– Doctor Galvin, there is a popular opinion that dementia and Alzheimer's disease is mostly a problem in the developed countries of the world. Is that due to the fact that these countries have higher life expectancy, or are there any other factors at play here?
The main risk factor for all types of dementia is age. And as life expectancy around the world was growing higher, we came to understand how serious this problem is in different countries and cultures. To a certain degree this indeed is a slightly bigger problem in the developed countries, because the generally higher quality of food supply and sanitation as well as availability of medication increase life expectancy, and hence there are more cases of Alzheimer’s disease and related disorders. And therefore a long time there in fact was talk about less developed countries or countries that had less Western lifestyles having lower incidences of Alzheimer’s disease. But when researchers started going into these areas - for example the Indian subcontinent - they realized that there was as much dementia there, it just wasn't called that, it was just considered to be a natural part of growing old. So it's a rampant problem across the entire world. However, there is another thing to it: one part of the modern Western lifestyle is getting away from home cooking and eating out in fast food restaurants a lot. This is not very good for your brain and it can be one of the factors that may increase the risk of dementia. So the combination of living longer and the introduction of modern technologies may actually increase the risk of Alzheimer’s disease for some people in the West.
– How high is this risk by the way? If you look at the freely available research data, it says that by the age of 80-85 about 50% of people develop dementia. Is this actually so?
It’s actually very hard to count the actual number of cases, so we use population estimates. According to those, at the age of 65 the risk of dementia is about 2%, but by age of 85 it increases to about 42%. That sounds really terrible – 42% of all 80-year olds have Alzheimer’s disease! But that also means that 58% of people don’t have it. And my research, and many other people’s research is trying to figure out why 4 out of 10 people develop Alzheimer’s disease but 6 out of 10 people do not. And trying to understand some of those differences may unlock the doors that we didn't really think were available before. In some ways you could say that we know everything about dementia now except for why it starts in some people.
– What do you think is the nature of this disorder? Is it completely physiological, related to the human body “wearing itself out”?
Today we understand a lot about the basic biology of the disease; we understand the development of pathology and the mechanisms by which amyloid proteins that form the plaques and tau proteins that form the tangles change from normal to abnormal, pathology-causing, protein. And it is facilitated by a combination of some genetic risk factors, altered biology as well as psychological and physiological changes that may occur at old age and put some people at higher risk than others. We believe that there are multiple pathways that lead to these diseases, but at the same time there are multiple ways to interrupt that process. And also interrupting just one pathway may not be sufficient, we may have to approach the disease from multiple sides at once.
NIH Image Gallery / flickr
In a brain affected by Alzheimer's disease, anomalous levels of the beta-amyloid proteins form plaques (brown) that develop between neurons and interfere with the cells' functioning. Anomalous clumps of tau-proteins form tangles (blue) inside neurons and damage the synaptic links between the neurons.
– As far as I know, these diseases are currently incurable, and the existing methods of treatment can only reduce the negative effects...
Yes, that is true, but, to be fair, in medicine we very rarely cure diseases: we cure bacterial infections and some cancers but that’s it. The rest of the diseases we do not cure but we treat them, and treat them very effectively, often reducing the symptoms and negative effects to a bare minimum. For instance, let's take diabetes or heart conditions: we can't really cure them, but we can achieve considerable improvement. So, in my opinion, it is not very fair to say that medicine has to cure Alzheimer's disease. I think we can be much more effective in treating the symptoms for people who have the disease. And where I think the money is, is in preventing the disease from ever starting. That would be the most effective measure.
Since we know a lot about the pathology of this disease and how it develops, there are a number of developed medical compounds that reduce that pathology. But the problem is, once someone already has the symptoms, then treating the pathology won't rid that person from them. You can remove the pathology altogether but the person will still have the disease, because the damage is already done. So, the clinical trials today that are being conducted around the world are trying to look at people who have no symptoms but the evidence of the pathology in their brain. And if we can remove the pathology before they have these symptoms, in theory we can prevent the disease. I think it's a very interesting and promising area of medicine. But also a very difficult one. Early diagnosis of this pathology today requires either a spinal tap or a PET-scan. A PET-scan is a nuclear medicine scan that allows us to visualize the pathology in the brain. But it’s very expensive diagnostics, which is not readily available everywhere, of course. Again, this isn't an issue in more developed countries with better resources, but in any country, including the United States, it depends on your location. In New York City you can walk out of your house and bump into a PET-scan, while somewhere like Montana there aren't many of them. So the disparity in this kind of technology across different areas is a serious problem. But it's the correct diagnosis of the pathology that can help us to develop a medicine to remove it.
Modern studies show that amyloid pathology may begin to develop two decades or more before any symptoms emerge. That may sound scary on one hand, but that gives us the window of opportunity of at least 20 years to make change, provided that we diagnose the pathology in time. So if you have the pathology that doesn't mean you’re doomed, you may figure out ways to prevent the symptoms of the disease.
Hersenbank / wikimedia
A healthy brain in comparison with a brain affected by Alzheimer's disease. Of note is the shrinking that occurred as a result of the disease; the brain has decreased in size.
Alzheimer’s Disease Education and Referral Center / wikipedia
The mass loss of cells completely alters the human brain as Alzheimer's disease progresses. This image shows a cross-section of the middle part of a brain at the same level as the ears. The cortex "shrivels", and the affected areas of the brain are the ones related to cognition, memory and planning. The shriveling is especially intense in the hippocampus, as well as in the area of the cortex that plays an important role in new memory formation. The ventricles (hollow spaces in the brain filled with cerebrospinal fluid) become wider.
– Speaking of the prevention of Alzheimer's, is it possible?
The National Academies of Sciences, Engineering and Medicine recently put together a review of what kind of evidence there is for Alzheimer’s disease prevention. And there are a couple of things that look interesting. For example, physical exercise. It appears to be more than just improving your cardiovascular fitness or even more than simply making your body stronger. It turns out that exercise has significant impact on trying to preserve neuronal brain cell structure, and it may potentially reduce some of the effects of the pathology. So a person who’s exercising regularly and actively, even if they have the pathology, they may be able to hold off the effects of that pathology. Another important factor is a healthy diet, and there is a variety of approaches here as well. And when I say diet I don’t mean restricting yourself to eating nuts and berries and things like that. We’re talking about changing lifestyle, choosing a heart-healthy and brain-healthy approach to food and nutrition. There is scientific evidence that healthy nutrition may reduce the risk of Alzheimer's disease and related disorders. There are also behaviors that you could change: people who smoke and drink alcohol seem to have a higher risk for a lot of diseases than those who do not, and Alzheimer's disease is not an exception. And of course, keeping yourself mentally active, or cognitive stimulation, is also very helpful. Even playing games that involve some cognitive activity can help: chess, checkers, cards, maybe even video games. Those things that challenge your brain seem to provide some protection. Social activity is also very important: people who stay engaged in the community, who often interact with other people also seem to have a lower risk of dementia. For example, reading a book is very good, because it's a cognitive activity. But belonging to a book club where you sit around with other people and discuss books is even better because in this case cognitive activity also includes a social component.
So, we already have a certain understanding of what people can do to protect themselves from Alzheimer's disease and dementia in some ways. And then we also have an understanding of the main risks. Obviously age is a tremendous risk factor: the older you are, the higher the risk. People with family histories of Alzheimer's disease are also at higher risk. Even though the disease itself is not genetic in a classic sense when you’re passing the bad gene on, if your parents had the disease it still puts you at a higher risk because you share a lot of the same traits, and you've learned a lot of the good and bad habits from your parents. So if they had a poor diet, and you haven’t changed your lifestyle significantly, then there’s a high chance you will have the same diet. If your parents were smokers or drinkers, you’re more likely to be a smoker or drinker.
Interestingly enough, of all the medical conditions, diabetes may be one of the strongest risk factors for Alzheimer’s disease: possibly it's an even stronger risk factor for dementia than it is for heart diseases or stroke. And if a patient's body is showing signs of insulin resistance, which is the pre-diabetes stage, the doctor can intervene and reduce the risk of Alzheimer’s disease, in addition to improving the insulin problem. The next risk is head injuries. Even if the patient has only had several minor concussions throughout their life, there seems to be a much higher risk for developing this disease. So we need to change the way people protect their heads. I can’t tell you how many children ride their bikes or skateboards or do other similar things without wearing any head protection. And every time you bang your head, you’re putting yourself at risk of developing dementia when you're older.
Besides, the risk factors include high blood pressure, high cholesterol, lipid abnormalities. These things influence your vascular health, and the cardiovascular system is closely linked with the brain. We have blood vessels everywhere in our bodies, including the brain, and most of the blood goes through the brain as well. So even if we simply maintain the healthy condition of heart and lungs, we will already be onto something. Depression and other mental conditions also seem to put people at a higher risk of developing Alzheimer’s or related disorders. There is also a lot of evidence that sleep disorders, such as sleep apnea (a condition of interrupted lung ventilation that often happens to people who tend to be overweight). There are a lot of other things as well for which the evidence isn't great but there’s still some suggestion of them. For instance, if you work on a farm and get exposed to lots of pesticides, that may increase your risk. In other words, the risk factors are very numerous.
– Can we talk about the mechanism of these preventive measures: the cognitive activity, the exercise, changing one's behavior or diet? How does all of it work?
Unfortunately it’s hard to study these things in a human, but what we believe based on a lot of animal studies is that what diet, exercise, social engagement, cognitive stimulation basically do is increase your cognitive reserve, i.e. the reserve of your brain cells and connections between them. The idea is as follows: every person's brain is a large structure consisting of interconnected brain cells, and the connections between them are called synapses. And people who have richer synaptic densities can afford to lose more synapses without any visible harm for their brain's functions before they generate any symptoms.
nobeastsofierce / 123rf
Every person's brain is a large structure consisting of interconnected brain cells, and the connections between them are called synapses.
We also think about how education can protect you from developing Alzheimer's disease. It’s not that going to school or university stops you from forming amyloids. But the more you use your brain – solve mathematical problems, enhance your mental activity, learn words in a foreign language. etc. – the stronger the connections are between your cells. Even if a person has already left formal schooling, it’s not about how much schooling they had, it’s about what they do with it afterwards. If that person continues to read, stays mentally engaged, tries new things, learns new skills, takes up new hobbies, their brain will definitely benefit from that. You can have a Ph.D. in astrophysics, but if after receiving it you sit on a couch all day and do nothing, you will soon lose all the benefits of that. On the other hand, you could have a 4th grade education, but by exposing yourself to constant new types of experiences such as music, literature, games you will gain a lot of brain strength and by the time you're old you are likely to build a very strong brain that will be able to resist dementia. Of course we can’t always control how many years of schooling people have, because sometimes economic factors enter into that. But it is never late to learn how to train your brain. Let me give you one example: my father has a 9th grade education, because of the economics. He had to drop out of school to support his family. And I remember that as I was growing up I never saw him reading a book. Now he is 70, and reads the books even I wouldn't read. He just finished James Joyce’s ‘Ulysses’. I can't read 'Ulysses', it's too difficult for me! And even regardless of how much of it he understood, but the fact that at 70 he took a thick modernist novel and went through it, speaks for itself. So his 9th grade education is irrelevant here. What is relevant is that he's keeping his brain active.
And as for physical exercise, it makes your muscles release a whole host of substances called neurotrophic factors. These factors not only support muscle health but they also support brain health. In addition to that, brain health may be supported by insulin, by vitamin D (the one that you get from standing in the sun) and many other substances. And the more things support brain health, the more brain can tolerate some of the changes that occur.
And by the way there is one more thing you should know about physical exercise: the secret of its effectiveness is that you have to combine three types of it. There is aerobic activity (like walking or jogging) which has good cardiopulmonary effects but it doesn't do anything for your muscle mass, anaerobic activity (such as resistance training or power-lifting) that helps to build your strength, and flexibility training (like yoga, tai-chi, pilates, etc.). So to really gain benefit for your body you need to do a combination of all these three types of exercise. Some people think exercise is exercise, so it doesn't matter what you do as long as you do it. But that’s not true. To gain actual benefits from it, the physical exercise should be diversified. And the same goes for cognitive and social activity: the more diverse it is, the greater the benefit for the brain health.
About 40-50% of people who die of old age but with no symptoms of dementia, have amyloid pathology in their brains. So they live long lives and do not develop the disease. And we can learn a lot from studying the difference between those people and the people who do develop the symptoms. In other words, we don’t know the exact reason, but we suspect that the more of these diverse activities you are doing, the stronger brain you are building. And a stronger brain can withstand a whole host of bad things.
– What do you think is the age at which a person should start thinking about the possibilities of Alzheimer’s disease, dementia and other related disorders?
At birth! It’s never too early to start thinking about that, that I can tell you for sure. Never too late either. I think that what we need to do as health professionals is to encourage our patients to start thinking about these things very early on, and the earlier we start working with these patients to develop a strong brain, the more effective this work will be.
Of course, you can come to me at the age of eighty, and there would still be many things we can do. But we can do a lot more if you come to me at fifty. So it's never too early and it's never too late, but earlier is definitely better.
– Could you tell us about your own projects related to dementia and other similar disorders? How did you take interest in this particular problem?
I took interest in it a long time ago, in the beginning of my career. For many years my research was focused on what is the best way of making the diagnosis of these diseases, on screening tools that can be used in a general health setting rather than just at research centers. So I have projects funded by our National Institutes of Health and the Harry T. Mangurian Foundation where we had to go out into the community and did some screening for dementia. But if you just approach some people you don’t know in the community and tell them you want to check their memory, they usually don’t like that very much, it’s frightening. So instead we designed a program here at Florida Atlantic University that had something like a “healthy body, healthy brain” approach to it. We started to invite people for free screening for diabetes, high blood pressure, bronchitis, COPD, depression and other things. So we examined the entire organism, and people agreed to that willingly. And as we started to look at the data, what we saw was that people who were having worse performance on the brain screening test also had worse metrics of their general health. We began to compare the results and look at some of these relationships between them, and we found some very powerful and interesting things. For example: people who have low muscle mass and low muscle strength or reduced mobility perform much worse on cognitive tests than people who have good mobility. But it raises a question: did poor muscle strength cause dementia, or did people who were developing dementia stop exercising? So, before proceeding any further, we had to answer this "chicken and egg" question. We started diving into this problem and we saw that even for people who do not have dementia, as they lose their muscle strength with age, their cognitive performance declines. But then they also become unable to exercise properly, so one leads to the other. We also looked at their sugar level, their lung volumes, their blood pressure, and we found that it wasn't a simple “1+1” equation, it was a complex algebraic problem with lots of different factors and variables. We decided to figure out how we could understand this problem a little better to solve it, so we began examining groups of individuals who do not have any documented problems and look at their health in general. And we found that even little changes in their exercise, their diet or their blood pressure caused them to subjectively report that they were feeling better, but also their test scores improved.
Charles E. Schmidt College of Medicine / FAU
Charles E. Schmidt College of Medicine / FAU
The Comprehensive Center for Brain Health at Florida Atlantic University conducts advanced research that includes deep phenotyping of the patients, creating their full health profile.
After some time we took up some principles of what’s called ‘precision medicine’, which is widely used in cancer treatment: they take a piece of the tumor of a cancer patient and look at all of its genetic markers and then design a special chemotherapy treatment based on that tumor. What you get is a highly personalized approach. Of course we can’t take a piece of a person’s brain, but we can use the same principle. Here is what we do: we look at all health aspects of the patient, compile their full health profile, and design a personalized treatment program for them.
And the second part of this equation is as follows. At an earlier time in my career I used to work with animals, transgenic mice specifically. Transgenic mice are genetically engineered mice: we take a regular mouse and we put a gene in it. We can pick a gene for Alzheimer’s disease, for Parkinson’s, etc. And this gene would have some pathology similar to a human disease. But the thing is, all lab mice are very similar to each other: they have the same genetic background, they live in the same cages, you give them the same food, they have the same access to water, the same amount of light, the same amount of exercise. Then we take a half of those mice and we give them some medicine. The other half we don’t do anything to, we give them a placebo. And we see that the medicine works really well in the group of mice that received it. But then you give the same medicine to people, and it doesn't work! Why is that? Because mice are almost identical, while people are different. Think about this: if you have 20 people and we want to treat their disease, you will have 20 completely different cases. For instance, person number one of these twenty has diabetes, hypertension and is a smoker. Person number two has a head trauma from playing soccer. Person number three has life-long depression. Person number four is a vegan, marathon runner and a college graduate. And so on. And if you give these 20 different people the same medicine, guess what's going to happen? They are going to respond in 20 different ways. So I came to this idea: why don’t we take people and make them more like those lab mice? Make them a little more alike. And it is possible, though not to the same degree as with mice. Moreover, that is exactly what we are doing at the moment. We take each individual and examine their risk factors, and then draw up a full health profile for that individual. Then we start to reduce the heterogeneity of the test group and make them more homogeneous. We can’t actually make them the same person, of course, but, for instance, if we take a person with high lipids, we can reduce their lipids. Then we take another person who doesn't have enough physical exercise, and we give them exercise. Then we take someone who is overweight and we give them a healthier diet. And this way, bit by bit, these people start to become a little more similar. And the medicine - incredibly! - becomes more effective, working in the same way for each of these people. So what we do is two things. The first one: we do the deep phenotyping of the patients, which is an individual assessment of their health. And it’s not just superficial, it’s a very long examination where we look at all aspects of their health: the health of their eyes, ears, brain, lungs, liver, kidneys, their cardiac health, etc. You've got your blood and urine tests, your MRI, all kinds of scans, physical and cognitive testing, psychological profiling, assessment of these people's personalities, their willingness to participate in experiments, how considerate they are of the world around them. And then we put all of these data together and we say to the patient: "Okay, we have collected all the necessary information on you, your complete medical profile, and here's how we're going to change you." And then we follow it up with a combination of medicines and non-medicinal treatment, lifestyle changes, health coaching, psychotherapy, exercise and many other things. We have only been doing this for 6 months now, but even within that time we have managed to dramatically change these people's health. I am even amazed of that myself! If you had told me twenty years ago that I would be talking about the benefits of yoga and vitamins for Alzheimer's disease prevention I would have laughed in your face! But people actually feel much better after all these things, and, as if that wasn't enough, we also measure improvements in their cognitive performance. We see reduced inflammation, we see better lipid profiles, less insulin resistance, and that’s reflecting to better cognitive performance. And the second part is that the group of those individuals (they will have amyloids in their brains) are put into clinic trials for innovative anti-amyloid and anti-tau medications.
And I think that this is a unique approach, because it's a combination of the holistic approach with the use of medications that are being tested across the world. Can we prevent Alzheimer's disease or dementia with that? It may be too early to say for sure, but I'm sure that the answer is yes.
For instance, I have a patient who came to us, and she was very concerned about the deterioration of her memory, though her family hadn't noticed any changes. When we brought her in, she was very thin and had very little muscle mass. She was indeed a little forgetful, but she did much better in the tests when we gave her clues. She had very high inflammatory levels as well, and the MRI registered the beginning of some changes in her brain. So we put her on anti-inflammatory protocol. We changed her diet, we gave her a personal trainer who started building up her muscle mass, we started giving her some counseling and psychotherapy in order to help her change her lifestyle. And you know what? She doesn't have any complaints anymore! Her memory and her mental health improved, but her physical health improved even more! Another gentleman in his 70s came to see me, a very successful businessman who had some concerns about his risks to develop Alzheimer's disease. What we found was some changes suggesting the early signs of diabetes that his doctor had not picked up. He also had some digestive problems, but his cognition was normal and his MRI showed no problems too. We put him on a gluten-free diet, we took him off dairy products, and prescribed him a variety of probiotics. We found that he had some slight vitamin deficiency, too, and we started giving him the active forms of the vitamins. Then we also found that his blood pressure wasn't as regulated as it could have been, so we tried to alter that. And again, this immediately yielded good results: all of his gastro-intestinal symptoms went away, his energy improved, the patient was able to get back to exercising.
Of course, these are all only anecdotal stories at this point, while we want to see the long-term effects of our program, to come to some big and important conclusions. But we already see significant effects of this complex treatment on the lives of those people who come to us.
Charles E. Schmidt College of Medicine / FAU
Charles E. Schmidt College of Medicine / FAU
– In conclusion, how do you think dementia and Alzheimer’s disease prevention research will develop within the next 15 years or so? And what do you think needs to be done primarily? What should the very next step be?
I think that now we’re very good at making diagnoses in specialty centers, but not very good at making them outside the specialty centers. And I'm sure that this situation is not only true for the USA, but also for a lot of other countries of the world. For instance, at your top medical schools in Moscow or St. Petersburg you also have highly qualified experts in medicine, neurology, geriatrics, and psychiatry. And they are capable of making expert diagnoses of very difficult conditions at the earliest stages of the disease. But for a general practitioner at some rural part of the country it’s very hard to do the same, because they don’t have all those tools available. And what we need to do now is to figure out how to translate that university expert experience to the use outside of universities and expert medicine centers.
Today a lot of people have access to the Internet, and this may soon become the basis to develop platforms for making early diagnosis. There are several companies now that are already designing apps that would allow people to do that on their own. Even right now it’s possible to do a lot of health monitoring with computer and phone apps. For example, you can measure your blood pressure by recording the pulse wave from your finger when you press it against your mobile device's camera. And if someone can create an app that would let us analyze an entire set of metrics, then patients won’t have to travel to another city to get to a specialty center but instead they will be able to sit at home with their phones or computers and diagnose themselves. So, if we meet again ten years from now to talk about dementia diagnosis, then I think that conversation will be very different, because the technological advances will make all the things I do now in my office available for you to do at your homes. Or maybe not all of them but at least quite a lot of them. And of course I really hope that this is going to be complemented by some new medication to be designed that could possibly reduce the risk of developing Alzheimer's disease.
I think that a certain role in this can be reserved for educational institutions, and it's mostly the role of raising awareness. Because the more people know about this problem and how to protect oneself from it, the better. In medicine there are things that you get regardless of your situation. For example, everyone gets colonoscopy at age 50 in the USA. But still medicine is mostly a consumer-driven industry. Your doctor will never ask you about your big toe unless you come to him and say “My big toe hurts”. Only after that they will start to examine you and will eventually find out that you have a slipped disk in your back. But you've come to see the doctor on your own initiative. Otherwise the doctor wouldn't ever know about your slipped disk. So education on the public side can help people treat their own health more responsibly, understand more about it. People have to come to the doctor and say: “I want to talk about my mental health, about my memory, I want to prevent Alzheimer's disease.” And people can’t really do that unless they are educated about the disease. So I think that education is a really powerful way of getting people and physicians to discuss these things until it’s too late to do something about it.
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