Hello and welcome to the latest episode of the Fitness Genes podcast. Today's podcast focuses on our latest trait report, which is APO and Alzheimer's risk. So today we're going to be talking about this latest gene, its influence on Alzheimer's risk, but also what you can do to mitigate any genetic risk through lifestyle interventions. Today I'm joined by two doctors. I'm outnumbered for the first time. We've got Dr. Gupta from Thrive Doctor and we've also got Dr. Stuk Grace from Fitness Jeans in his usual role as well. So, welcome both. >> Thanks very much. >> Thank you. >> Dr. Gupta, we'll start with you. This is your first time joining us and it's very exciting to have someone join us. We do enjoy it, don't we, Stuart? So, if you could just explain uh who you are, your personal background and also your role at Thrive. >> Absolutely. Thank you for having me. My name is Dr. Gupta. I'm founder of Thrive Doctor. We are a team of longevity doctors based in London uh working with people remotely on a one-to-one basis to help people live longer disease-free lives. It's been absolutely fantastic to come across fitness genes and build a partnership between Thrive Doctor and fitness genes so that we can use datadriven insights to optimize people's longevity. >> Wonderful. And Stuart, for anyone who's not familiar with yourself at this point? >> Sure. Yes. So I'm uh Dr. Stuart Grace. So I'm one of the co-founders of fitness genes. My background is more academic. Uh I'm a neuroscientist was a research Oxford for many years specializing in neuromuscular disease and neuro degeneration but my day job at fitness genes is to build the scientific models and the analysis that hopefully will benefit many of your customers. Excellent. Um so so as I said at the top today's focus is on APOE. Um and APOE is something that we have covered at fitness genes before. Uh so we do have a couple of uh reports relating to APOE and brain health and inflammation. Uh so some of our members uh may be interested as to why we're exploring this topic again. Um and I think just as a sort of a brief summary, you know, this is I think by far the gene that we get the most questions about. It's it's it's something that's quite provocative at times. It's it's something that people, you know, do send a lot of questions about. And I think a lot of that comes from the fact that it was popularized by Chris Hemsworth in his documentary Limitless in 2022. And off the back of that, a lot of people have kind of been interested in discovering their own personal APO risk factors. So for anyone who hasn't seen that episode, Chris Hemsworth uh found out that he um carried two copies of the risk variant that we'll go into a detail about and from that has kind of made lifestyle interventions to help mitigate his risk. So Stuart, why why has this come back round at this kind of point in time? Is there anything kind of new that we're sharing with customers with this latest report? >> So yeah, this one so the the old uh trait specifically looked at general health with APOE and neuro inflammation specifically this uh will identify specifically the alles associated with aoE and AD risk. So it is very clear on what risk profile you have. Initially we didn't do that because we for one prime example we didn't have the the afterare. So now with collaborations with Dr. Gupta we can actually enable people to understand what to do. Also I think there's a lot more knowledge around the the reality of having these risk variants that increases the molecular hallmarks associated with Alzheimer disease i.e. what's happening within the cell, but it doesn't necessarily mean you're going to get Alzheimer's disease. And a lot of the modifiers associated with mitigating that risk are lifestyle. So for me, I think we're at a point where actually there's decision making that can happen in someone's life that can be very beneficial and there's things we can do about it. So this is why at this point I I thought it was actually very important if people wanted to know the risk to know their risk and then also to know what to do about it because there are things you can do that really will make a difference. >> So so although APO has been included in our reporting previously we're being a lot more specific in terms of the gene variance people carry and then being more specific I guess in terms of the guidance that we can provide following that as well. Wonderful. Okay. Excellent. So did I mean as people who've seen their personal result may be aware we're looking at the relationship between APO and specifically Alzheimer's risk for this report. So Dr. Gupta, if I could come to you as as as a medical doctor, this includes kind of, you know, uh your your specialty and your expertise, if you could just help me understand what exactly Alzheimer's um disease is and also how prevalent it is, you know, within a UK context, but also wider potentially as well. >> Yeah, absolutely. So Alzheimer's disease unfortunately is one of the fastest growing chronic diseases globally and it's responsible for the majority of dementia cases. Between 60 to 80% of all dementia cases so globally it's thought in excess of 30 million adults have Alzheimer's disease. Who it typically affects is people in their 60s7s and 80s. uh risk factor. One of the biggest risk factors is age as well as genetics and as uh we've also talked about is the lifestyle side of things. The way it typically affects people is their memory is the perception. So how they think and they feel and also their ability unfortunately to look after themselves. So the thing that I would really want to um get across the message would be even though this is or can be a debilitating disease that affects us later in life. This is also a slowb building disease. So there are decades of opportunity in 30s, 40s, 50s and 60s in reducing the known risk factors and preventing the chances of this disease taking away our independence later in life. So yeah, so not not about acting, you know, once you've turned 60 65 and your your risk really increases. I mean I was for in preparation for this report I was reading that your risk doubles every 5 years after 65 and within an aging population I guess that's quite concerning for you who's practicing in the medical field. >> Absolutely. So around one in three uh people over the age of 65 uh sorry one in three people over the age of 80 may be susceptible to Alzheimer's disease around 1 in 10 in the 60s. So as we get older our risk does go up and the same is true for heart attacks for strokes. This is something that we can't control, but as we alluded to and we'll we'll dive into later, there's a lot that you can do, day-to-day habits, how you eat, how you sleep, uh your social connections that can change your whole trajectory and the earlier we do this, the better. >> Great. And so Stu, over to you. What are the sort of I guess biological mechanisms that are driving Alzheimer's? >> Sure. Yeah. So it's a disease of the brain and we know that brains are incredibly complicated and they're associated with pretty much all our biology biological functions and bodily functions and the core components of a brain we may be aware of of neurons. So these are cells which will receive signals and this signals can be from hormones, it can be from other signaling molecules in the brain. It can be from sight, you know, light. It can be from touch. It can be from other neurons. You know, a network of communicating neurons enable us to form memories and to respond to outside stimuli. So, because of the nature of the neuron, they're highly structured. So they have uh soma or cell body where they do a lot of the processing where the nucleus is and they have dendrites where they can receive signals and axons where they transport signals and sinapses again where they can send signals to other neurons. So you've got this quite stereotypical basic structure of a neuron but there's a lot of diversity in the brain. We know there's different regions the neurons in your eyes that in your hippocampus your peripheral neurons that excite your muscles will have different structures. But because of these requirements of the the nerve to send electrical signals and then to send messages onto other cells including neurons, you need lots of proteins that are transporting messages enabling electronic signal to go down the neurons to repair the neuron to adapt the neuron to new stimuli which then enables us to create memories. And there's many many proteins in the cell enabled to do this. Now there's two proteins in particular that are associated with AD. One is called amaloid beta and one is called toao. So amaloid beta is a regulatory protein. It's involved in synaptogenesis. So the creation of new sinapses which are important for neurons, neuronal repair, neuronal growth. It's involved in the immune system within the ner nervous systems. Towo is specifically more uh associated with the transport of molecules down the neuron. So if you think about you if you think about there's neurons that go from a brain all the way down to the bottom of our leg these incredibly long axons and you need to transport things down there and some things come back as well and tow this protein is associated with the transport of molecules and and actually visicles and other components down the axon. So these are important for the structure of the neuron the maintenance of the neuron and also how a neuron works. So these proteins are normal functioning proteins but as you age as Dr. Gupta described you know age is a risk factor these adaptations to the neuronal system can change and these proteins can start to misfold start to dysfunction or actually they can become modified in a way that they don't behave in the correct way and these eventually can cause aggregates of proteins within the neuron that stop the neuron from working. So just basic memor memory function can go the way it can repair itself stops functioning the ability to form new neurons can be constrained and then ultimately that can lead to neuronal death and this is kind of the end stage of what you think of Alzheimer's Alzheimer's disease being so you have early dysfunction this often happens in the hippocampus uh region of the brain associated with memory and then over time you get many other processes that then lead to the risk. So you can get inflammatory processes. You can have effects of the bloodb brain barrier. This permeable sorry semi-p permeable permeable membrane that provides nutrients to the brain but also keeps other proteins out. The mitochondria. So mitochondria transported to different regions of the the neuron. These can become defective create oxygen species that can then degenerate the neuron further. So there's all these interplay of different mechanisms that lead ultimately to neuromal death. Tao and amaloid beta and particularly the increased oligorization or modification of these proteins that ultimately form aggregates is are the key biological or molecular hallmarks of Alzheimer's disease. >> So yeah and and in the reading I was doing around it was talking about kind of like plaques forming. Is that is that what you mean when you talk about aggregates? >> Yes, exactly. Now now there's again you've told me not to go too technical and you've open you've opened a massive door for me. There's a lot of >> I thought that was me trying to simplify it. >> Yeah. Yeah. Sorry. Yeah. You've uh opened the barn door now. So there's a lot of debate on you know what seeds Alzheimer's are the plaques actually pathological are they endstage is it the olymerization is it the different interactions what comes first is it amaloid pathology or tow pathology but ultimately in the key literature people talk about these plaques and it's it's these proteins that become dysfunctional and stop the neuron from working properly. in essence. >> Okay, >> great. Thank you. So, so let's have a look at actually what is then driving those biological processes and Dr. G, you sort of touched upon the fact there are kind of those lifestyle risk factors as well as the genetic risk factors we'll look at. Age is obviously something that's really key that we're looking at here, but what are the things that people might be doing in their earlier life stages, you know, their 30s, their 40s as you touched upon that may be driving this risk of them developing Alzheimer's in later life? >> Yeah, absolutely. So aging and genetics are risk factors that we can't modify, but there is a huge amount of our risk profile that is modifiable. Your day-to-day habits shape your brain health far more than most people realize. So the first big hitter I would focus on is your metabolic health. So poor glucose control, insulin resistance, midlife weight gain, this all increases the inflammation in the brain and the and accelerates the disease buildup. This is one of the strongest and most modifiable risks that we have. So if you are pre-diabetic, this is probably unnecessarily increasing your risk profile. The second thing I would talk about is sleep. So long-term sleep deprivation, fragmented sleep, sleep apneoa. This all impairs the brain's nightly cleaning cycle if you like. So if you are having poor quality sleep or disrupted sleep, that system will fail. As Dr. uh doctor talked about these dysfunctional proteins, these plaques can accumulate faster than the brain can clear them. Uh so focusing on sleep is a very big hitter. Good return on your investment if you're able to fix this. The other thing to think about is your cardiovascular fitness. So your brain and your heart are very connected and most of the risk factors that are going to increase your risk of heart disease are also going to increase the risk of your pathology of the brain. So thinking about if you've got a sedentary lifestyle, low V2 max, poor vascular health is essentially going to reduce the blood flow to the brain and it's going to accelerate your brain aging. Uh fourth thing to think about on the long list of things we can optimize is your stress. So unfortunately a lot of people today are stressed in there between work and life balance. Um but high cortisol we know does shrink parts of the brain, increases inflammation. So over a period of time it can absolutely change your whole trajectory if you are able to address this. Um other things to think about is your cognitive and emotional inactivity. So if you are under stimulated whether that's intellectually or socially this is very clear evidence is clear that this does accelerate the decline. So the good news is that everything that we've just talked about from a lifestyle perspective is modifiable. And the good news is also that when you do improve one of these things, it falls into the others and you'll see benefits across the board. Not just from an Alzheimer's point of view, but also from a heart perspective, a diabetes control. Your overall life expectancy will improve if you optimize some of these risk factors. >> Yeah. And I think that's quite reassuring kind of, you know, communicating with people how in control they are of their of certain risk factors. So Stu, let's move on to the the risk factors that they can't modify, which is their genetics. So can you just give a bit of a an intro in terms of APO and the gene variants that we're looking at and their associated risk? >> Sure. So I guess there there's two frames of genetic risks. I'll quickly just touch on the familial, the rare variants. So there are certain variants which are very rare in the population. Uh generally coales in families. So you'll have families where they'll get people with Alzheimer's and we're talking earlier Alzheimer's here and these you'll find mutations in the proteins associated with uh amaloid for example or the processing of it. So this is uh generally an onset in their 50s but incredibly rare. So just as a familiar form of Alzheimer's that's genetic but we're not going to touch on that today. So I guess one of the key I guess what is known as the master accelerator of AD pathology is ApoE. It's a protein as you said we get asked a lot about uh this protein. So just as a a bit of background what what is aoe? Well it's a protein ass sorry it's a gene that's associated with creating an epipop protein. So so this is something that's associated with lipid transport and metabolism. So why lipids important? I think it's very interesting to hear about the cardiovascular risk because obviously aoe has both been associated with increase of Alzheimer's but also cardiovascular risk as well. So you actually can see some of the interplay between the genetic eeology here. But the brain is I think dry mass is about 50 to 60% lipids. So fats are a form of lipids. Thinking about cholesterol. Well, what are the lipids doing? Well, they they're all the membranes. They're the visicles. So these little things that transport the neurotransmitters. They're neurons are insulated by something called myelin. This is made from lipids. You got glee which are cells that support the neurons. These are all uh coated in lipid membrane. So lipids are incredibly important in the maintenance of neurons, the formation of new neurons, the the energetics of neurons as well of course and apo is a central protein that's associated with getting the right lipids to the right place. So we may think of fats and lipids as a very generic thing, but actually there's loads of different versions and species of them and actually different neurons will have different blends of lipids which will actually alter the the the mechanisms within that neuron and also the the identity of that neuron. So Appoe is going to be processing your neuron neurons. You can recycle waste using lipid membrane visicles as well. And of course we've got these buildup builds up of aggregates and proteins in the cell. So ApoE is very important for this homeostasis of the neuron. Okay. So let's go on to ApoE in terms of the genetic variance. So we have three general alles with ApoE. ApoE4 which is associated with increased risk. ApoE3 which is what is the ancestral so the protein that was there at the beginning in evolutional time and that's general risk it's kind of hate to use the term normal but in in scientific circles people call it normal but the wild type or ancestral and then we've got ApoE2 which actually has been shown to have a protective effect and these alles are caused by two genetic variants that change the amino acid composition that alter the the mechanisms and the biology of those proteins. So why does the risk factor increase risk? So you can have two variants from each uh parent as you alluded to with Chris Hemsworth. You can have E4 and E4 which means you can carry two of the risk factors. So when you have this mutation the protein is modified. So this impacts your ability to clear amaloid and the amaloid plaques primarily. So it sees and accentuates the uh the pathology. it can increase and because you get these buildup of proteins that increase neuroinflammations. So Dr. Gupta was talking about inflammatory processes within the cell you get the increase of new inflammation. This can damage neurons uh and lead to further sort of more indirect effects that lead to the degeneration. It also enhances the the risk variant can enhance the spread of tow which is the other associated protein. So ultimately it the E4E4 reduces the ability of the cell to deal with the age related buildup of the proteins associated with AD. Now I'm talking the molecular hallmarks here. Now when people look at bre people with E4 E4 or epson 4 epson 4 every single patient at autopsy will have a buildup of amaloid and and tow however not every patient will have presented clinically with AD in their lives. So this is a highly penetrant and fully penetrant variant in terms of the molecular hallmarks of AD, the buildup of these proteins and the other affected processes, but it doesn't necessarily mean you're going to get AD, but it does increase your risk three to fourfold. Now there's a lot of quotes of 15 times and all that sort of stuff but really what you're seeing is you've got a lifetime risk and these are generally positioned after 80 of going from sort of five to sort of 15% to 30 to 50%. Uh which you know that's a very significant risk but again it doesn't say necessarily you're going to get AD and it is these lifestyle factors and other genetic modifiers too that will be uh increasing and and decreasing that risk profile accordingly. So in a population it increases it three to four times. On the individual there are many more factors at play. Also Alex we've lost Alex. >> We've lost him. >> So we might as well carry on talking for a bit while we get him. Yeah. So So anything else to add to that? I think the things I would focus on with um ladies and gentlemen regardless of what their age or their family history or their genetic profile has said is remember that the Alzheimer's risk is not fixed. Yeah. >> So focusing on things that you can change can absolutely be the difference between getting Alzheimer's disease present in your life. as you mentioned, proteins may accumulate, but that doesn't mean that you'll be diagnosed or affected by Alzheimer's disease. >> Um, so focusing on what we can, making those changes decades ahead of time can change your overall uh trajectory. Um, and typically these things are the strategies are simple but very powerful. The the challenge is looking at it across the board and maintaining the the the adherance the habits of how are you going to eat, how will you move, how you maintain intellectual, social connections and optimizing your metabolic health. I wouldn't want anybody to falsely be reassured that they're genetically low risk for Alzheimer's so that they can fall to bad habits and potentially develop it. and equally somebody who is ApoE E4 who is carrying a high-risk Alzheimer's genetic variant um not think that this is deterministic this is not a curse most people with this gene will not actually develop Alzheimer's disease in their lifetime so it's not a curse the power is with the individual sure the bit because again AD starts to present in terms of the brain structure in the hippocampus and of course because that's actually if you Think about brain development. Neurons are very long lived as in we don't as adults produce many but the one place in the brain we can produce more is in the hippocampus and I know exercise is a big driver of increased hypocample neurogenesis. So I think the activity is also a very important point. I think in terms of because our our user base often talks about supplementation as well and from what I've really seen omega-3s are really important. And of course, you're getting through food as well. And also vitamin D. Make sure you're getting ample amounts of omegas and vitamin D's in the diet as well. >> Absolutely. A question that I get a lot I'd love to forward to you is what would you say about So given that there's a huge overlap of risk factors for developing diabetes and developing brain pathology, especially Alzheimer's disease, would you say that there's shared risk factors and nothing more? Or would you say um that there is some credence to labeling Alzheimer's as type three diabetes? >> Yeah, that that's exact. I I think I as scientists we like like to compartmentalize or clinicians as well. It's very it's it helps us build narratives to understand that this is you know it's a systemic and so I used to work in uh uh new early stage neurogenerative disease and the first thing because the the first thing that presents to the clinic is memory >> problems you think of it wholly as a brain and it's going to be a systemic disease you well you look at withoe you've got the uh mutations associated uh the E4 E4 mutation it increases cardiovascular risk actually E2E2 also has some risks in terms of some rare forms of cardiovascular disease as well. So you've got these tradeoffs within the body and actually the the some evidence suggests that E4 E4 earlier in life has some advantages over memory formation and everything else as we think of uh aging as this quite linear sort of deterministic process but actually bulges created many trade-offs. You see this with some of the Bracka 2 mutations as well which are associated with breast cancer. they may actually improve fertility early in life but then may have a negative effect later or in midlife in terms of breast cancer. So I think there's all these interplays between uh the different the different conditions but I think cardiovascular health is very important particularly managing blood cholesterol blood triglycerides. Yeah. And again the interplay between diabetes and cardiovascular diseases is very tight as well. You know the glucose metabolism insulin resistance is essential to managing these conditions. So I think you're absolutely right. I I think they're all scientists. We like to separate them into different categories and the one thing we're doing with our new release with fitness genes is we've categorized at brain aging, metabolic aging, cardiovascular aging. But the way we rank our recommendations actually comes from every system. So if someone has even if someone within the system has none of the risk variants associated with brain aging. So the brain aging is downranked but they have increased risk of cardiovascular disease and also blood glucose. In solving those problems you're ultimately supporting your your brain health via the mechanisms you've described. >> Yeah. It's it's impossible to get an individual improve their glycemic control, improve their V2 max, um, not improve their brain health. Spot it into it. And then knowing the nuances of your genetics and and obviously your bloods and everything else well enables you then just to target different sort of specific uh interventions accordingly because the health marketplace is very noisy full of interventions and some work and some will be very efficacious in some people and some others >> not so much. So >> so I think we're not getting Alex back but I I can I can wrap this up. So thank you very much for joining us. Uh I think it's been been a great chat. I'm sure Alex would agree. Uh so uh no nothing else to add really but you know thanks for joining us and we're looking forward to the collaboration in the future and I'm sure we can talk on many other subjects. Again obviously we don't just look at Appoe we look at lipoprotein A varants hyper familial hypoglycolma. There's lots of other different genetic traits that actually are really important for understanding our long-term health risks. That's something I think we probably can talk about again. >> Absolutely. It's so so useful what you're doing at fitness genes giving us the data to the individual. It's it's very easy to manage mass populations categorizing them cheap and convenience with BMI with arbitrary total cholesterol number. But getting the real individual data points allows you to build a personalized plan and arm that person with the knowledge that's going to change their whole trajectory. And it's important to remember this is not deterministic. This doesn't make you certainly get a disease, but with that knowledge, just an analogy I wanted to throw in. I was thinking about as we were preparing for this podcast is the Michael Kane analogy. I don't know if you come across it where he says, "Use the obstacle." So, if he's going on stage and he trips over a chair, he doesn't reset the scene or try and pretend it doesn't happen. He uses that chair to make the scene better. So, that's exactly how I use people's genetic data or glycemic data. use that information to add years to your life, implement these changes, and you're you're doing these benefits that otherwise you wouldn't have had had you not got that worrying risk factors. >> That's that I love that. That's a really good analogy. And unfortunately, Alex, you missed it. >> Stuart, >> did you just take complete control of the podcast? Did you step into my shoes expertly? >> I used the obstacle. >> Sorry. I I I ran into some technical difficulties and and very much panicked, but thank you. Thank you for making sure the conversation continued without me. I'm sure Dr. Gupta was making some very good points as as you were as well. >> No, fantastic. And uh we went totally technical, totally off piece. We weren't regulated by you at all. Uh no, I think we've we've I think summed up everything we needed to sum up. So, Alex, do you want to uh say >> Yeah. No, absolutely. So, so yeah, if you if you've covered everything that you need to, um, so this this report is now available for all fitness genes members. Um, so everyone who has access to their fitness genes results is able to log in and view their particular APOE variants, see their genetic risk, but also those lifestyle recommendations that Dr. Copter just touched upon to uh, help mitigate that risk as well. If you haven't received your fitness genes results, uh, then absolutely there's opportunity to do so. APOE is just one of the reports that we deliver. We have over 180 genetic reports that look at uh weight loss, muscle building, brain health, inflammation, hormone health, women's health. So we've got a whole catalog of reports that you can go through including your APOE result. Excitingly as well for this particular report through Dr. Gupta and his his service at Thrive Doctor. For the first time, fitness genes members can now go and speak to a medical professional regarding their particular Alzheimer's genetic and lifestyle risk. So that's I think that's a really exciting step for us, Stuart, isn't it? Because it's the first time that actually rather than just reporting on, you know, these risk factors that there is that afterare that people are able to access and go and schedule time with Dr. Gupta and and some of his team to actually discuss what this means for them personally and how they can really build in their recommendations into their daily schedule as well. So, um yeah, any any sort of closing remarks before we round off, guys? >> I think we've we've done them without you. Yeah. No, I think it's a great summing up. No. >> Excellent. So, yeah, if you are a fitness member, please go and view your APOE uh result. If you'd like to discuss your personal result with Dr. Gupta will provide links to allow you to do that as well. If you're not a fitness genes member and you're interested in discovering your own personal APOE variants and your Alzheimer's genetic risk, then please do go to fitness genes.com and you can find both our DNA analysis home DNA analysis test and DNA data upload options there. Uh so we look forward to you joining us soon. For any questions that you have, you can either find Dr. Gupta at thrived doctor or as always you can come and speak to us at supportfitness jeans.com. So Dr. Gupta, thank you for joining for today. I'm glad that you were here so Stuart had someone to speak to when I disappeared. Stuart, thank you for your time as always as well. >> It's a pleasure. >> Cheers, guys. Pleasure to see you. Thank you. Take care.