Studies Look at Generational Differences and Associations between Cognition, Sensory Changes and Blood Biomarkers

Transcript

Intro: I'm Dr. Nathaniel Chin, and you're listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us. 

Dr. Nathaniel Chin: Welcome back to Dementia Matters. Today I'm joined by Dr. Natasha Merten, assistant professor in the Department of Population Health Sciences and Department of Medicine, Division of Geriatrics and Gerontology at the University of Wisconsin–Madison. In August 2022, Dr. Merten published a paper on generational trends in cognitive function, which found that younger generations, such as the baby boomer generation, have better cognitive function than older generations like the greatest generation, those born between 1901 and 1924. Additionally, Dr. Merten was a presenter at AAIC 2022, showing results from her study on associations between sensory and motor functions and blood-based biomarkers for Alzheimer's disease and neurodegeneration. She joins us today to discuss her work studying sensory and cognitive aging and dementia. Dr. Merten, welcome to Dementia Matters. 

Dr. Natascha Merten: Thank you. I'm happy to be here. 

Chin: So to begin, you are a psychologist and an aging epidemiologist with a research focus on human aging. Your approach to human aging is holistic and you are focused on how general aging processes impact brain aging and sensory processing such as hearing and vision. With this background, how did you get involved in dementia work and specifically sensory processing? 

Merten: Everything basically started when I was doing my master's in psychology back at the University of Bonn in Germany. Here during my master's thesis, my work focused on the genetic basis of human cognition, and I became very interested in different cognitive function and how they change with age and how they are associated with each other and what actually is human cognition. That kind of laid the foundation of my interest in the human brain. Then, I went on to conduct my PhD at the German Center for Neurodegenerative Diseases, also in Bonn, Germany, and my PhD was at the University of Bonn in epidemiology. I went to continue my work looking at sensory functions in addition to cognitive function while we were starting a big cohort study on aging, the Rhineland Study. That study also focused on sensory impairments among other bodily functions and aging as a holistic process, and I became responsible for the hearing assessments in the study and the cognitive assessments. So I started learning about the senses and it became more and more obvious to me that we can only perceive our world through our senses and that basically affects how we think about our world, so everything is intertwined. That got me motivated in sensory functions in the first place. 

Chin: That makes so much sense. Now that you say it though, that our senses are how we perceive the world and information and of course then that influences how our brain manages, manipulates that information, so it seems like there's a perfect overlap there.

Merten: Exactly. While my PhD was focusing on hearing function, I went on in my postdoc in my scientist position and in my work now moving forward to also look at even additional sensory systems, also incorporating the visual system and trying to understand smell and other sensory systems basically to understand the whole concept of our interaction with the environment as a human being and how our brain perceives the world. 

Chin: That's just fascinating. I'd like to start by discussing your work showcased at AAIC 2022. You presented about the work you're doing looking at midlife sensory and motor functions and long-term changes in blood-based biomarkers of neurodegeneration and Alzheimer's disease. Before we get to the actual work, why do you think sensory and motor changes may be helpful in identifying early changes in cognition? 

Merten: Well, we know that the changes relevant for Alzheimer's disease and neurodegenerative diseases start early, often decades before we can measure any clinical symptoms. We still need, and we yet need, relevant and less expensive biomarkers to determine who will eventually turn out to get one of those diseases. Our current measures like PET scans or cerebrospinal fluid biomarkers are rather expensive and invasive, and we still lack less expensive and less invasive screening tools that we could also use in the larger population. In that context, sensory and motor functions are actually pretty handy because we can measure sensory and motor functions very easily. It's not invasive at all to conduct a hearing test or a vision exam, for example, and studies from us and others have shown that sensory and motor changes are associated with cognitive changes. We still don't understand the exact order of those changes and the underlying pathology, but we have some evidence that they at least we know that they decline together so the question would be whether we could utilize sensory and motor changes as markers for early changes in the brain as well. 

Chin: So in the study that you presented at AAIC, can you tell us about the study participants that you looked at? 

Merten: We invited participants from the Beaver Dam Offspring Study (BOSS). The Beaver Dam Offspring Study is a longitudinal cohort study on sensory and cognitive aging that was started in 2005 with almost 3300 participants. The participants were on average 50 years old at the baseline at the study start, and the participants actually were the offspring of participants of the epidemiology of hearing loss study, which was a population-based study also on sensory and cognitive aging in Beaver Dam in Wisconsin. While the participants of the epidemiology of hearing loss study must have lived in Beaver Dam to become participants, the Beaver Dam Offspring Study participants just needed to be offspring of those participants and they did not need to live in that area. However, currently, around 70 percent of our participants still live in Dodge and Dane County, so very close to Beaver Dam or in Beaver Dam itself. So these participants have then been re-invited after five years and after ten years again. We then also are going to see them again in my newly funded study for an 18-year follow-up. So we basically assessed their sensory and cognitive aging already three times and we are going to measure them again for a fourth time, and those participants are the participants that I conducted the study in. 

Chin: That's incredible that you have been able to get participation from the offspring of people who are also a part of a longitudinal study. I mean you could say that research participation kind of runs in the blood of the participants that you're looking at, Natasha. 

Merten: That's also something that we've actually have experienced in our conversations with our participants that they report, like even those that don't live in the area anymore, For the previous exams, many of those combined visit with their parents to a visit with our study facility. So they basically came to join the study, but they also went and saw their parents. 

Chin: That's so convenient, and so nice, of course, for science, and when you say the word “exam”, can you tell us what types of evaluations are you actually doing when you see these participants? 

Merten: For our, let's say, standard battery, we measure their hearing, vision, and smell functions. For smell, we have an order identification test. For hearing tests, we measure a simple pure tone audiometry test, which is basically the simple hearing test that people know from their ENT visits where you have to click when you hear a tone and then we measure tones of different frequencies. We also have a more complex word recognition task where participants have to identify words while there's also a background speaker. Then, we test visual acuity and contrast sensitivity for vision. We also, for the motor functions, which was part of the work that I presented at the AAIC, we have an eye-hand coordination and motor speed task. We also ask them for their physical function with questionnaires. We assess their general health with blood works, with cardiovascular assessments. We measure their height and weight, and we ask them for a history of health conditions, medication intake, and also ask them about their current lifestyle. 

Chin: These are pretty thorough investigations that you're conducting at each visit. Knowing the participants that you're looking at and this thorough evaluation, what did you end up finding? 

Merten: For this particular work that I presented at the conference, we found that those participants that had worse hearing function and worse motor function at the baseline, the first time we saw them, were also those people that had a faster increase in those blood levels of a marker of neurodegeneration called neurofilament light chain (NfL) protein. So they had faster increases in those blood levels over time as compared to those that did not have a hearing and or a motor impairment, and that NfL marker is considered a marker of neuronal injury and general neurodegeneration. So that was pretty fascinating to see that hearing and motor functions could predict changes over the next 10 years in that biomarker. However, we will need more follow-up and longer studies to further investigate these changes and whether we can use sensory and motor functions as screening tools for neurodegeneration, because there are still a lot of unanswered questions. This is why we are going to continue the work. 

Chin: Right, this is why you have gotten such great funding. It's such an important question, And I guess, and I'm sure you probably can't answer this, but what I'm wondering is, do you think these results, this type of finding that you have, could it change if people had their sensory impairment, like hearing loss, actually corrected with a hearing aid? 

Merten: That's an interesting question. For this particular work, we are considering the hearing and vision and olfactory loss and motor changes all as biological markers for impairment. Basically, measuring those impairments, we know that they have some kind of neurodegenerative risk or impairment going on in their body and we are not as much interested in how they function in their day-to-day life, meaning if their hearing or vision is treated at that time point. For this particular question, whether having an impairment will tell us something about if there's pathology going on. It's not really relevant if they are treated or not for that particular question. 

Chin: Sure, if that makes sense. First you have to understand if having the impairment has a mechanistic or biological effect on cognition. That makes perfect sense, but you can see the excitement in my voice, the potential that you might be leading us to as far as ways of helping people with their cognition, so looking more holistically though at aging and cognition, you studied thinking abilities in different generations by using two different research populations, one of which was this Beaver Dam Offspring Study. Can you share with us who else you studied and why you wanted to investigate generational differences? 

Merten: As you already commented on when I was introducing how the Beaver Dam Offspring Study participants became Beaver Dam Offspring Study participants, the other cohort that we studied was their parents' generation, the epidemiology of hearing loss study. That study was started in 1993, and the participants of that study were on average 66 years old at the study start, and the great thing about those two studies is that they have been utilizing similar tests and so it's very easy for us to combine the data. Combining the data from these two studies allowed us to study four different generations, the greatest generation, the silent generation, the baby boom generation, and the generation X. The research has shown that, or we know with our aging populations, that we are expecting more and more cases of dementia and cognitive impairment, particularly in Western generations. But interestingly, recent research has also shown that the age-adjusted, the age-specific prevalence and incidence rates of dementia have been decreasing, meaning that if we look at people who have the same age from different generations, in younger generations there are actually less participants at the same age that get the disease. That is kind of good news, and there are some factors that people have been speculating that could be reasons for that. One factor would be that the education has increased over the past generations by a lot; There's improved health care and medical care; There's better treatment of cardiovascular diseases and diabetes, for example, and generally people may have been adopting healthier lifestyles. That could all be factors that are underlying these changes, but for really understanding how generational trends are developing and what are the differences over the cohorts, it is very essential for us to understand those generational differences in cognitive impairment and cognitive function in order to quantify future burden and healthcare needs in our aging populations, and obviously this will also be interesting because it may help us to identify areas for intervention and prevention strategies. 

Chin: So with your study, what exactly were you looking at when you were comparing the generations and then what did you find? 

Merten: We looked at age-adjusted performance in various cognitive domains. We looked at processing speed, executive function, attention, and verbal fluency and we found that more recent generations compared to the greatest generation were better in those particular cognitive functions. Interestingly, those generational differences were also stable even when we adjusted for among age, also sex, education and other health-related mediator variables, basically, these factors that I just said like diabetes, cardiovascular disease. When we measure socioeconomic factors, healthier lifestyle, even when we included all of those factors in the model, they still showed some benefit. That actually is interesting because that may mean that there's even more room for improvement, or at least there has been some room for improvement and we should find out what that was. 

Chin: So compared to the oldest generation, the greatest generation, the more recent ones, the more recent generations, perform better on some of these cognitive functions. What do you think that means though? 

Merten: As I had started on, just started off with is that some of those factors and some of those changes that we see are due to the known improvements in education, medical care, healthier lifestyle. That could be like, we know that education is a protective factor for dementia and is considered to improve cognitive reserve and slow cognitive decline, and we know that cardiovascular diseases contribute and are risk factors for dementia as well. Another big factor is the lifestyle changes with regards to this massive decrease in prevalence of smoking that has occurred since like the mid 1960s and also an uptake of physical activity. But then as I said, there's still this remaining difference that we see when we adjust those factors that we already measured and added to our models. We still see some benefit and there may be other factors that may have led to that, so that's basically mainly speculation but factors that could have contributed to that are the availability of vaccinations against infectious diseases and more widely use of antibiotics, because we know that inflammation and infections may contribute to cognitive decline and dementia as well. We also have better environmental surveillance and regulations of pollutions and toxins in food, water and air, and that may have led to better environments and less neurotoxin exposure, for example, that would be helpful for the brains of aging generations. Finally, the more recent generations may now be more active in cognitively stimulating occupations than future generations may have been, so there could be a number of sources that could explain that. 

Chin: Well, this is fascinating and there's a lot of opportunity to actually study and determine these things, and I wonder though, in your study, you did not see a continued improvement in cognitive function from the baby boomers generation to the generation X, the youngest of your group, and I'm wondering why do you think this happened? In essence, is your study saying that generation X simply isn't smart enough or reaching their full potential? 

Merten: One explanation would be that we already had this improvement in education; We already had good treatments in cardio for the big cardiovascular risk factors that we know of; We already had a healthier lifestyle that occurred in earlier generations before the Baby Boomers or before the Generation X. Basically this benefit was there already, and there's potentially just a biological limit on how much it helps you to have more education, how much more buffer do you get by the same level of education. Maybe there's some kind of biological limit because we assume we can't live forever, maybe we will someday, but currently we think we are not going to live forever, so that could be one of the pathways and that's obviously a big debate in how much we can do to those biological limits. Also, other people have been thinking there may be counteracting and disadvantageous processes happening in the younger generations. We know that the prevalence of obesity and diabetes are increasing in those younger generations. They are risk factors for cognitive decline and dementia. Also more mental health problems, loneliness, depression, and anxiety may be happening in those younger generations. While we adjusted for those, again, in our models, we don't really think that these may be the most prominent explanations for our particular results, so it could also be other factors like exposures to microplastics, consumption of processed food, the increased sitting in the younger generations. I think there's a lot more research needed to try to understand what the mechanisms are behind those differences that we see, but it's very fascinating.

Chin: I think there's a lot to gain there. There's a lot of potential, and you're not talking about just improving the wellbeing of an individual, you're talking about a generation of people and figuring out those mechanisms, so incredibly important, Natasha, and to end, when you reflect on the work we've discussed today, what's next for you? What does the next five years look like? 

Merten: So I have just started my research program and I'm just launching my new research program as an assistant professor at UW–Madison. I'm starting that with a big R01 grant that I received from the National Institutes of Health. In that study, as I had started talking about a little bit earlier, I'm going to re-invite those BOSS study participants for a neurocognitive aging study in an 18 year follow-up, and we are expecting to see about 2000 participants. They will be on average 70 years old, so it's super exciting to see them again and study them again, and I want to continue understanding the shared etiology and this co-occurrence of sensory and cognitive changes and try to find early markers for these changes in these multiple systems because my motivation is really to understand aging holistically, and because I'm convinced that if we find good markers for multiple age-associated chronic conditions, this is kind of the way to go because then we will inform future treatment and prevention methods that will also potentially benefit multiple chronic conditions at the same time. So it does make sense to try to find those common pathways and common mechanisms and understand them all at the same time even though it's complicated. 

Chin: Well congratulations on your research projects and you're doing wonderful work. I'd like to thank you for your time today and I look forward to seeing what you end up finding out with this R01. 

Merten: Thank you so much for the invitation to this podcast. It was a pleasure. Have a good rest of the day.

Outro: Thank you for listening to Dementia Matters. Follow us on Apple Podcasts, Spotify, Google Podcasts, or wherever you listen or tell your smart speaker to play the Dementia Matters podcast. Please rate us on your favorite podcast app -- it helps other people find our show and lets us know how we are doing. Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center at the University of Wisconsin--Madison. 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 of Dementia Matters was produced by Amy Lambright Murphy and Caoilfhinn Rauwerdink and edited by Haoming Meng. Our musical jingle is "Cases to Rest" by Blue Dot Sessions. To learn more about the Wisconsin Alzheimer's Disease Research Center and Dementia Matters, check out our website at adrc.wisc.edu, and follow us on Facebook and Twitter. If you have any questions or comments, email us at dementiamatters@medicine.wisc.edu. Thanks for listening.