Exclusive Dr. Hyman+ Functional Medicine Deep Dive: Alzheimer’s Disease

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Hi everyone. Welcome to another episode of Hyman Digital Functional Medicine Deep Dive. I'm Dr. Cindy Guyer and I'm honored to be speaking to you about the dynamic brain lifestyle and functional medicine strategies to reduce Alzheimer's risk and optimize cognitive vitality. By background, I'm an internist by training. I'm also board certified in integrative and lifestyle medicine with additional training in functional medicine. I currently work as a consultative physician at the Ultra Wellness Center in beautiful Lenox, Massachusetts. Alzheimer's disease in particular is a really timely topic. A couple of things that have been in the news recently. There was a press release in September about another monoclonal antibody treatment designed to clear amyloid beta from the brains of people with Alzheimer's disease, reportedly showing that it was able to slow down rates of cognitive decline by about 27%. This has not yet been published nor peer reviewed, but people are desperate to find some kind of treatment for this devastating condition. We'll talk about why just starting targeting amyloid is probably not going to be enough, but people really are looking for something that could make a potential difference. There was also a recent announcement by Chris Hemsworth, the actor, as part of his limitless series that he found out he has two copies of a gene called APOE4. In population studies, this is correlated with a 10 to 12 fold potential higher of the development of Alzheimer's disease, and it tends to show up earlier than people who only have one copy or don't have any copies of that gene. So that has also gotten a lot of people thinking it's been top of mind. And again, we are going to talk more about the importance of gene environment interactions and how your genes are not your destiny. One question that also often comes up as we're thinking about, oh gosh, I forgot where I put my keys. Does that mean I'm getting Alzheimer's disease? are there changes in memory that happen with age? And the answer is absolutely. And one of the most obvious ones is this slowing down of processing speed. So when you were 20, here's an example, and you thought you were doing 10 things at once. What you were actually doing was not multitasking, you can do them all at the same time, but your brain was able to shift back and forth amongst those 10 things at split-second imperceptible speeds. So it felt like you were doing them simultaneously. As we get older, the rate at which we can toggle back and forth slows down. So now it feels like you might be dropping something or it's just harder to hold all at that at the same time when in reality, as I said, you never really were. That's normal with aging. Another example would be, if you want to remember something, you have to attend to it. So if you've got a lot of distractions and you walk in one room and then you forget where you put your keys, that's also normal. With dementia, that is reduced cognitive functioning in multiple areas ranging from thinking, remembering, learning new things, verbal fluency, ability to carry on a conversation, reasoning skills that start to interfere with daily function and activities. Some examples would be getting lost on familiar routes that you've driven for years, being taken in by scams, forgetting to take care of monthly bills, frequently misplacing things and being unable to find them. One of the interesting things that's emerging is the same factors that increase risk of pathologic memory changes, known as dementia, may also impact the trajectory and the rate at which we progress with the so-called normal changes with cognition that occur as we get older. I have to share this really interesting story and in particular, Two of the big areas that seem to play a role with both are how healthy are our blood vessels and how physically active are we. And I want to share a really interesting anecdote. I just came back from the Annual Conference of the American Lifestyle College of Lifestyle Medicine, and they honored as two recipients of their Lifetime Achievement Awards, people who were known for their lifelong contributions to the champion in championing the importance of physical activity. First was Dr. Ken Cooper, who's probably a familiar, almost a household name for many of you. He founded the Cooper Clinic and he has studied the role of exercise primarily in cardiovascular prevention. And here he was at 91 years old, up on stage being interviewed, still actively goes to work and is engaged in research. And not only did he show up for the awards ceremony, he was attending the entire conference to claim and get his continuing medical education credits. So it was a really powerful tribute to also not just physical activity, but the importance of lifelong learning, being a lifelong learner. The second person was Elaine Lalane, who accepted the award on behalf of her husband, Jack Lalane, who again, familiar household name, who really brought exercise into the living rooms of Americans across the country. and he died in 2011 at the age of 96 and was still exercising daily until he died. Elaine was his partner in exercise and at the age of 97, she just published a bestseller on his life and contributions, and she was witty and articulate in conversation, and those two were just great role models for how we want to stay active, stay engaged, and hopefully optimize our cognitive vitality. Not a study, but still inspiring nonetheless. So what's the scope of the problem? Alzheimer's disease is estimated to currently affect 6.5 million Americans. It is the most common type of dementia. Vascular dementia is the second most common type. Micro mini strokes and microvascular changes in the brain, although there is considerable overlap. Some experts think that vascular dementia and Alzheimer's disease exist on a spectrum. In fact, if you look at people who have Alzheimer's disease, you'll see evidence of vascular changes as well, and at least 40%, if not more of them. This unfortunately is more than 10% of people over the age of 65 those numbers are projected to reach 12.7 million by 2050. In addition to that, 47 million Americans may have increased amyloid that you can now detect by specialized PET scans without any cognitive symptoms or memory changes yet. And people are really concerned that this is going to portend a tsunami of increased cases down the road. It's not just about the people whose memory is affected by Alzheimer's disease. It's for all of the ones who love and care for them as well. If any of you have cared for a loved one with Alzheimer's disease, you know how devastating it can be to witness the slow loss of parts of what made them who they were, and perhaps even get to the stage that they no longer recognize you, they can no longer walk or feed themselves. this is a devastating illness with no current cure. There is hope. There is hope. This is the depressing news. So previously, you could not make the diagnosis of Alzheimer's disease until somebody died. It was what we call a pathologic diagnosis. Of course, what people experienced before they died was these progressive changes in memory and functioning that affected daily life. But what you would see in the brains of people who had died with those types of dementia was a triad of three things: this sticky plaque called amyloid that builds up and accumulates around the neurons in the brain, tau tangles, which are snarled up tangles that seem to play a role with nerve damage and shrinkage and loss of neurons. So that is the classic triad that is a vicious feed-forward cycle that is pathognomonic of Alzheimer's disease, which we see clinically as cognitive changes and dementia. so how do you diagnose Alzheimer's disease before that? Well, you can do memory tests. They're not super sensitive. And remember, there's a matter of degree. At what point does somebody tip over into this gray zone that's called mild cognitive impairment, where there's some changes in memory that, that a person or their loved ones may notice, but they're still able to function versus dementia. Mild cognitive impairment, while not all people who showing some of those signs progress to Alzheimer's disease, it is a marker of significantly higher risk of progressing in the future. Genetic tests, and we're gonna talk more about this, they inform risk, but they don't diagnose disease. And one of the really important things about that, I mentioned APOE4. There are plenty of people who have double E4 copies and they don't have dementia or Alzheimer's disease. On the flip side, there are people who have zero copies of the APOA4 gene and they do have Alzheimer's disease. So it's not a perfect predictor. It informs your potential risk. Remember how I mentioned it was a pathologic diagnosis made at autopsy? Well, in recent years, there are specialized PET scans of the brain that can detect amyloid deposition, and you can also do spinal taps and detect ratios of these two forms of the amyloid protein in the spinal fluid that bathes the brain. And both of these are playing a role with the notion that the accumulation of this plaque occurs well before somebody has symptoms of memory changes. There are currently at least eight different labs who have developed a blood test for these amyloid ratios, these two amyloid protein ratios, and it does seem to correlate pretty well with PET scan and spinal fluid levels. But don't rush out and do this. This is not a wellness test. Right now, it's primarily in the research realm. It does show correlation, as I mentioned. There's a real need for standardization. It's not clear who's got the best test, what's the best way to do it, and what are you gonna do with that information? That being said, it does open the door for better ways to track people before the onset of symptoms as new effective therapies start to come into being. That's where I think it's going to be playing a big role. I do not advocate that people, unless they're in a memory prevention center and research trials that they get these blood tests done, but stay tuned because I think they're going to increasingly become more important. So I want to show you this slide. If we take this dotted line as when somebody's memory starts to be noticeable and detectable and interfere with their daily quality of life, there is this 15 to 20 20 year window where amyloid beta deposition, these plaques start to accumulate in the brain. And as that progresses, it can trigger the immune cells in the brain to start reacting with more inflammation. And these tau tangles that I mentioned, they're a later finding. So the tau tangles start to accumulate and at some point there's a perfect storm where neurons start to die, and then somebody reaches that point of showing signs of memory. That is critically important because by the time somebody has enough changes on their memory test that it raises a concern, they already have changes in the brain that this has been going on for a long time. So the prime window to think about prevention, yes, the things we do all our lives from birth on also can play a role with reducing risk, but it may be that 40 to 60 year old window when most of us are starting to even think about preventive health because we've kind of been invincible before that. But that's when we really need to step up our game in terms of identifying all of the potential contributors that could be playing a role with us to prevent the progression and the accumulation of the amyloid plaque. I would add in here, it's not just about plaque, taut tangles, and neurodegeneration. There is another component of neuroinflammation that can be both the initiating event to amyloid plaque in the first place and a perpetuating event that keeps it going. Step back for a minute. Why would we have this protein in our brains that causes a problem? Does it have a function? Is there something else that it's responsible for? Well, amyloid is more likely a mediator than the root cause of Alzheimer's disease. Amyloid production is part of an immune response to injury, infection, neurologic insult, or inflammation. And under physiologic conditions, it probably plays a role in fighting infections and repairing injury. That's why removing amyloid alone without addressing those underlying contributors to its excess formation, such as infections or vascular injury from high blood pressure or diabetes, it's somewhat analogous to that cartoon most of you are probably familiar with when you see a person frantically trying to mop up water from the floor from a sink that's overflowing without reaching up to turn off the faucet. We have to go upstream. What we see is the triad of amyloid, tau, and neurodegeneration. has many potential intersecting paths to get there. We talk a lot in functional and integrative medicine about getting to the root cause. Amyloid is not the root cause. It's a reaction to something else. We need to always be thinking about those something else's and what we can do. Now, before we jump into all of that, I want to review a few key concepts that are really important to keep in mind throughout this talk. the first I've alluded to, it's the concept of epigenetics. The genes that we inherit from mom and dad, they are variably expressed. They are modulated by the environment that's washed over those genes from the intrauterine environment to birth and beyond throughout the course of our lifestyle. Again, that is a really important message because we don't have any control about our parents and what we came into the world with, but we have tremendous control over the choices that we make in our daily lives with the foods that we eat and how we choose to live that can modulate those genes and have the biggest impact on our health and well-being. The second concept is one called neuroplasticity. And that refers to the idea that the brain has the ability to form and reorganize synaptic connections and even grow new neurons, especially in response to learning or experience or following injury. When I was in medical school, this is huge. When I was in medical school, we learned that the only neurons you were born with, that was it. And if they ever were damaged or gone in any way, they weren't coming back. We now know the brain continues to make new neurons and connections well into adulthood. And this concept really offers hope to anyone facing stroke, traumatic brain injury, mood disorders, addiction, and neurodegenerative conditions. Another concept is this one about dynamism, flexibility, and adaptability. So even things we used to view as inflammation and stress. We thought of them as universally bad. Well, they're not. Their key process is important for survival, just like amyloid has a role too. And the key is to be able, if we take the example of inflammation, we want to be able to generate an inflammatory response when called upon. If we get an injury, we get an infection, that's part of how we recruit the cells to the site of that injury or infection, deal with the invader, and then start to lay the seeds to repair the injury and then turn the inflammation back off again. In fact, it's really interesting to think about how sophisticated our immune systems are. Did you know that at the same time we initiate an inflammatory response to something, our immune system is already planting the seeds for resolution at the exact same time? And here's a key clinical pearl, omega-3 fatty acids that we get from fatty fish, for example, they contain molecules known as resolvins and protectins that help the immune system plant the seeds to resolve inflammation when it occurs. So when we think about resilience, it's not a static process and it's not about whether we have stress or inflammation, it's about the dynamism and the ability to bounce back. So we're in healthy situations, we're awake and we sleep, we exercise and we recover. we feast and we fast, we have stress and then we relax and we recover, we have inflammation and then we resolve it. So our bodies do really well when we allow the recovery periods and the oscillations. Interestingly enough, the same is true for use of calories. I mean, a very healthy metabolic system is able to utilize whatever fuel is available and sometimes it might be a higher fat meal, sometimes it might be a higher carbohydrate meal, and when our metabolic pathways are healthy and resilient, they can also toggle back and forth to what's available to us. So when we think about loss of resilience, it's when we're constantly missing the recovery period, missing episodes of fasting, missing relaxation after periods of stress. That's when the system becomes out of balance. and when we're talking about Alzheimer's disease, again, it's a really scary topic. So those can generate a lot of fear, a lot of uncertainty, but there is a lot that's under our control, and that's where we want to focus our energies, what factors are in our control. So now let's talk about a little bit about genetics and lifestyle. I mentioned the APOE4 gene. So APOE is one of at least 20 to 30 different genes that have been studied for their potential interaction with lifestyle to play a role with risk of Alzheimer's disease. The APOE is the best studied one and it has several key functions in the body. It's involved in cholesterol regulation and transport, repair of brain injury, and it plays a role with the immune response. There's three different sizes of this APOE that exist. There's APOE2, APOE3, and APOE4. So if you think about this, you're gonna have two copies of the APOE gene, one from mom and one from dad. The most common combination is to have two E3s. That is about 50% of the population, and that's considered average in terms of risk of Alzheimer's disease. APOE2s might actually be protective. Those are fairly rare. If you have one copy of the A2, it's actually associated with a lower than average risk of Alzheimer's disease. One copy of the E4, keep in mind this is population predictions, not individuals. You'll see about two to three times as many cases in of late onset Alzheimer's disease, not early onset, late onset Alzheimer's disease in people who have one copy of the E4 gene as opposed to people who don't have any copies of the E4 gene. And as I mentioned at the very beginning, if you look at all the people for whom two of their copies are in E4, there's about 10 to 12 times more higher prevalence of Alzheimer's disease in that group compared to people who have none. But again, not all double E4s get Alzheimer's disease. I cannot underscore that enough. Interestingly enough, one of the ways, another way that E4 may play a role with risk, it could have been an adaptive advantage because there's evidence that people who have one or two copies of the E4 gene have a much more robust immune response to infections. That may have been adaptive back in our gatherer-hunter days where the main goal was to make it to reproductive age so we could pass our genes on. If we could fight off all the pathogens and bacteria and fungi and parasites that we were exposed to on a regular basis, that was one of our biggest threats to survival outside of starvation. It may have been an adaptive advantage that that robust immune response that can tip over into maladaptive chronic inflammation may no longer be adaptive as we get older. So it's just interesting thought and theory. So what else does ApoE4 do? It can alter these microglia. We're going to learn a little bit more about the microglia in a minute, but it can shift the microglia towards what we call this pro-inflammatory disease associated phenotype. I love the acronym DAM, DAM. Apropos, I think. ApoE4 astrocytes, we're going to learn more about them as well. They're less efficient at clearing amyloid. Astrocytes are responsible for producing most of the cholesterol in the brain that plays a role with getting cholesterol down to neurons so they can create myelin that coats them and keeps them healthy and safe. ApoE4 also binds to insulin receptors and reduces insulin sensitivity. Here's some evidence of how strongly it interacts with lifestyle and cardiometabolic risk, which you're familiar with. In the presence of type 2 diabetes without an E4 gene, there's almost a doubling risk of Alzheimer's disease. If somebody has both type 2 diabetes and an E4, there is a five and a half fold increased risk of Alzheimer's disease. So they interact with each other.

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