we can't identify what the genes are. Which makes it really challenging as a provider because we love looking at genes because it gives us a clue to what the possible underlying pathophysiological mechanism that may be driving the disease

that they may be at risk for. When we don't have that to grab on to, we're really grabbing at straws and just throwing everything under the kitchen sink at a person because we don't really have a good clear sense of what pathway they're on. What do you say to that person who's 40, who's having these sleep disturbances, while they're awake, everything is totally fine. The idea here being that those sleep disturbances are the canary in the coal mine for this problem occurring in their brain. What do you say to that patient as far as steps to take to maximize the odds of avoidance or at least maximal delaying? There's no one-size-fits-all here, so it really depends on the person, and the first thing

I would want to do is definitely check out their genes. So let's say you do this, and they don't test positive for either of these two genes. Let's say you have access to everything. What do you want to know? What else do you want to know about this person? What toxic exposures could they have? Or did they grow up? Were they drinking well water? Were they drinking city water? All those things matter.

So let's say they grew up on a farm, but now they don't live anywhere near it. So their exposure is in the past. It's no longer present. And let's assume that there's nothing that's actively contributing to it from an exposure standpoint. And now you're just kind of going on defense as far as what you can do. Okay. assume that there's nothing that's actively contributing to it from an exposure standpoint, and now you're just kind of going on defense as far as what you can do. Okay, so first and foremost, a movement assessment is absolutely key. The one thing that I think is so fascinating about this disease is that we see abnormal

movement patterns in these patients years and years before tremor, slow movements start. And the patterns that we see are very similar among people, most frequently, and maybe we should rewind a little bit here. So our bodies are naturally asymmetric. Just like our brains are naturally asymmetric, we have, despite the way they look, our bodies look symmetric, our brains look symmetric, our brains look symmetric, but we know that the right side of the brain has certain functions and the

left side of the brain has certain functions. So the left side is really a language verbal side and the right side is more of a visual side, emotional side. We have a dominance for one hand and one leg. So in people who are right handed, which is most people, we'll see the symptoms start of Parkinson's disease start in the dominant hand and be most severe in the dominant hand. So taking into account someone's hand in this, the pattern of movement that we usually see is patients don't really load the left leg and they won't spend time on the left leg. So most of their time is spent on the right leg and they don't really load the left leg and they won't spend time on the left leg. So most of their time is spent on the right leg and they can't really sense or get a good sense

of grounding through the left leg. And the right arm is stiff and not swinging very freely when they're walking. That is something, if you see REMSLEEP behavior and this abnormal movement pattern, I want to deconstruct their movement and make them sense on the left side and free up the right side, which often starts with breathing because they're also not really breathing into the right apical lung or the right lung at all. So first deconstructing that into what is their abnormal breathing pattern? And how can we get them to feel on the left side and move the right side more freely?

Obviously, this overlaps a lot with stuff that Beth Lewis and I talk about. And you and Beth, of course, are very close and work together with patients as well. Is the idea here that you can start to train out the pathology, if that makes sense? Yeah, I think I like the way you put that, train out the pathology. I think that everyone has asymmetries in their body. The problem is when that asymmetry goes too far in one extreme and that can happen for a lot of different reasons. It may be triggered by an orthopedic injury. For me, for example, I actually noticed this. So I had a spinal fusion when I was just a teenager. And I thought I was totally fine until my med school

boyfriend took me skiing. And I realized I could not control my right leg. No matter what I did, I couldn't get my brain to talk to my right leg to make my right leg internally rotate. And that showed me that there is some poor control between my leg and my brain. That neuronal circuitry is just not developed appropriately. And that's what you're trying to reinforce because by building up stronger circuitry between all aspects of your toes, your fingers, your breath, that's how you're training out these abnormal movements. But in a sense, it's not really training it out.

It's reinforcing the movements that you may have neglected because you just swung so far in one direction, either left or right. Let's assume you proceed through that. You do the assessment. You find some of these early warning signs. You begin to work on the training. What else can you do? Again, let's not necessarily even use the word prevent, but delay the onset of this.

In association with the REM sleep behavior disorder, patients aren't getting a lot of REM sleep. So, I think sleep tracking is really huge in these patients. So, you know, better than I do, even that different sleep stages affect different functions in the body. REM sleep is really important for not just memory formation, but also dealing with your emotions. That's how our bodies handle anxiety, depression, stress throughout the day. These patients often have a lot of anxiety and a lot of depression and often aren't getting enough for REM sleep. So optimizing their sleep with simple sleep hygiene is huge.

One of the things I tend to worry about with sleep trackers is that they can create more anxiety. And so my fear with that is you take that patient who's probably by now pretty nervous. And you say, we're gonna start tracking your sleep and lo and behold, oh, your REM sleep is quite interrupted. Is that a good piece of information to have? I think it's a good piece of information.

I agree. There is a person for a sleep tracker and there is a person that should not have a sleep tracker because you're just going to enter a vicious cycle. But knowing that they aren't getting enough REM sleep is really huge, specifically for Parkinson's disease. So we know that the melatonin signaling pathway in Parkinson's disease is off and they've actually done studies where they put people in front of bright light. So lightbox therapy for Parkinson's disease early in the morning, 20 to 30 minutes a day, 10,000 locks. And that actually helps regulate the melatonin signaling cycle and helps improve REM sleep in these patients.

So knowing that, I think it could change outcomes. I'm going to be having Matt Walker back on the podcast in a few months, and we're going to go into much, much more detail about both the pharmacology and the supplement side of how you can augment various sleep stages. Matt's helped me a lot with this kind of stuff. The other question I suppose I have, you mentioned anxiety, how do we know which one's the chicken, which one's the egg here? You know, by the time somebody is even told this information, even if they're completely asymptomatic, it seems to me that that would produce anxiety. And so how do we know that the anxiety was pulling

a causal role versus it's just the response to what's happening. From personal experience, if you just talk to patients, a lot of them will tell you, I've never been an anxious person, but in the last five years, my anxiety is just through the roof. And I think it has something to do with the dopamine signaling. So if you think about, is it a chicken or the egg thing in terms of sleep? That's another question because the sleep is promoting anxiety.

If you're not getting enough from sleep, you're not dealing with the anxiety. So that's a whole cycle. Again, whether it be dementia or Parkinson's disease, these things disrupt sleep. Of course. And disrupting sleep maybe makes them worse. Exactly. But knowing that you may be at risk for one of these diseases, this is what we see every day, whether

it's a risk factor in terms of a genetic risk factor or a pro-dromal symptom in terms of REM sleep behavior, I think knowing the data doesn't tell you anything in terms of what's going to happen to you as an individual, we haven't ever tried to do anything for people who have REM sleep behavior disorder. Just like previously, we didn't try to do anything for people who had apoe gene, apoe for gene. We just kind of thought, well, you know, they're at a higher risk for dimension. We're just going to let them, yeah, that risk. Well, this is our opportunity to do something about it because ultimately our treatment options, once 50% of your dopamine and urgent cells are dead, aren't so good. We're just giving people back leave adopa, that isn't going to change the outcomes that this person ultimately is facing, but maybe starting earlier, knowing that this is a red flag, maybe we are going to delay on set of full-blown symptoms, or maybe we're going to slow the loss, and maybe

at that point, the dopam orgic cells could be reversed. We could repair the damage that's done, or at least if we can't, we can stop any more from happening, and they may never get the disease. Well, that last one is certainly interesting, if we believe that we have a sense of what the environmental trigger is. Of course, it seems to me that I don't actually know how the NIH is allocating resources to the biology of this disease. So I can't comment as to whether it's adequately funded or inadequately funded, but it would seem to me until we have a very clear sense of what's happening at the cellular level with

the dopamine-producing cells, that's the thing we want to be able to halt. It's great to now shift our mindset from diagnosing breast cancer when it's metastatic to when it's a one centimeter early lesion, but at least with breast cancer, we know what to do when it's early. You cut the damn thing out, done. And we knew that 200 years ago, probably longer. Certainly in the 17th century, 18th century, we knew removing, and then by the 19th century, but late 19th century knew removing, and then by the 19th century, but late 19th century, we actually had perfected the sterile way to do this. That's what we're still missing, I think, here is. So step one is, we now think we can figure

this out 20 years before it's happening. Step two is removing the causative agent. Right, there's no way to cut this out. We're not looking at a tumor that we can cut out. But we also haven't ever studied doing anything this early, which is a huge loss in my opinion, because we know that these people are at risk. So we should be doing things. And even if we're only moving the needle, a small amount by certain lifestyle interventions or supplements, which we know also play a role in disease risk specifically, B vitamins, then we're moving the needle maybe just a little bit, but maybe a little bit at the right time actually moves the needle a large amount.

You know, we can think about that, like how do we do that clinically with our patients? It's one thing. I think the challenge is how do you scale that up to being the standard of care, where without a biomarker, it's very difficult to do that because prevention is too long a study. You know, it's actually the one thing

that has made our progress for ASCVD so great. There's really two things. One is we have a really good biomarker, an APOB and LDLC. LDLC being not quite as good, but still decent. We have this causative agent. We have this thing that is necessary, though not sufficient, to cause the disease. And when you have something like that, you know almost without exception that lowering that thing will lower the incidence of disease. And then it simply becomes a question of how long do you need to study it in your given population to see the reduction?

We don't have that biomarker here. Now we're going to talk about Alzheimer's in a minute. We're going to talk about other potential biomarkers there. And I'm very curious to understand from you the utility that we think of, for example, serum amyloid or tau. But is there anything on the horizon with Parkinson's that we can even point to be at radiographically, you know, a blood biomarker would be the most desirable? Are there people working on this sort of thing?

We didn't really talk about the difference in terms of histopathology for these diseases. So Alzheimer's disease is what we call a tau apathy. So you see a lot of amyloid and tau proteins. Parkinson's disease, Louis body are called alpha-sinuclean apathy. So a different toxic protein builds up in these diseases. While we've advanced a lot in terms of our ability to develop blood-based biomarkers for amyloid and tau. We haven't done so well in terms of alpha-synuclein, so you can biopsy different parts of the body and get a good sense of alpha-synuclein deposition. So there is a school of...

An alpha-synuclein being this other protein deposition. Yeah. And is it a misfolded protein? Exactly. It's very similar to amyloid. It's very similar to amyloid. It's analogous to amyloid. It develops into little lewibodies that go into your brain cells, but also other parts of your body, which is what I'll talk about in a second, and caused a generation of brain cells.

Do we have the contrapositives? So we know that there are lots of patients on autopsy that have amyloid and tau who were cognitively normal. Sounds like we don't have the opposite. We don't have people with Alzheimer's disease that are missing amyloid and tau. Is that correct? Yes. Suggesting that amyloid and tau, if anything, are necessary but clearly not sufficient. What about on the other side with alpha-synucleon? Do we know that there are people who live a normal life with this present in old age,

and at the time of their death, it's there as an incidental finding? It's a good question, and I think there is a threshold before symptoms will present. So, when we're looking at how much alpha-sinucleon, which will correlate to how many dopamine allergic cells have been lost. What is that number? How much deposition do you need for clinical symptoms present? And answered your question, there are studies that show there is alpha sinuclian deposits in this person's brain and this person's gut in this person's skin and this person's salivary glands. But this person didn't have Parkinson's disease. Well, what if that person lived five more years

with they have Parkinson's disease? I don't know, maybe. So lots to unpack there. Is the alpha-cinuclein accumulation directly proportional to the death of dopaminergic cells? Yes, pretty much. So that means patients with Parkinson's presumably have more of it than Louis body?

Not necessarily, because in Louis body, you primarily have alpha-cinuclein, but you can also have amulet and towel accumulation. And in Parkinson's disease, although it's still considered an alpha-cinuclein opathy, you could have towel deposition. So I like to view these diseases as a continuum. I think the way that we have been trained to view these diseases is just wrong. They are neurodegenerative processes and the underlying mechanisms are shared between all of them. That's why we really have to start viewing them as such related diseases. Whether one person develops an alpha-synuclein process or an amyloid towel process is really less relevant in terms of

what is the pathogenic mechanism that's driving that abnormal protein to actually be deposited. And yes, that starts with adequate risk stratification, risk assessment for a person because it's clear that this person may be on the path to developing an alpha-cinuclein opathy, but what's driving that? Well, it's still all a neuroinflammation autophagy problem. So let's dial back and start more basically with what are the commonalities between these diseases and can we target one and affect the outcomes of many? So let's not talk about Alzheimer's disease then. This is the kind of the elephant in the room, at least six million people in the United States have it. That incidence also seems to be kind of

rising disproportionate of the population. You always run into the question, are we just diagnosing it more? Are people getting sicker? You know, what's at the root of this? But let's not pick it up at the pathology. So again, this is not really a movement disorder. Therefore, it's not really something where we see the office in a clean accumulation. Everybody thinks of this female lens of being an amyloid towel problem. Let's explain people again. What is amyloid? What is how? Let's explain, you know, what's the APP protein and how does it get cleaved and how does it turn into amyloid, etc. Yeah, so toxic proteins, what are we looking at? So amyloid protein, amyloid can be misfolded into things called amyloid plaques. And if they're not cleaved properly, they are sticky and they

fold up into cells in the brain and can cause a whole slew of problems, including neurodegeneration. Tao is something that will develop into an equivalent called a neurofibralary tangle in cells. Alpha's in nucleon on the other hand, does the same thing. It develops into Lewy bodies. So basically, these are physical structures. These are actual proteins that, due to misfolding, end up inside the neurons themselves, do they end up adjacent

to the neurons? Where do they actually accumulate? Inside the neurons. Inside the neurons. And I assume that the critical problem is the relationship between that protein and the inflammatory state that comes with it, or does the protein by itself interrupt the neuron minus the inflammation? That's a great question. Does the protein change cell signaling? Is that what you're asking? Correct. By itself. Or is it the inflammatory process that's triggering? Yeah, I'll give you the

analogy. We know that cholesterol by itself, when the APOB particle carries the lipid, the sterile, into the subendithelial space, that's really not a big problem. When it gets oxidized there, and the inflammatory response comes to repair it paradoxically, that inflammatory response is what leads to the tissue damage that results in atherosclerosis, that results in the plaque formation, and ultimately the plaque rupture. So in that sense, our bodies are doing the damage to ourselves. I'm curious as to whether that's the case

in neurodegenerative disease. That's what I believe the case is. Whether or not there's some contribution that is directly related to impaired cell signaling once these proteins build up in the neurons, that's possible. But I think the bigger problem is what you just pointed out, which is once these proteins develop the whole inflammatory cascade that drives neurodegeneration is the big problem. So it's essentially our body's reaction to these proteins being built up in the brain

that are causing a problem. Okay, now historically this was something that you only got to figure out on autopsy. Person had dementia, you clinically thought they'd dementia, nobody was trying to distinguish between front and temporal, boxypital, those are all details. This person was normal, they're no longer normal, and maybe we'll do it in autopsy on grandma, and we'll figure out that this is what she had. But a lot of that's changed recently. What's an amyloid PET scan, and how does that shed light on this? Let's even rewind it to just a regular PET scan, so an FDG PET scan, which is really helpful when we're thinking about this whole fronto-temporal

pridoxypital pattern, because if you get a FDG PET scan, you're looking at glucose hypometabolism in the brain. Well, where is the brain hypometabolic? Maybe I'll even just tell people what's going on. So FDG PET, you label glucose with a radioisotope. And when you inject it into them, the PET scanner is not an anatomic image, like an MRI or CT scan. It's a functional image.

It's just looking for glucose uptake. And so typically when you do a PET scan, the brain really lights up the most because you're seeing so much glucose traffic to the brain relative to its size. And so what you're saying is hypomotabolism shows up as less signal in that area, which says, hey, there's less metabolic activity. Less glucose went to this part of the brain versus this part of the brain versus this part of the brain. Correct.

And that less glucose correlates to neurodegeneration in that part of the brain, or at least eventual neurodegeneration in that part of the brain. So looking at patterns of hypometabolism in the brain can be rather helpful in differentiating between things like gluibody, Alzheimer's disease, frontotemporal dementia, because you see different patterns of glucose hypometabolism. So that can be helpful, but it's not perfect. It doesn't tell you what the underlying protein deposition is and if there's underlying protein deposition and you can see abnormal patterns, quote, abnormal as a part of normal aging. So metabolism in the brain changes as we age and that's

not necessarily a pathology. It could be just a process, normal process of aging. Emolid pets, there are three different tracers that are available and FDA approved now. Essentially, they all have the same sensitivity and specificity, but what you're looking at with an amyloid pet is completely different than metabolism. You're actually looking at a tracer

that is tagging onto amyloid deposition in the brain and you're scoring what that tracer looks like. So how diffuse is that uptake in the brain? So here it's the opposite. And you expect to see the area with pathology being the big signal as opposed to the lack of signal being the pathology with the glucose pet. Correct. So, amyloid pets can be helpful in terms of showing us, is there amyloid deposition in the brain?

But, there's a caveat there, because we can see amyloid deposition in the brain incognitively normal people. And in fact, amyloid is abnormal, but in many ways it's normal. I've had an interesting study and this is sort of unrelated, but I can never get this fact out of my brain where they looked at young healthy people and young healthy 30 or 40 year olds and they made them sleep deprived.

So they said you couldn't go to sleep and then they did amyloids scans and CSF biomarkers for amyloid and found that after a single night of sleep deprivation, emloid deposition increased by 5%. Well, that's because emloid is present in everybody, but we just start to clear it. Exactly. So looking at an image at one point in time and saying that there's emloid building up in the brain, does that mean that that person is on the path that's Alzheimer's disease if they're cognitively normal.

What does that mean? Is that reversible? It doesn't really tell us very much more information. To me, this is the thing that I'm most intrigued by is what does it mean that there are people never mind just having an amyloid pet positivity. There are people who die, and when you buy up to see their brain, you can't really

distinguish their brain from somebody who had Alzheimer's disease from the amount of amyloid that's in there. It's very difficult for a pathologist to look at this and tell you what this person looked like when they were alive. And that's different from the heart. A pathologist can look at your heart on autopsy and can clearly distinguish who was healthy from who was not. Which is not to say apathologist in a blinded fashion can tell you that this person had a heart attack, because if they died quickly enough, you might not see the damage. But it's a stunning indictment of our ignorance of the brain. Not to oversimplify the heart, but the heart in some ways is an easier organ to understand. It behaves in a more mechanical way than the brain.

This makes it very difficult then to really stratify risk in an individual. That to me is, this is really less a philosophical discussion for me and more of a practical one, which is where do we need to act and how do we need to act and how do we measure progress? Along the same lines there is looking at amyloid in terms of what does that tell you about cognition because the two could not be related at all. So if someone could have a ton of amyloid deposition in their brain and be cognitive-villainormal, as you said, but does that mean that they're in this weird, delicate balance of if there's any more neurodegeneration or any more amyloid or any more tau, which we'll talk about soon, build up that they're going to just fall off a cliff and symptoms will present, or does that mean nothing in

terms of cognition? And this comes up a lot more recently with all of the new studies. What are we looking at? Are we looking at amyloid deposition? Amyloid biomarkers? Are we looking at people's cognition? What marker should we be following? And I think you and I both agree that it really should be

cognition. I've made a note to actually come back to cognitive testing. And I think it's super interesting. Let's go on to talk about these neurofibularity tangles. And where do we see them being distinct from amyloid? And then I want to come back and talk about amyloid serum amyloid as well, and the advent of that in the past few years. Right at the start of COVID, sometime in 2020, they FDA approved a Tao scan. So there isn't a Tao scan. Again, both amyloid and Tao scans are not covered by insurance. So the clinical utility of these scans is pretty low

just because the cost of them is so high. It costs several thousands of dollars to get these scans. You have to pay out a pocket. But Tao scans are... And there are a ton of radiation. So these aren't scans. You just want to be doing willy-nilly.

It's not like, hey, I'm going to go through McDonald's drive through Get a Burger Fries and then go head over and get a Tao scan. I mean, I want to say they're in the 10 to 20 milli seaverts. Yeah. That's an insane amount of radiation for shits and giggles. You need a real reason to do that. Exactly.

There's a school of thought. Let's rewind a little bit here. So there's a school of thought that says, and I don't necessarily subscribe to the school of thought, but you first have amolied, then you have towel, then you have neuroinflammation, and then you have neurodegeneration. So amolid is thought to be one of the first markers, but I don't really agree with this 100%, and I think every person is different, so you can't really make this hard and fast rule. But looking at Tao scans in the setting of also having an amyloid skin could be helpful.

If you're just looking at Tao scans, you're looking at does this person have Tao accumulation in the brain? These Tao scans may be more sensitive, may, may be more sensitive at detecting Alzheimer's specific Tao versus other Tao related to other Tao opities like frontotemporal dementia. But the utility of the towel scan is that it tells us more about the progression or the likelihood that someone will develop cognitive impairment. So if someone has positive towel on their towel scan, the likelihood that they'll ultimately develop cognitive decline is higher than just amyloid.

So looking at them together, although we would never do that because of radiation and cost concerns, like you said, if you had the amyloid and Tao simultaneously, at the same time, you could get a pretty decent snapshot of what someone's brain looked like and where they are. It is Tao also this thing like amyloid where it's there all the time and we're clearing it and it's our potentially our impairment of clearing it that leads to the pathology. So you're asking, is tower aversible? Actually, I wasn't asking that, but we should discuss that.

I guess what I'm saying is, look, we know that amyloid is present all the time. Again, using sleep as an example, sleep is a very powerful tool to clear amyloid. Is the same true of tau? I don't think we have a good answer for that. We don't really know, because we really haven't been looking at tau for that long. Is there no serum biomarker on the horizon for tau? So there is. We can talk about serum biomarkers now because I think it's a good leeway. So C2N, if it's okay if we talk about the persivity test, came out recently and that's actually a great marker for amyloid. So it shows you the amyloid beta 40 to 42 ratio. So it encompasses someone's ApoE status.

So it gives an amyloid probability score based on someone's ApoE status. So it gives an Amoled Propability score based on someone's ApoE status. And the accuracy predicting just from the simple blood test, a positive Amoled skin is around 80, 81%. So super, super high. When you add tau, which now is not clinically available, but is available for research purposes. So tau217 is a new biomarker that has been brought to this game and looking at ratios of phosphorylated to nonphosphorylated, p-tao217, it adds to that.

So you're looking at accuracy of around 90% to amyloidskins. As you know, we've got one patient in particular who we're using this emuloid serum emuloid level to track interventions in and in particular one kind of unusual intervention, which is RAPA MISON. So too soon to really know with an end of one, but very interesting that rapamycin is dropping his serum amyloid score. Well, this patient is fascinating in so many ways. If you want to think about just biomarkers, because we collected every single biomarker possible minus the towel scan on him,

first and foremost, the old school way of diagnosing these diseases was to do a spinal tap and look at cerebral spinal fluid. Well, we did that. We looked at amyloid. I was kicking and screaming not to, but you enrichered overruled me. Yes, I know. The patient was such a good sport. Such a good sport. Bless him. So we looked at CSF biomarkers in him, and actually they were all normal, all negative,

but we got the proscivity, C2N's proscivity test, and that showed that it was positive, that the likelihood of him having amyloid pathology was high, we discussed this with so many people, including our neurodialogist colleague, and she was like, let's just do an amyloid scan, like let's get to the bottom of this. We did an amyloid scan scan and he had amylid deposition

in the brain. So this brings us to another really, really interesting and exciting direction for these serum tests because we're noticing that they may be more sensitive at detecting early, early Alzheimer's disease pathology, even better than amyloid scans, even better than CSF dial markers. And certainly more available. I mean, CS, I don't think people understand like, yeah, lumber punctures are not the most invasive procedure in the world, but if you have one patient that needs a blood patch, you just never want to do that procedure again to somebody. But looking at that and then having the ability to so readily repeat measures, while we don't know if we can follow Amaloid over time to see if our interventions are actually

effective, in theory it makes a lot of sense. And as you pointed out, we put them on a slew of neuroprotective agents and tried to optimize everything possible for him and including Ropomycin. And his amyloid biomarkers have gone down and now he's considered normal, low probability of having Alzheimer's disease, but we know that his skin was positive. So really fascinating case. Let's segue then into something that I think is

the art form of this, which is the cognitive testing. It's in some ways the hardest part because it's not easy to standardize. I mean, there's a reason that we have someone like you in our practice because this is not something that me or Eve Suzanne, Abby, like the rest of us can't learn to do this. We can't outsource it to a computer. We can't tell our patients to go take a test that will give us the results. There's real subtlety to this in terms of everything from movement to vision to all factory to these things. So give people a sense of what a cognitive test looks like. What does a gold plate cognitive test look like?

If you're really trying to probe the earliest leading edge of these types of diseases. So I will also correct you that some of it can actually be self-administered, but some of it needs to be administered by a trained professional. You can get a lot of information by having patients do some things by themselves, but paying attention to them gives you a lot of clues. Well, by all means correct me and point out what can be completely done automated, but I think part of it comes down to the art.

I mean, Richard has done a great job of helping me understand what you learn by watching somebody take the test as well. Yes, that's the art of this assessment. So first and foremost, getting a sense of their old faction is key because olfaction. That's why I can't do this test today. I'm so congested.

I'm just like nine things that we make them smell right? Yes, there's nine things, although we might be elaborating that battery to include a lot more. So stay tuned for that. Right. I'd fail that test visually today. So one of those things that we make people smell and why does this matter so much? Well, I can't tell you what they are because then there are patients on the call that may

know the answers to the test. Very well. Okay. So there are nine things that you're going to have to smell. Yes. And the idea here is cranial nerve number one is your olfactory nerve. Correct. So you have basically, from your nose, a cranial nerve that goes straight to the front

of your brain that presumably is like that leading edge of immediate access to a cranial nerve that could be degenerating, is that the thinking? Yeah, and if you think about just sense of smell in general, it feeds directly into the amygdala and the hippocampus, so the whole memory circuit. If you think about the hippocampus, so the whole memory circuit. If you think about odor is actually one of the strongest sense that relates to memory. If you smell something that you smell before, you just get very nostalgic for whatever that experience is. Positive or negative? Yes. It's very, very ingrained into memory. So, it's one of the first nerves for lack of a better word, first parts of the nervous system to degenerate in these diseases.

And it happens not just in Alzheimer's disease, it happens in Louis body, it happens in Parkinson's disease. When it does happen in these cases, we actually note that those patients are more likely to have cognitive decline. So it really does relate to memory. So yes, first and foremost, olfactory testing. Has COVID changed that with people? COVID has made this so, so difficult because the earlier strains of COVID really did impact

sense of smell. And for some patients, that sense of smell has taken months to a year or more to recover. And for other patients, you know, it still hasn't really recovered. And what are the implications of that long term? I don't know if we know yet. Does it relate to later likelihood or higher likelihood later of developing a neurodegenerative disorder? I don't know, but it's something interesting and something that only time will tell.

Okay. So they get these little sticks, these little cards, and they have to go through that exercise. What other types of things do we test for in cognitive testing? So memory function is another one, but there are so many domains to memory. So there's registering the information, reading, registering, auditory, and visual registering of information which go into memory, then the encoding process.

When you hear something, do you remember it? When you hear something, do you remember it? When you see something, do you remember it? And does it matter how you report that you remember it? Is it reporting it by writing versus reporting it? Orally, do those things matter as well? So for most people auditory processing is more difficult. And when you're doing auditory processing, all of it has to be done auditory.

They're auditory. So I would ask you, I'm going to read you a story and you're going to tell me everything you remember from that story. And that's your immediate one learning of the information, so I'll read it to you three times. You'll try to remember as much as you can. How much did you learn over those three trials? That's all auditory. And then in 20 or 30 minutes, how much do you remember? That's delayed memory. So you're looking at immediate learning, working memory, and delayed memory.

Now, how do we ferret out the people who underperform these tests because of distraction? That's why we do attention tasks. So there are a whole slew of different attention tasks and speed of processing tasks. So there are a whole slew of different attention tasks and speed of processing tasks. Usually you have to get people in a quiet room undistracted, make sure their cell phones are off, make sure they're not doing anything on their computers

to really focus on the test. But you have to add in these other cognitive exercises which are looking at their attentional capacity because often you will see distraction is a huge, huge confounder when you're looking at memory. If you're not paying attention to something, you're never going to remember it. I can think of, imagine me trying to take this test at home,

would be a disaster compared to if I woke up in a quiet place and got to take it under those conditions. Yep, we tell people, get a good night's sleep. If you didn't get a good night's sleep, we're not going to do the test for you because you're just not going to do well on it. Make sure you do it. First thing in the morning is really better

or sometimes you feel relaxed. Don't try to squeeze it in between work meetings because you're going to rush. And again, not really focus on the test. So there are things that you should do to optimize your chances of giving this your best shot. Treat this like it's the one shot. You get it the test. So there are things that you should do to optimize your chances of giving this your best shot. Treat this like it's the one shot you get at the SAT.

Exactly. Your MCAT. Okay. So those sound really stressful. What else? Visual spatial processing and episodic memory, which is really really difficult for a lot of patients. Actually, it's one of the ones people struggle with. So trying to see where an object is and remember the sequence that you saw that object. So you're given a series of objects. When did you see this? And what order? And what order put them in the order that you saw? So like a series of cards, for example. Yes. So you got to remember if you saw the car before you saw the garbage can. Very difficult. And it's easy when you're only shown four or five or six objects,

but when you're shown 10 or 12 objects, it becomes very, very challenging. So that's really testing your working memory, but also some visual spatial. Visual spatial skills are tested a lot by writing and drawing, copying cubes, drawing clocks, old-fashioned things from med school that you probably remember actually give a lot of information. And there's still things we use today. copying cubes, drawing clocks, old-fashioned things from med school that you probably remember actually give a lot of information and there's still things we use today. What about horsepower, like executive function, problem solving, IQ test stuff. IQ test stuff. So verbal learning and being able to pronounce very tricky words is actually a really good proxy

for IQ and is one of the ways that we look at that. Just showing us an understanding of what this person's cognitive reserve is because having that foundation is really important for understanding how you should interpret the results to follow, because if someone's IQ is much lower than you expected, then you really have to interpret the rest of the results in the setting of that. So there's obviously a language bias then. So if you're encountering a patient for whom English is their second language, how are you able to administer this test and not be misled by it? So there are different versions of the test, and if English is not your first language,

it's just something that we note because we could get access to all different versions of the test, but it is challenging to do that because the norms are all different and you have to just purchase a bunch of different forms and norms. Ideally, you would do this in person, but I know since COVID, it became more possible to do this remotely. Do you still feel that's the case? Yes, there are certain pen and paper tasks that we send to patients because you do need to do some of the motor activities by writing, but pretty much we can do everything remotely now. How long does it test take?

Oh, an hour, an hour and a half. Okay, it's less than any thought. I thought it was longer. Other things that we test for, so executive function is really, really broad and really cross-cutting on a bunch of different tasks, but without giving away too many secrets, thinking about naming certain categories of objects

or naming certain words that start with specific letters, that's how you look at executive function. Now, how do you retest people? What's the frequency at which you can retest so that you don't run the risk that they're learning the test and improving because of getting better at the skill of the test as opposed to getting cognitively better? So you change the forms first and foremost, so you don't really administer the same test

multiple times. Interestingly, ApoE4s are immune to the learning effect, so they actually don't learn as well. So you can retest them in about six months and learning isn't really a factor to consider for them, but there are equations to correct for that when you're looking at normative values. How often does the FDA use the performance on a battery of tests like this as an endpoint? When the FDA is using things they're looking at, things like mini mental status and the Montreal Mocha test. Tell folks what these two not-so-helpful tests are. One is the Trump test, so if people have heard of that, how Trump based a very difficult

cognitive test, well, I guess that was one of these where you have to name. This is a lion. These are a sequence of numbers. Just repeat them back to me forward and backward. So they're basic 30 question tests where you're asked what the date is. Where are you? Who's the president? Who's the president. They're very basic and rudimentary. These are tests we would use in the emergency room when we wanted to know if someone was psychotic or heavily under the influence of alcohol drugs, things like that. To be fair, they do give you a very good sense of if someone is very cognitively impaired,

they're going to do very poorly on this test. But for most people who come to you and say, I just noticed some forgetting things, they're probably still going to ace the test and it's not giving you a good sense of, well, is it an actual memory problem or are they distracted? Like we pointed out before, is it an attention problem? Like there are so many things that can go wrong when someone says that they're forgetting that you really have to dissect that problem more. The potential risk here is that we're not using a sharp enough outcome tool to measure either drug efficacy or timing, and that kind of gets to another question, which is, are we looking at intervening too late?

So I think most people are familiar with the notion that the track record for Alzheimer's treatment drugs is pretty abysmal. How many FDA-approved drugs are there for treatment of Alzheimer's disease? Well, if you count, we have denepazil or aerosept. We have, so there's a couple in the same class, I think there's three of them, and NAMENDA, those are the big ones and adjacanemab. I mean, that's all we're looking at. And adjacanemab being the most recent one approved about a year and a half ago. Which now has had a lot of backlash and Medicare is not paying for it. So it's been a whole big mess.

We've discussed this on a previous podcast. But I won't rehash it. But the gist of it is basically this was a drug that was targeting emily directly. It really split the FDA. And I think members of the advisory panel even resigned over its approval. If you're in the bull camp on that, you'd say that drug is misunderstood, that drug would have efficacy if used early enough and if you use the right metrics to assess its performance, if you're in the bear camp,

you'd say it's an incremental drug that if it has any benefit, doesn't come close to justifying its cost. I don't know the answer to that question, but this gets back to, we need to do a better job at identifying what stage someone is in the disease process and where when and how the disease can be reversed if it can be, which I think that it can be. I think the breast cancer example is really apt here, which is my fear with all of these neurodegenerative diseases is we are acting at the wrong time. Exactly. And it's exactly like saying, we take a bunch of women with stage four breast cancer and we do lumpectamies on them. And they don't live any longer. And we think therefore the lumpectamie has no place in the treatment of breast cancer.

When reality, the lumpectamie has no treatment in the place of women with metastatic breast cancer. When reality, the lumpectomy has no treatment in the place of women with metastatic breast cancer, and it is the standard of care in women with stage one breast cancer, and it will save their life. That's my fear is when it comes to neurodegeneration. As you said, we don't know the stages. We don't know the difference between stage one, stage two, stage three, stage four, and we certainly don't know what treatments to apply when, and most of the treatments that are being applied are being applied at what would be the equivalent of stage 4 exactly. So by that time, what can you really do because you can't reverse the neurodegeneration once it's already happened. You have to start earlier and another large target for these drugs and new biotech companies are the inflammation process and neuroinflammation, which is a huge factor. And I do think plays a huge role. But again, the question is, in who and when

and without having a plethora of biomarkers that you're looking at to really handpick patients appropriately, I don't know how will show effect efficacy of these drugs. Let's go back to something you alluded to very briefly earlier, which is the role of the visual and auditory systems in these diseases. So I think it's generally well accepted that there is an association between hearing loss and dementia. Is it Alzheimer's specific or all forms of dementia? It's all forms of dementia, but most of the literature is surrounding dementia as a broad term, which they usually mean Alzheimer's disease. I've talked about this with Richard quite a bit, and he's really of the mindset that there's

a causative relationship there. And that's a big deal, because, again, if you can just say, well, there's an association between hearing loss and dementia. It's like, well, okay, yeah, I mean, that makes sense. But if you think that that relations causative, and that's why it's just so important to understand causality, it means that treating hearing loss will reduce the risk of dementia. It means that screening for hearing loss early and treating it aggressively will improve outcomes. And that's totally different from just saying, yep, they're just highly associated. So Richard's view is that, yeah,

we should be doing this. I think you share that view. Yeah, we should be doing this. So there are a lot of schools of thought on how this is related to neurodegenerative diseases and Alzheimer's specifically. But the one that I think I like the most or the two that I think I like the most are. When you can't hear your increasing cognitive load to the brain, which is taking cognitive function or taking cognitive abilities away from other processes of the brain. So for example, memory function, working memory, because your brain is focused on trying to hear or trying to see it's using all of its power to do that. And it's diverting resources away from building memory function. But the other factor, which I think really relates to the movement aspect is our brains

need sensory input. And when you aren't giving that sensory input to the brain, you lose that function. And hearing is so important for verbal processing. Vision is so important for visual spatial processing. These are all cognitive functions that if you're not giving the sensory input that the brain is craving, you're probably not building those pathways anymore. You're not diversifying your brain, your brain's experience. Again, I don't know if those things are right, but if there is a causative relationship between visual and hearing loss, those two

mechanisms make a lot of sense. I want to make sure I understood them. The first is, if you were becoming deficient in those areas, you're wasting, quote unquote, more of your cognitive energy on the acquisition of those inputs to the system. And in doing so, you're detracting from the capacity to do other things. We have a finite amount of this reserve. The second thing is you're now deficient at gathering inputs that foster the neurodevelopment, plasticity, formation, creation of better outputs.

So you're going to process information worse if you can't hear. You're going to process your environment worse if you can't see. Correct. So you'll move worse, you'll think less. And there's clinical evidence to support this. So there's something called recredescence and stroke. When someone had a stroke a while ago, it might have been a small stroke, it might have been a large stroke, but they pretty much recovered from their stroke until their bodies under some sort of other stress. So they have a

urinary tract infection or an ammonia, something that puts any sort of stress, that stroke, those symptoms that once were a part of their old stroke, come back out called recurred essence. It's like the brain can't handle doing too many things at once. It can only deal with that wound in its brain by having all of its brain power focused on it. If it doesn't, then it's diverting some of its resources someplace else, then those symptoms come back out again. It's sort of similar to that.

Well, let's talk about oral health. This is something you're interested in, something you've spent a lot of time thinking about. It certainly makes sense. As you know, become more and more interested in this idea that the health of your gums, the health of your teeth is actually quite a strong predictor of the health of you as an organism. It's hard to have very poor health in your mouth and have very good health in the rest of your body.

How do you think this pertains to the brain specifically? 100%, I could not have said that better. So there are certain red complex pathogens, three bad guys in particular. One, treponema, denticala, pijingevalis, and T. Forcintia. These microbes are associated with a higher risk of amylo-deposition, tau-deposition, and inflammation.

So knowing if you have these red complex bacteria, which drive peridontal disease. And I'm sorry, these are all gram negatives, what? Gram negative bacteria, right? So when you have a high colonization in your mouth with these bacteria, your peripheral inflammation is driven way up. And when you think about somebody who has an ABOE4, for example, a 3, 4, or 4, or 4, why would you ever want them to be under any more inflammation? If you know E4 is priming my gurgly activation, then adding any layer of something that's going to trigger more inflammation is just a bad idea.

So focusing on oral health, especially in high-risk patients, is huge. And I think really an overlooked part of this whole picture. There is some debate, and there is some evidence for this that potentially these bacteria can ectopically migrate either through the blood or through cranial nerves to the actual brain because they've identified them in autopsy specimen. But I don't know if that's true. I don't know if it's the bacteria going to the brain themselves that's causing damage. I think it's more of the inflammation that's triggering part of

the damage and it being in such close proximity to the brain, having all of these cranial nerves kind of right there, right by the mouth, I think that's the bigger issue. And do we know if the greatest driver of that risk is simply poor oral hygiene? Poor oral hygiene, but also which comes first here. So dendolin plants root canals just external hardware in your mouth. Those are just they're just nitrous for these bacteria to form on and we notoriously don't clean them as well. People who wear retainers that night after their braces or a mouth guard because they grind their teeth at night. They aren't really cleaning these specimen very effectively. And they're just loaded with bacteria and often, blossoms overlooked. And it's not just flossing. Flossing is great,

but really using a water pick or an interproximal brush or something that goes in between the teeth that has a little feather at the end that you're really scraping away. The bacteria is what you need. Let's return to AD and double click on the genes. Again, I think most people listening to this, if they've spent any time listening to this podcast, they're very well familiar of the ApoE4 situation. We've got these three isoforms for the same gene ApoE, you've got the two, three, and four isoform, and they can combine in every possible way, so there's six combinations. The normal one is the 3, 3 combo, that's 556% of the population,

correct? The high risk gene is the 4. The high risk isoform is the 4. The low risk isoform is the 2. The 2 seems very rare. I don't think I've ever seen a 2 2. Maybe I've seen one person with a 2 2. I've never seen a 2 2, but 2 3 is 2 fours. And it's 5% loss and 5% population. But let's talk about the four fours and the three fours. These are your higher risk populations. Your three fours are probably 20 to 25% of the population. Four fours are one to two percent of the population. In our practice, it's four, five percent of our practice

is four four, but I think we have a selection, a little bit of a selection bias, maybe more than that actually. Obviously, when you were still at Cornell, you saw lots of 4.4, as I was probably a quarter of your population. You've often said, and Richard said this as well, you don't get that stressed out when you see a patient, when you have a really clear sense that their risk is predicated through their e-fornus, not to make light of e-4, but you kind of talk about it like it's the enemy you know. Easy peasy, piece of cake.

So first, expand on why you would make such a statement, and then too, I want to talk about the things that are able to either make the e-for worse or potentially even make the e-for better, meaning reduce the risk or amplify the risk of e-for. We know what to do when we see an Apoe 4. It's when somebody doesn't have an Apoe 4 and has a family history very notable for dementia Alzheimer's, some neurodegenerative disease, also a Louis body which E4s are at risk for Louis body dementia too, which is something that we frequently overlook. So when we see a 3-3 and we see a family history, then we start scratching our heads like what is the pathogenic mechanism that's driving this person and this family to develop Alzheimer's or a related neurodegenerative disease. When we see an

apoe 4, we kind of understand more about how that impacts the body. We understand its role in peripheral cholesterol, which also relates to its role in central or brain cholesterol. We know how it impacts their ability to metabolize carbohydrates. We understand kind of what we're up against when we see it. And I just want to emphasize because so many people come and they're so afraid once they found out that they have an apoi for, or they're just so afraid

because they have a family history and they don't want to know what their genes are. But your genes are not your destiny. There are ways that we can intervene to mitigate some of the detrimental effects of these genes. So what are some of the other genes that are cousins of E4 that travel with E4 or that frankly don't, but add independently to risk or subtract independently from risk? ApoC1 and Tom40 are two genes that are located right around the ApoE4 upstream and Tom40.

And that's two M's in Tom, right? Yeah, Tom with two M's, 40. And they are tightly associated with Apoe 4, meaning they're linked. Most people, if they inherited the quote, harmful copy of Apoe 4, I'm going to say quote, because I don't know how harmful it is anymore. Now that we're better at managing it, but they'll also inherit the, quote, harmful copy of Tom Fordy, harmful copy of ApoC1. Most cases, 90% of the time,

but in some patients, they don't. And are these protein coding genes or are they in the non-coding regions that Tom Fordy and C1, ApoC1? They're protein coding genes. So when you don't inherit them, and you're looking at someone who is a 3, 4 or a 2, 4, 2, 4s are really great examples, because if you see that they inherited the lower risk variance in Tom 40 or aposiva, then I'm thinking, well, they're less likely to behave like an e4 and more likely

to behave like a 2-3 versus the other way around. Then I get very worried about their e4 expressing themselves and I start thinking we need to really hammer down on their cholesterol. We need to do much better with vascular risk factor control. So the Tom 40C aposoc one can swing the balance. Yes, so it does provide a huge piece of information for a small portion of people, but for that small portion, it's really, really life changing and changes management. So what about genes that are less tightly linked to apoi for that either up or down, turn the risk?

So cloth, those are big one. And I know you're, it's my favorite gene. Yeah. Love you, some cloth though. So cloth though seems to offer a protective role against a boy for it doesn't completely erase the harmful effects of a boy for, but it really does lessen it. And it has an effect on the rate of cognitive decline. So if you have clotheau heterozygosity, then we're more optimistic about how we look at that.

Just so people know we're talking about we say heterozygous, meaning you have one wild type, and then you have one of the protective one, which is the KLVS SNP. Yes. And we were talking about this the other day. In the literature, this is, And we were talking about this the other day. In the literature, this is like, I don't know, one in six people would be heterozygos. It's actually pretty hard to make this diagnosis because there is no off the shelf test for this SNP. No, there's not. You need whole genome sequencing. Which again, for the listener, that is a real impediment to this work right now. It is. You know, we have some e-forrs in our practice, e-for e-forrs, who you and Richard have looked at and you don't even think they're worth talking to.

They're so uninteresting, which is a good thing. Like, if you don't want to talk to them, that's a good sign. E-for-e-forrs, think about that. I remember the first time Richard met some of these people two, three years ago, he's like, no word. This person has nothing wrong with them and will have nothing wrong with them. And I'm convinced that they are, you know, cloth okay, LVS is, but it's not just

that you got to spend all the money on the whole genome sequence. It's that you got to get somebody to go through the data and pull out the sequence. Yeah, Richard and I are working on a process of streamlining this. It is so labor intensive. It's a little back of the napkin, mom, and pop right now, but you have to manually go through the genome and pull

out all of the relevant SNPs. There's no SNPs, meaning portions of the DNA that pertain to risk. There's no vast way of doing it. And more than that, you have to do it in a logical way, because if someone has an E4 versus an E3, you're going to look at a completely different set of genes and a completely different set of SNPs or variants, then you are going to look at for someone who's... It's so frustrating that... The re... Like, this is such an easy problem for AI to solve. Yes. And it doesn't need that many resources. It just needs somebody to say, you know what? We should just automate this once and for all,

spend a few million dollars on the process, and everybody can drop their whole genome sequence in there, and you can get the answer. That's what we're trying to do a better job and work on, because I think we can develop a software that is able to do this more rapidly, but right now it is so labor intensive and so expensive. Yeah, I also think that the KLVS cloth amutation would be a great crisper target one day.

Yes, it might be. Yeah, I think the belonged Jeviti benefits of that transformation would be enormous. But going back to just teaching a software how to do this, part of it is and thinking about the example that you pointed out that there's E4-4s that we're just not interested in. Part of that is you have to understand that person's risk factor. So if they have no family history of Alzheimer's disease or a neurodegenerative disease, whatsoever, they are a lower likelihood of getting this a disease later, even if they're 4-4. The other one, I know we've talked a lot about is mitochondrial haplotype.

This is a bit more complicated because it's not a gene per se. So explain what the mitochondrial haplotype is and what it tells us about risk and how difficult is that to measure. So the mitochondria going way back to evolution. So they were once thought to be their own organisms that the body sort of devoured and developed a symbiotic relationship with. So they are one of the few organelles in the cell that have the only organelle in the cell that has their own genome. So the mitochondrial genome has genes that relate to oxidative phosphorylation or how the body makes energy. So the cox genes and NAD genes, all of these genes are encoded

in the mitochondrial DNA. Mitochondrial haplogroups are labeled based on what different variants are found in different genes in that mitochondrial DNA. And there are more than 4,000 mitochondrial haplotypes. So there are a ton of mitochondrial haplotypes. And again, they're based on what variants are common among all members of a shared group. So for example, there is a risk SNP that, I wouldn't say risk, there's a SNP that is associated with mitochondrial haplogroup H and all members that are categorized as haplogroup H have this variant. Two things, one, how difficult or easy is it to determine your mitochondrial haplotype? Is it as complicated as, is it more clotho or more tom 40E4? So it's very, very difficult. 23Me generates their own mitochondrial

haplogroups, and the way that they do it is they have a few markers that they pull out of the DNA that pertain to each specific haplogroup. So that's how they are identified as someone's haplogroup. It's actually not perfect. If you really wanted to know someone's haplogroup, you have to sequence the entire mitochondrial genome and use specific software to do so. No, I don't think 23 and me can do that, right?

No, obviously not. 23 and me cannot. But you can do it through whole genome sequencing, adding on mitochondrial DNA sequencing and analyze the mitochondrial DNA sequencing, and analyze the mitochondrial genome, but you need specific software to do so, and it's really much more challenging than the whole genome or the... So why does this matter? Why do we want to know the haplotypa, haplogrip of the mitochondria?

How does it tell us less, I mean, let's just assume it tells us risk is up, even if it's telling you risk is higher, what insight does it impart as far as preventative strategies? So super helpful in understanding risk, especially for Apoe 4s, but also for other neurodegenerative diseases. And interestingly, the same haplotypes that put you at risk for Alzheimer's also put you at risk for Parkinson's disease.

So for example, haplotype H, if you have this haplotype, end your in ApoE4, it seems to enable the E4 or acts synergistically with the E4. So when we see that combination, we become a little bit more concerned about this person versus somebody who is a haplogroup K because K seems protective,

especially for Aoi-force. Okay. If you have someone that's a type H, do you have any sense of what preventative measures are more important than others? So just knowing what type of haplogroup they are gives us insight into how their mitochondria are behaving. So if we know someone isn't an efficient are behaving. So if we know someone isn't an efficient energy producer or their mitochondria aren't acting efficiently, let's rev up their zone too. Let's try to get them as many mitochondria as we can. Let's increase their density of mitochondria because that might circumvent some of the negative effects of their mitochondria, just not working as efficiently at generating ATP or energy.

So talking about that, talking about exercise, my view has largely been that there's probably no activity that you can participate in that will have a greater impact on your brain's health than exercise. Now, obviously, you have to take that with a caveat. All the exercise in the world won't help you if you're sleeping four hours a night. It can't offset that much damage. But in terms of additive activity, it seems to me exercise matters more than anything else. It certainly matters more than the finicky nuance that someone might make in their diet

of like, oh, I'm going to take out nightshades and all of a sudden that's going to fix all my problems or something sort of idiotic like that. Would you agree that exercise has the most potential to improve brain health, and that's not just in the healthy, but obviously in the preventative strategy? Wholeheartedly, I think exercise has the potential to move the needle the most. What is it about that? Because exercise does so many things. What do you think are the levers that it's pulling? When I think about exercise, I kind of break it down into categories in my head.

So there's the coordination, proprioceptive balance type exercise, which you can include dance under that, for example. Some people don't really think about dance as an exercise, but it's an incredibly powerful exercise for the brain because you're not just getting the physical heart rate elevation. You're getting the cognitive training, which is involved in the coordination and the choreographed movement. So you're trying to process the visual information and make your body do that activity or do that movement, which is both a cognitive

workout and a physical workout. So this is a way of increasing cognitive reserve, increasing neuroplasticity that has probably a different effect than something like zone two, for example, which is involved in improving someone's energy metabolism and inefficiency, which is very different than strength training, which is equally important for building muscle mass and metabolic health and so on. So you have the metabolic component, right? You have the vascular component. You then have like BDNF. What role do you think BDNF plays here? So I think BDNF plays a huge role, do you think BDNF plays here? So, I think BDNF plays a huge role, but it's hard to say how much that plays versus how much just higher intensity cardio exercises increasing cerebral blood flow, which is increasing

nutrient oxygen delivery to the brain. But BDNF is what we call a fertilizer for the brain, so it helps protect new brain cells, but also helps grow new brain cells specifically in the temporal lobes or the memory centers of the brain. So stimulating BDNF is one of the potentially large benefits of exercise specific. Does anything stimulate more BDNF than exercise? I don't think so. What a way to do this hypertension play here? There are certain organs that are so clearly related to high blood pressure, negatively. So the kidney and the heart, there's just no ambiguity. More blood pressure is just bad for the kidney, is bad for the heart. One baseline perfusion levels

are met. Obviously, every organ suffers if blood pressure is too low in a pathologic sense. So if somebody's hypophilemic and shock or something like that. But 120 over 80 is all you need to perfuse the kidney and to perfuse the heart. And we now know that 135 over 85, that's going to start causing damage. What do we know about that with respect to the brain? The sprint mind study looked at this and lower is better. So 120 over 70 more strict blood pressure control seems better for cognitive outcomes long term. I will also circle back and say that what we see in some of these diseases, especially the Louis bodies and Parkinson's is autonomic instability. So blood pressure fluctuations,

which is very tricky to deal with because what we'll see is at night someone may have higher blood pressure when they're laying flat, but when they're up and about during the day, when you're actually measuring their blood pressure, it's not very high. So you could be misled living a full paradise thinking that they're actually, you know, normative, which we'll consider less than 120 over 70 or brain, but they're not. So you really got to check what their blood pressure is at night when they're laying down or first thing in the morning before they get out of bed. So I'm just going to get back up on my soapbox, flying back on it. So I was on my soapbox a minute ago, pleading for somebody to do the AI work.

So we can figure out everybody's cloth, those status and mitochondrial haplotype, like that. This might even be a slightly higher soapbox. People know how much I'm a fan of continuous glucose monitors because that type of information, whether you only choose to wear one of these things for a month or you choose to wear one for a year, even if you're not diabetic, the insights are profound and they will forever change the way you think about eating, exercise, stress, and sleep. 100%. They just show you that in your play. As much as I'm a fan of that, I would right now get rid of CGM for the non-diabetic.

If I were ZAR for a day, if in exchange I could have a continuous blood pressure monitor that was perfect and seamless and you could stick a patch on and have real-time continuous blood pressure monitoring. That would be even more valuable for the reason you just stated. And this is one where I just lose sleep over it for myself and for my patients, which is I really don't know what my blood pressure is most of the time. Even if I check my blood pressure twice a day, sitting at my desk, tells me nothing about what my blood pressure is, the other 23 hours, 59 minutes, and 30 seconds of the

day. And that we don't have a tool to do that yet. Well, and I've tried every supposed, continuous blood pressure monitor out there. The ones that work are so cumbersome that you can't use them, like the clinical grade stuff where it's a cuff attached to a big battery pack and you're walking around and it looks like you've got an LVAD. I mean, those work, but they're not practical. And then the little wrist bracelets and stuff are total garbage. So we're just sort of waiting for some technology to change the game and I just can't wait for this and I hope it occurs soon because it's such an urgent need, not just in terms of everything we're talking about,

but when you start to think about cardiovascular disease, imagine not knowing if you were a smoker. As dumb as that sounds, like, you can't tell if you smoke or not, but you might. No, we have no data. And what's worse is it's very difficult to think of how you could develop a device that isn't interfering with your sleep, because if you want to check it when you're sleeping, you don't want

it to cause another problem, cause you not to sleep. But then you start thinking about, well, even if you did have just high blood pressure at night, what can you do? Well, there probably are things you could do, because they're short-acting medications that you could maybe just dose before bedtime, and you know, during the day when your blood pressure is fine, you're up and around great, but at night when you're actually hypertensive, which is half of your day, essentially, you are treating that, but right now,

we're just living in full spare dyes because we have no idea what your blood pressure is doing at night. Okay, so good to note or bad to note, but good to note that we've got to keep our blood pressure low here as well. Yeah. We all know that Alzheimer's disease

disproportionately affects women 2-1. My belief personally, which is not unique, is that I think it's the hormone reduction that's doing that. I think very little of that is explained by women slightly out living men. I really think it's the sudden loss of estrogen in particular, and maybe testosterone, that feeds into that. What do you think is driving this 2-one gap between men and women in Alzheimer's? So, something that's interesting and recently discovered in nature, I think it was published

in April or maybe May, but we can link to it in the show notes. The MGMT gene, so the MGMT gene is a very powerful DNA repair gene in both men and women, but there are certain variants in this gene which seem to independent of ApoE influence Alzheimer's risk specifically in women, and this gene is related to breast cancer as well. So what is it about women that put them in a different category even in terms of what genes matter than men. It's more than just hormones, I think, but I don't know the answer. I do think hormones play a huge role, as you pointed out,

and the menopause transition, which is a huge area of research right now and something that we really focus on in our patients, is something that has to be a high priority in women specifically because of this role of hormones, but I think there are other factors at play. And just thinking of the counter argument to that when you think about Louis body Parkinson's, well, that's much more common in men, a two to one prevalence in men versus women. And is it sex and hormones that are driving that? Probably, but in what way way I don't know.

That's actually where I was going to ask you is what do we think is explaining the opposite, which is why are men getting a Louis body in Parkinson's 2-1 more than women? I don't know. I don't know what it is about the male sex. That's really giving us a higher risk or a lower risk for disease. But easy to point to hormones as the answer, but I don't know if we have the data out there to actually say that.

I think one day will be better at really pinning down someone's risk in terms of incorporating biological sex and genetic risk to give someone a more accurate understanding of what their individual risk is, and then be able to give someone a more accurate understanding of what their individual risk is and then be able to give them lifestyle and preventive strategies based on what we find there, but I don't think we're there yet. It's hard to know what to do with hormones, especially in men. So, kind of thinking about this in terms of a wrap-up, right?

It seems that there are two big themes that have come up here. One is the higher your cognitive process, the higher your cognitive reserve, the more likely you are able to weather a storm here. So similarly, in a recession, it's easier to weather a recession if you're not living paycheck to paycheck. It sounds like if I've understood you, the same is true on the movement disorders

that maybe the more facile true on the movement disorders, that maybe the more facile you are with movement, the more reserve you have to combat and delay the progression and or onset of the Alpha-Cinucleon-based pathologies as well. Which might, by the way, be the other reason why a diversified portfolio of exercise matters. When you think of brain health, it's not just the cognitive piece, but it's the movement piece, too, because there are nerves throughout our whole body, not just our brain. So when we think about how do we optimize our brain health, it has to be, yes, diversifying your cognitive experiences and managing your vascular risk factors, but also bringing in the movement piece is such a huge piece of

the puzzle and something that I don't think people have really come to realize because we've been so hyper focused on looking at what's the blood work show. Let's look at what the movement pattern show to. Yeah, this is something we're really excited about. You and Beth working on together with our patients and then hopefully we can sort of figure out a way to share this more broadly, which is adding movement to cognitive testing to identify these problems as soon as possible. Again, on the movement side, we've been doing this for a long time and you know, you can sort of say,

I know you're not in pain now, but because you move that way, you're going to suffer an injury at some point. It might be a year from now, it might be 10 years from now, but you're in the wrong path. If you make these changes now, you're in a better path. When we can start to make that same relationship between movement and movement disorders, I mean, that's fantastic. That's taking it to the next level, and that's where we need to be. And for all the people that are listening who may be at risk for one of these movement disorders or have a loved one that is suffering from it, getting to the crux of the movement problem might be the key to answering the question of how to prevent the disease.

So I don't want you to overstate it, but my final question for you, Kellyanne, is with ambition, but not wishful thinking. Where do you think we can be in five years with respect to everything we've talked about today? I will say that no one has incorporated exercise and movement the way that we're looking at it now. I think just that alone is going to push the needle so far in the direction of making it advance in the world of movement itself. In the world of Alzheimer's,

like I said, they're so related. Whatever we learn about one disease tells us so much about the other disease, we have to stop thinking about them as so separate and more think about them as a continuum. I don't know what the future holds, but I think if we start changing the way we're viewing the diseases and put them more broadly under the term of neurodegeneration, identify what the problem is from the get-co, not look at amyloid, not look at tau, not look at alpha sinuclion as the ultimate problem, but scaling way, way back. I think we can get much further than we've been. And you think we would be able to do that

with a better attention of finer tooth comb, un-cognitive testing, which includes all of the dimensions you've talked about, plus movement assessments. You think that those together, even before biomarkers, can start to give us that very early indication of where someone might lie on a spectrum. And genetics. I don't think you can do this without understanding genetics and family history. I think with those pieces of information,

yeah, we can move the needle pretty far. And you're confident that we can then target preventative strategies. Yeah, once you understand what someone's at risk for and understand what their baseline is, you can curate what strategies there are to prevent it in a particular person. We were talking about this last night.

I just don't think there's any set of diseases that are more frightening than this. I think when you look at all the big buckets on the death bars that we so festitiously keep track of, yeah, heart disease is the number one killer. Cancer is the number two killer. I think we accept those risks. I think we kind of get it deep down. I think we all kind of hope we're going to die of a heart attack in our sleep when we're

96 and that's that. Then nobody wants to die that way and nobody wants to die period, I suppose. And certainly nobody wants to get cancer. But there really isn't any of these neurodegenerative conditions that doesn't just leave you feeling completely petrified yourself and then completely at a loss for what to do to help somebody who's suffering from it. I applaud you for being able to go into the world's one of the three most depressing fields of medicine and then somehow carve out an optimistic piece of it. Honestly, our waiting list at Cornell was more than five years long and what one patient actually

said, I was told by my doctor that it's harder to get into this clinic than it is to get into college, which is really, really sad, but that just goes to show the tremendous need for people to start re-evaluating how and when we're looking at disease, so, so much need. And the first thing that patients would say when they would come to see us is how petrified they were. They saw their family member go through such a disease that robbed them of essentially the person that they were. They're no longer able to communicate. They don't recognize them. Like that's a terrible thing. In so many ways, so much more terrible than a heart attack, at least you still have your cognition. I mean, granted none of these things are good, but just losing your whole person is just so, so hard. And that experience for so many people really drives and empowers them to do everything that they can to ward off

the disease. And most people would leave in tears just because they feel like for once someone is listening and there's something that they can do to anything that they can do to just change their fate and their fate may not be what their parents' fate was or their grandparents' fate was. It's huge. Okay, and thanks for sitting down with us and walking through all this stuff. It's super interesting and I'm excited about what we can do together. Yes, me too. Thanks for having me.

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