Age is the greatest risk factor for Alzheimer’s disease, but who and when it strikes is unpredictable. Recent research can help us understand how brain changes, genetics, gender, and environment and lifestyle factors affect risk for Alzheimer’s disease. Guest: Elizabeth Mormino, PhD, assistant professor of neurology at Stanford University.
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Transcript
Introduction: Welcome to Dementia Matters, a podcast presented by the Wisconsin Alzheimer's Disease Research Center. Our podcast is here to educate you on the latest research, caregiver strategies, and available resources for fighting back against Alzheimer's disease. I'm your host, Nathaniel Chin. Thanks for joining us.
Nathaniel Chin: Welcome back to Dementia Matters. I'm here with Dr. Beth Mormino. Dr. Mormino earned her PhD in neuroscience at UC Berkeley, where she performs some of the initial studies using amyloid PET scans in clinically normal people. Her work contributed to the evidence that the Alzheimer's disease process begins years before symptoms start. In 2017, Dr. Mormino joined the faculty at Stanford University where she now focuses on combining imaging and genetics to predict cognitive trajectories over time. Thank you for joining us, Dr. Mormino.
Beth Mormino: Thanks, Nate, for having me here.
Nathaniel Chin: So to start I really want to lay some groundwork and provide some background information for our audience. Can you talk to us about the amyloid protein that you research, and who has it in the population?
Beth Mormino: The amyloid protein is a smaller protein from a larger protein called the amyloid precursor protein. This is a normal protein that's found in everybody's brains, even fetuses have this protein. For unknown reasons it kind of goes haywire in the context of Alzheimer's disease and builds up. There's a lack of clearance that's thought to happen, and these amyloid proteins eventually become deposited in these plaque structures, and these plaques have been associated with Alzheimer's disease dementia.
Nathaniel Chin: So it's really important for us to hear; everyone has the amyloid precursor protein. Does that mean all of us have the amyloid protein, this beta amyloid?
Beth Mormino: Yeah absolutely. We're all producing this smaller amyloid fragment, and we don't really know what it does. We know it probably has a normal function in the brain. We don't quite understand that, and we don't understand why it starts to accumulate at a rate that seems to be not normal given its association with Alzheimer's disease dementia.
Nathaniel Chin: But, then it is normal for our brains to clear it?
Beth Mormino: The idea is that we're producing it, and then we should be clearing it at a certain rate. I think understanding why this isn't happening, and how this leads to dementia, is obviously of great interest to the research community.
Nathaniel Chin: You are showing very interesting findings with amyloid and cognitive decline. You also happen to be combining genetic risk, and so I did want to ask you about that. People come to my clinic with results from at home genetic tests and they tell them these results say they carry a certain risk for Alzheimer's disease. But from your perspective as a scientist who studies brain science and genetics, what's the rest of the story with genetic risk and these available tests?
Beth Mormino: I think this is a very important question in the field right now, and I think on the one hand it's very exciting that we have so much data and that individuals can get that data. It's very, I think, empowering from the patient's perspective, and also from the individual and the community's perspective, that we can start to understand this data with respect to ourselves. I think that in general in medicine where we're going more toward that model rather than having physicians acting as a gatekeeper to that information. I think that's really exciting. I think for Alzheimer's disease specifically, these genetic risk factors are just risk factors. If you're say positive for something like APOE-e4, which is the most established genetic risk factor of late onset Alzheimer's disease, that does not mean you're going to get Alzheimer's disease. I think there needs to be an awareness that it's a risk factor, it's not something that will cause the disease with 100 percent penetrance. So that's something that is important to keep in mind with interpreting these genetic results, that it's simply a risk factor. The biggest risk factor for Alzheimer's disease is aging. That's a risk factor we all are going to share over time. I think with the interpretation of these genetic results, I think it's potentially empowering but I don't think that they should be over interpreted especially the individuals person level. If you are a normal person with good cognition and you get the unfortunate result that you're positive for one of these risk genes, I think it's important to do the research or talk with your physician and really understand what the actual risk is. That this is not a sentence, that you are going to get Alzheimer's disease -- it just elevates your risk to a certain degree over a pretty long follow-up period. I think that information might change over time as we learn about more genetic risk variables, and perhaps combining different genetic risk factors to really come up with a risk score for an individual. I don't think we're actually there quite yet to really, with high confidence, be able to grab a genetic profile and predict for that person what their risk of dementia is in a 5- to 10-year window.
Nathaniel Chin: It just seems to me that Alzheimer's disease is such a complex process. Then it makes sense that there's a complex network of genes, but now you're saying too that it's not just the genes, but something else is at play as well.
Beth Mormino: Yeah or it might not be the genes that we're measuring. We tend to focus on genes that are common. So variants, like APOE, for instance, will be found in 20 percent of the population or so, APOE-e4. As some of these other variants we're looking at are also very common. Many people have them but there's also ideas that it could be these rare variants that are driving a lot of disease, and those are really hard to measure with the current technologies. You really have to do a whole genome sequence to get out rare variants. You know you could imagine a situation where there's thousands of rare variants that cause Alzheimer's disease that are spread out across the population. Finding these rare variants would be quite difficult. It could be that the genetic component is large, but we haven't discovered these genetic variants just yet, because they're very rare. They also might vary by genetic background. For instance, most of our studies are completely focused on European samples, and this is more of a huge problem with research in general. It tends to be the case that in many of these university settings it's super educated European individuals that volunteer, and we know there's some genetic diversity across different groups of people. It's been shown that when you look at genetic risk factors in self-identified whites compared to blacks, for instance, different genes show up for their association for Alzheimer's disease. I think we have a lot to learn on the genetic basis of what is driving this disease.
Nathaniel Chin: Now you have a paper coming out in Neurology looking at genetic risk and its impact on amyloid and cognition. What did you find in your investigation?
Beth Mormino: In this study we found a few interesting things. I mentioned earlier that we have these different genetic risk factors for Alzheimer's, and they don't necessarily directly relate to amyloid itself. Which is a little counterintuitive, because we think of amyloid as being so central for Alzheimer's disease. What we found is that this genetic risk kind of score, it's an aggregation across many different genetic factors, wasn't really related to amyloid at all. Even if you had a high genetic risk score, that didn't indicate that you're more likely to be elevated in terms of amyloid; but what it did tell us was that if you had elevated amyloid and also a high genetic risk score you declined faster. It suggests, and you mentioned this earlier, this idea that Alzheimer's disease is this complex phenotype and there's a lot of stuff going on. I think the combination of genetics and imaging and the improvement of prediction in that space really suggests that we need to combine these different modalities to truly understand who is at risk. I don't think it's going to end up being a simple one factor. It's not going to be just amyloid or just genetics. It's going to be the combination of these events that is driving the disease and our ability to identify who's truly at risk.
Nathaniel Chin: In another study that you've published this year, you looked at gender, amyloid, and cognitive decline. Now you had some very interesting results there. Can you tell us about that as well?
Beth Mormino: This paper was quite interesting in the sense that it's been established that women seem to be more at risk for Alzheimer's disease. There's ideas, there's a lot of debate about this. We know women live longer, for instance, and age is the largest risk factor for Alzheimer's disease. It could just be simply the fact that women are living longer so more likely to get AD. We also know from autopsy work that women seem to sometimes have more pathology than men. It seems that there tends to be just these slight differences in women and men when it comes to risk factors for AD. Few studies have really been able to explore this as a function of amyloid status. That's what we set out to do in this study, and what we found is that women were not more likely to have elevated amyloid. When they did have elevated amyloid they declined faster. It implies that there's some heightened vulnerability to women when they're confronted with this pathology. We don't understand the mechanisms underneath this at all, but it does have a couple of important implications. You know one is that you know women and men throughout the lifespan obviously have very different courses. There's the hormone kind of changes, that's an obvious one, and then there's also the genetic differences as well. It could be that there are these amyloid genetic interactions that differ across the sexes that cause women to be more vulnerable. It could be something about menopause and in midlife where we know a lot of these pathologies are starting to accumulate. That's obviously different for women and men but it implies that we might need to --when we decide both our research studies and clinical trials -- that we might need to consider sex as kind of a basic factor that influences trajectories. You know if women are declining faster, we in clinical trials, we might need to look at groups separately or at least make sure it's counterbalanced and in that sort of way. I think it will be really interesting going forward, especially from the basic science perspective, to try to understand what actually is the mechanism. Why is it that amyloid seems to be more consequential to women than men in terms of cognitive decline?
Nathaniel Chin: Where does tau burden fit into disease and people without symptoms?
Beth Mormino: In Alzheimer's disease we tend to think of these two pathologies. Amyloid, which we've talked about a lot in this podcast, and then also tau, which forms these neurofibrillary tangles in the brain. Then in Alzheimer's disease dementia we typically have these two proteins, but we know that both these proteins start to accumulate well before symptoms. Amyloid for sure, and even tau, it also starts to accumulate before individuals have symptoms; giving us the opportunity to understand that the contributions of these two proteins to decline. Interestingly the tau it seems to for reasons we don't understand really, begin in the medial temporal lobe, which is the brain regions involved that are critical for memory. Being able to remember what you ate for breakfast yesterday or what you did last week. For some reason it begins to accumulate there. With recent advancements in imaging we can now actually look at this protein. We didn't have this before the last few years or so. Now we can do PET scans that tell us both about elevations in amyloid and also in tau. What we're finding is that in normal older individuals some of them will see this elevation in amyloid and also some of them will start to see this tau in the medial temporal lobe. It's very kind of early sign of the second pathology, and so far what is suggested is that the subset of individuals that have this early tau seem to be the most at risk for memory decline. Which makes sense because that's the brain regions that are the most involved for memory. It's exciting because even though you know it's kind of scary to think about getting a scan and to learn that you have this pathology in this region, but it's so restricted. When you look in Alzheimer's disease the tau is really everywhere throughout the brain. In normal individuals even though it's a little bit of signal in the medial temporal lobe and it seems to be bad for memory, I think from a drug targeting perspective it's really exciting because you're able to capture it when it's so focal. If we ever did have a treatment that stopped tau accumulation it seems like that would be the ideal time to really intervene, to find people that have this just beginning signal that we think is bad and stop it before it spreads to the rest of the brain. Which that probably is a critical event for dementia actually losing the ability to function in everyday life.
Nathaniel Chin: Well with that I'd really like to thank you for being on Dementia Matters, and the next time you're visiting we'd like to have you on again.
Beth Mormino: Well thank you. Thank you so much for the invitation.
Nathaniel Chin: Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center. The Wisconsin Alzheimer's Disease Research Center combines academic, clinical, and research expertise from the University of Wisconsin School of Medicine and Public Health and the Geriatric Research Education and Clinical Center of the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. It receives funding from private, university, state, and national sources including a grant from the National Institutes of Health for Alzheimer's Disease Centers. This episode was produced by Rebecca Wasieleski and edited by Bashir Aden. Our musical jingle is Cases to Rest by Blue Dot Sessions. Check out our website at adrc.wisc.edu. You can also follow us on Twitter and Facebook. If you have any questions or comments, email us at dementiamatters@medicine.wisc.edu. Thanks for listening.
