With the rise of genetic testing, many people wonder about their genetic risk for Alzheimer’s. Carrying two copies of the ApoE4 gene could increase your lifetime risk of developing Alzheimer’s by 91 percent. Those who carry the PSEN1, PSEN2 or APP genes will develop a form of early-onset Alzheimer’s disease. But are there genes that could protect you from developing Alzheimer’s, and could lifestyle changes alter the course of your genetics?
- While the ApoE3 gene is the most common, appearing in 75 percent of the population and believed to play a neutral role in developing Alzheimer’s, research suggests that carrying the ApoE2 gene may protect against Alzheimer’s
- Researchers are still looking into the role that brain-derived neurotrophic factor (BDNF), the group of proteins responsible for growth of nerve cells during development, plays in Alzheimer’s disease, but some studies suggest certain variants may protect against dementia
- Studies have found that epigenetics, or modifying environmental and lifestyle factors to alter how your genes interact with one another, could also reduce Alzheimer’s risk
Being Patient spoke to Dr. Nathaniel Chin, Director of Medical Services at the Wisconsin Alzheimer’s Disease Research Center, about how certain genes impact Alzheimer’s risk, why lifestyle changes could prevent cognitive decline and whether Alzheimer’s researchers are more focused on prevention or finding a cure.
Being Patient: What do researchers know about how genetics could impact Alzheimer’s risk?
Dr. Chin: We use genetics in most of our research to assess the participants that enroll in our studies. We know that there are certain genes that are very much associated with the development of Alzheimer’s disease, and so knowing whether people have those genes is important in determining whether the other factors that we’re looking at play a role as well. So we need to control for the presence of those. In particular, we look for for ApoE and more specifically, ApoE4. That has a very well-researched genetic linkage to the development of Alzheimer’s disease.
Being Patient: What do researchers know about how ApoE4 is related to Alzheimer’s?
Dr. Chin: There are three versions of ApoE. There’s ApoE2, ApoE3 and ApoE4. ApoE3 is the most common version in the population and that is what we would consider to be a neutral risk. If you have ApoE2, some research suggests that is a protective factor in the development of Alzheimer’s. ApoE4 increases your risk for developing Alzheimer’s. There are two versions: You get one copy from each of your parents. You could have any combination of the two. We know that there is an increased risk with one version of ApoE4—many studies say 2–5 times the risk, and then if you have two copies, or one from both of your parents, then it’s about 12–15 times the risk.
Being Patient: What is the exact function of ApoE in our bodies?
Dr. Chin: ApoE is related to cholesterol transport throughout the body, so it can be made in the liver as well as in the brain. It is what truly carries around our “good” cholesterol from the liver, throughout the rest of our body, and into our brains, where our brain uses it, or all of our cells use it, to build the material of our bodies. There is an association between certain versions of ApoE and cholesterol use within the brain.
Being Patient: What is it about ApoE4 and the transport of cholesterol that increases Alzheimer’s risk?
Dr. Chin: Researchers are constantly looking into this question. There is a lot of research going into the underlying pathway for how ApoE4 relates to Alzheimer’s and it’s a worthy thing to investigate because of that strong association. The more we know about it, the more we can understand the pathways and then eventually, develop targets to intervene. ApoE4 is related to brain cell health—so, whether or not our brain cells have enough of the structure to be a solid cell; it relates to our synapses, which is the connection between cells, and that’s how our cells communicate. We know that ApoE deals with the maintenance and the health of those connections. There’s more and more evidence that ApoE is also related to vascular and blood vessel health between our brain cells and what feeds our brain health. The more we look into it, the more we see how related it is to so many different functions within the brain.
Being Patient: How close are researchers to providing personalized risk reports, based on genetics, beyond looking at ApoE4?
Dr. Chin: That’s a tough question. We are getting closer and closer to developing what we call polygenic risk scores, or really just scores that include genetics and other factors. We’re much closer now than we were years ago, but to the point where it would be available for the public—I think that would be years from now. I think a lot of that is because we should be very certain what it is we’re looking at before the general public has access to it because we don’t want to make mistakes or to lead people down the wrong path, scaring them or inducing other side effects without knowing what it is we’re studying.
Being Patient: Several early-onset genes have been identified in addition to ApoE4, including PSEN1, PSEN2 and APP. Do these findings suggest there could be more genes that may elevate our risk of developing Alzheimer’s?
Dr. Chin: I think these studies are showing that there’s a lot more to the picture than ApoE. We are going to find more and more of these genes—maybe not to the same degree that ApoE is, but that will have their own role and they’ll work synergistically for or against the development of Alzheimer’s.
A recent study had hundreds of thousands of people in it, and they used a family history as their phenotype, meaning they took a look at a group of people and divided them between whether they had a family history or not. Then they looked at their genetic code and for specific gene mutations that were more associated with Alzheimer’s than not, or a family history or not. It doesn’t show a causal relationship; it doesn’t mean that these genes cause Alzheimer’s, but it showed a signal that they’re more associated with each other, and I think it’s important that we’re careful about that. Researchers discovered three new genes; two of them dealt with blood pressure and one dealt with a clotting factor. Frankly, the blood pressure one made a lot of sense. A lot of studies show the relationship between blood pressure and Alzheimer’s, and blood pressure and the development of the protein that leads to Alzheimer’s. I think we’re getting closer to finding more solid evidence for other genes, but I don’t think we’re at the point where we can say definitively that it’s ApoE, it’s this, and it’s this.
Dr. Chin: At our institution, we spend a lot of our energy focusing on modifiable risk factors for prevention and improving cognition among those who already have cognitive impairment. I think as a whole continent, we need to focus more on prevention and healthy behaviors and less so on the consequences of knowing your genetic risk. There are many people I’ve encountered who are very frustrated with the health care system, how they’ve been treated and the plans that have been made after the diagnosis. I think it’s taking time, but hopefully, we are having a shift in the health care culture and focusing on behaviors, prevention and just a meaningful way of living so that we all can age the best way possible.
Being Patient: Various studies look at how certain regions have a lower incidence of Alzheimer’s, even in areas where many people have the ApoE4 gene. Are scientists focusing more on how genes or lifestyle increases Alzheimer’s risk?
Dr. Chin: You’re speaking to something that science is very much investigating: epigenetics. We are not just our genes. Our lifestyles modify what our genes do to us. Epigenetics is this idea that we can activate and deactivate different genes based on how we live; those genes could then interact with other genes, such as ApoE, and really, a person’s genes are very unique because of how they’re living their lives. So that example of the population in Africa, as well as the five blue zones throughout the world, we’re seeing that it isn’t just your genes—it is your lifestyle. We can’t necessarily change the genetic code itself, but we might be able to change how that genetic code translates to our bodies.
Being Patient: When we talk about genetic risk, are we talking exclusively about Alzheimer’s, or dementia in general? Are there different genes associated with different types of dementia?
Dr. Chin: Yes, there are. ApoE is specific to Alzheimer’s disease because of ApoE’s association with the amyloid protein. The amyloid protein is the one that is abnormal in the brain that eventually leads to further changes and what we would describe as Alzheimer’s. There are other genes related to Parkinson’s disease and Parkinson’s can cause dementia later on in life, as well as Lewy body dementia. Then there’s frontotemporal dementia, and there are some genetic associations. These are not as strong as ApoE is to Alzheimer’s, but these are still being actively investigated as well.
Being Patient: What do you tell patients who have an elevated risk for Alzheimer’s because of ApoE4, or the early-onset genes, about what they can do to lower their Alzheimer’s risk through lifestyle?
Dr. Chin: I have a very specific plan that I talk to my patients about. Most of if, if not all of it, is based on the research that is currently being done—a lot of it at our own center here in Wisconsin. First and foremost is physical activity; publications come out on a weekly basis that show those who are physically active end up doing better. We know that’s for the heart and vascular system, but we’re also showing evidence of physical activity and its effects on the amyloid protein that leads to Alzheimer’s. The first and most important thing I tell my patients is to get up and move. Any movement is good movement, but I really want people to raise their heart rate and to be physically active: moderate physical fitness.
I also talk about diet. I think diet and what we eat is extremely important, and we have lots of research on that. There is the MIND diet by a Rush University professor, Dr. Martha Clare Morris, who came and spoke at our center and has really shown a lot of promising results in her research, which is a combination of the Mediterranean and DASH diets. I also talk about the importance of being social. We know that people who are social can have an improved mood because they are challenging their brains and enjoying their quality of life. Sleep is another factor. There’s a list. Of course, not smoking is important. I have had success in getting people to taper down or quit smoking. You just have to find the right ways to motivate people and I think this concern about aging and dementia is a strong motivator.
Being Patient: Have researchers looked at how much exercise people need to do to maintain a healthy brain?
Dr. Chin: You’re right, it’s too generic to just say that you need to exercise, and in my clinic, I go much further into that. The American Heart Association recommends 150 minutes per week of moderate aerobic activity. I recommend to my patients who are over age 65 that that’s the goal and what we’re working towards. It doesn’t mean starting tomorrow, that’s what you have to hit, but the goal is roughly 30–40 minutes per day, 5–6 days per week so that you can hit 150 minutes. When I say moderate aerobic activity, that really means that you’re reaching 70–75 percent of your maximum heart rate. In our research center, we do the Talk Test. If you can do an activity and you’re able to talk and sing, that’s considered light aerobic activity. That’s good, but that isn’t what we’re looking for. If you can’t talk or sing, that’s considered vigorous. That’s great, but you could do a little bit less. Moderate is being able to talk and not sing. I have this conversation with my patients; I’m really looking for that sweet spot. If you can do vigorous, I’m all for it. I think the more, the better, but for safety’s sake and just so we know what we need to reach, moderate aerobic activity is good.
Being Patient: When people are diagnosed with MCI or Alzheimer’s, is it too late for them to make lifestyle changes since plaque has already built up in the brain decades before Alzheimer’s symptoms appear?
Dr. Chin: Research is still looking into this, so we’re not entirely sure. Some studies have shown benefits of exercise alone for people who are walking at a fast enough rate for their heart rate, and that their course is better than those who don’t. There’s a well-known international study called the FINGER study. They combined exercise, diet, health promotion and education; over a two-year course, participants also performed better on certain testing. So there’s evidence that points to lifestyle changes having a meaningful impact, even after you have developed symptoms of cognitive impairment. I tell my patients that even if I’m wrong and the physical activity, diet and social activity that I’m prescribing to you doesn’t change your course, in the end, I’m improving your function and quality of life and that is the meaning that we’re looking for as we’re getting older.
Being Patient: Can you give us an idea of how important it is to understand how our genetics are related to Alzheimer’s to push us towards finding a cure?
Dr. Chin: Genetics are part of the biomarkers. Other biomarkers include the protein that I’ve referred to, amyloid, and then amyloid actually induces another protein called tau. Then those two together lead to cell death and the breakdown of our cells, which we would call neurodegeneration; that simply means our cells and the brain are dying. So those are biomarkers. Those can be obtained by PET scans, imaging scans or lumbar punctures. We’re also looking into ways of using simple blood tests to look for some of these.
When we look at all of these biomarkers together, this is how we’re studying the pathways to the development of Alzheimer’s disease. The more we know about our genetics, the more we know about these biomarkers and can figure out what the different factors that lead to Alzheimer’s are, when they come into play and the things we can do to stop the disease’s progression to produce meaningful results.
Being Patient: When people have the early-onset genes, it’s discussed as if they’ll definitely get early-onset Alzheimer’s. Can you tell us about the difference between those genes and ApoE4, and whether the former group is even more helpful to research?
Dr. Chin: The early-onset population is critical to research because they have a higher certainty or risk of developing Alzheimer’s. I use the word risk there, but when a person has a family member with early-onset, they have every right to go and meet with a genetic counselor to discuss the reasons, risks and benefits to getting a genetic test.
You’ve already mentioned the early-onset genes: PSEN1, PSEN2 and APP. Those three are very well known and studied. There’s lots of studies going on nationally in that population. People can go and have that genetic test done. That isn’t done through a direct-to-consumer private organization, so you can’t get that through 23andMe, but you can get that at a university in your state or at certain health care institutions. There is value to that if a person is prepared for that knowledge. I say that because of those genes I mentioned, you only need one of them to develop Alzheimer’s disease. With that risk or level of certainty, there’s a lot of consequences.
Being Patient: Researchers say comorbidities raise your risk of Alzheimer’s, which suggests that Alzheimer’s may be a by-product of something else going on within our bodies. Is it important to analyze the connection between the risk of developing other diseases and linking these findings back to Alzheimer’s?
Dr. Chin: Absolutely, and I think the idea of what we call multi-morbidity, or having multiple diseases, relates to what you mention. With Alzheimer’s, I think it’s critical that we don’t have this pristine population of a person with no medical problems who develops Alzheimer’s, but instead, a real population with 5 to 10 medical problems and people on 20 different medications so that we know what all the factors at play are. This really speaks to the idea of all the different genetics. What we’re finding is that there’s not one clean disease with Alzheimer’s; there’s different flavors to it and there’s many reasons for the development.
Being Patient: Researchers believe ApoE2 could provide a protective factor against Alzheimer’s. Is there anything else in our genes that reduces our risk of developing Alzheimer’s?
Dr. Chin: There are studies showing that this gene called BDNF, which leads to the development of new brain cells, has certain variants that are protective against Alzheimer’s. We are also looking at other genes that are related to anti-inflammatory properties. It’s not just about the negatives with our genes. There are positive things too. Looking at people who have lived over 100 years and don’t have any cognitive issues, we know there might be some genetic variants to them that shows this idea of protective or resilience as far as their cognition goes.
Being Patient: What do we know about BDNF and how much research has gone into it in terms of its protective benefits against Alzheimer’s?
Dr. Chin: We’re currently assessing the protective benefits of it because like ApoE, where there are three different versions, we know that there are different versions of BDNF, or as we call them, mutations. We’re still looking into, what is it about one version versus the other that makes it protective? How protective is it?
Being Patient: Regardless of genetics, should everyone just be living a healthy lifestyle to prevent Alzheimer’s?
Dr. Chin: As of now, there’s not a lot we can do that’s unique to people who have ApoE or any genetic risk factor. At the end of the day, a person living a life filled with meaning and activity, whether it’s physical or social, is doing the best thing as far as prevention. Hopefully with these genetic studies, we can figure out more pathways and interventions that may not require medications, but will reduce our risk.