Dr. Scott Sperling

Welcome to Meet the Authors, a podcast brought to you by a collaboration of the Society for Clinical Neuropsychology and the journal of Neuropsychology. My name is Dr. Scott Sperling, and I’m grateful to be your host. In this podcast, Student Leaders in Neuropsychology will discuss prominent recently published studies with the authors who undertook the research allowing for a behind the scenes look into the development, implementation, analysis and future implications of cutting edge neuropsychology research.

Today, our student leader, Dr. Josh Fox-Fuller, will be discussing an exciting new paper entitled Multi-Domain Modifiable Dementia Risk Factors Are Associated with Poorer Cognition in Midlife, with two of the paper’s authors, Dr. Yen Ying Lim and Ms. Lisa Bransby. I’d like to now introduce our student leader and esteemed guests. Dr. Josh Fox-Fuller is a postdoctoral fellow in Clinical Neuropsychology at Michigan Medicine in Ann Arbor, Michigan.

He received his Ph.D. in clinical neuropsychology from Boston University after completing his pre doctoral internship at Emory University. Dr. Fox-Fuller has conducted research related to autosomal dominant Alzheimer’s disease, in work with collaborations in Medellin, Colombia. Welcome, Dr. Fox-Fuller. Thanks for having me, Dr. Sperling. Dr. Yen Ying Lim is an associate professor at the Turner Institute for Brain and Mental Health at Monash University in Melbourne, Australia.

She’s the primary investigator of the Healthy Brain Project and the Better Brains Trial. Her primary research interests are in understanding the nature and magnitude of genetic, biological and lifestyle risk factors on cognitive decline and clinical disease progression in Alzheimer’s disease. She’s also interested in development and validation of web based cognitive tests for the early detection of cognitive dysfunction in Alzheimer’s disease.

And Lisa Bransby is a final year Ph.D. candidate we just learned is a month away from finishing. Congratulations, Ms. Bransby. Final year candidate at Turner Institute for Brain and Mental Health at Monash University in Melbourne, Australia, and is awardee of a Dementia Australia Research Foundation Ph.D scholarship. Her research focuses on modifiable dementia risk factors and how they relate to cognition and biomarkers of Alzheimer’s disease. Lisa is also interested in understanding factors that influence the feasibility of dementia risk reduction.

So welcome again, Dr. Fox-Fuller. Welcome, Dr. Lim and Ms. Bransby.

Dr. Josh Fox-Fuller, Ms. Bransby, Dr Yen Ying

Thank you. Thank you for having us. I’ll now turn our discussion over to Dr. Fox-Fuller.

Dr. Josh Fox-Fuller

Yeah, thank you again, Dr. Sperling for the invitation to join you today for this conversation. So in this paper, the authors categorize modifiable dementia risk factors into domains and examined that higher number of domains of modifiable risk factors was associated with both objective and subjective cognition in healthy midlife individuals.

So to start off for those people who may be listening to this podcast episode before reading your paper, do you mind just briefly summarizing some of the main findings of your work?

Ms. Lisa Bransby

Yeah, sure. As well, thank you for having us again. So this paper, as you said, sought to categorize a bunch of different modifiable dementia risk factors into risk domains.

And the reason for this was to find a way to synthesize a large and comprehensive range of these risk factors. So we classified them into five domains, and these included mood symptomatology, risky lifestyle behaviors, cardiovascular conditions, cognitive and social engagement and sleep disorders and symptomatology. In this paper, we defined each of these domains and operationalize them as well.

And so we wanted to look at how reporting risk across multiple of these domains relates to cognition. So what we found is that, first of all, about 92% of our middle-aged sample had at least one modifiable dementia risk factor. So that suggested that almost everybody had some modifiable dementia risk. And 67% of the sample also reported risk across two or more domains.

So we saw in the sample that most people had multi-domain risk as well. And when we looked at the relationship with cognition, we saw that compared to people who had no risk factors at all, those who had risk in three or more domains showed worse learning and working memory performance and greater subjective cognitive concerns. The magnitude of these relationships was moderate to large and also compared to no risk factors, people who had risk across all five domains also had worse psychomotor function and attention as well. So that’s basically the gist.

Dr. Josh Fox-Fuller

Yeah, thanks for sharing that, I guess, 10,000 foot view or the overview of the paper. The group that’s sort of behind the podcast, you know, we all read over the article and prepared a few questions that we’d like to ask you just to kind of get into some more of the nitty gritty of the research and to hear your thoughts on some parts of the methodology and maybe the implications of that work.

So the first question we have for you is that the results seem to indicate that mood and cardiovascular modifiable dementia risk factors are more strongly associated with learning and working memory and subjective cognition than perhaps with attention or psychomotor processing speed. So one question we had was kind of thinking as a future neuropsychologist and Dr. Sperling as a neuropsychologist, as to why you might think this is the case in particular?

Ms. Lisa Bransby

Maybe Yen can add to this but I think maybe for such a young sample middle age group, it may be something like psychomotor function or attention. We’re not going to see such major effects related to these risk factors in such a young group. So that’s probably one possibility. Yen, do you have anything to add there?

Dr. Yen Ying

Yeah. So I think it’s worth noting too, that the sample is enriched for people with a family history of dementia.

So we really, even though they’re all cognitively unimpaired and they’re normal and they’re healthy, we have specifically gone out and targeted a group who are, you know, at risk of developing dementia. I think the differentiation between attention, psychomotor function and learning working memory is interesting because I think attention and psychomotor function probably something that we see decline kind of more with age and certainly through our other sort of older adult cohorts like Abel and ADNI and things like that.

You do see this kind of pronounced deterioration with age on these attention tasks, but with memory tasks it seems to be a little bit more specific to things like tau pathology or amyloid pathology or even cerebrovascular disease. So we think that, you know, in the absence of actually measuring some of these biomarkers in this kind of broader sample, one of the inferences that we’ve drawn is that this deterioration specifically primarily in the memory domains, might be more kind of indicative of a more sort of Alzheimer’s or neurodegenerative disease process.

That said, we also do see that greater modifiable risk factors are associated with also higher subjective cognitive concerns. And we do know that cognitive concerns are also associated with mood especially. So there is that sort of what exactly is driving some of this deterioration. Is it kind of like a beta type pathology or is it something else, some other sort of non AD neurodegenerative pathway?

We’ve been exploring this a little bit more in some of our more recent papers through Able and also through the Healthy Brain Project to try and understand some of the biomarkers that underlie this decline.

Dr. Josh Fox-Fuller

Yeah, I think this leads perfectly kind of to the next question that we have prepared. So it’s almost as if you are reading our minds a little bit.

So we’re curious about your understanding of the literature and this paper in particular sort of what your thoughts are regarding the five main modifiable disease risk factors that you talk about? If you think some of them are kind of classified more into having a direct effect on the pathophysiological causes of dementia or like, for example, if they have more of an impact on a beta propagation or if others have more of an effect on bolstering cognitive reserve, or if some of them have, you think impacts on both. I want just hear some of your thoughts on that.

Ms. Lisa Bransby

Yeah, probably all of the above. I would say something that I’ve definitely learned throughout my Ph.D. is that modifiable dementia risk is extremely complex. And as we saw on this paper, that most people had multi-domain risks so people are showing a variety of different risk factors, which if we’re assuming that they do relate to outcomes in the brain that they’re probably relating to a bunch of different mechanisms.

So there are animal studies that show that mood symptoms through overexposure to cortisol and things like that are related to increased amyloid in tau There’s a lot of research to suggest that cardiovascular conditions are not related to Alzheimer’s disease pathophysiology, but increased risk for dementia through cerebrovascular disease mechanisms. As you said, cognitive reserve is likely related to cognitive and social engagement.

There is also evidence to suggest that poor sleep is related to increase amyloid in the brain. So it’s likely that if people have a bunch of these different risk factors that they are relating to complicated mechanisms in the brain, probably multiple of these things.

Dr. Yen Ying

So just to jump in and add to that too, that in human studies we haven’t really seen a terrible amount of evidence to suggest that these sort of multi-domain we would put it together in kind of a composite that they will lead to a beta pathology or anything like that.

I think there is some evidence to suggest that perhaps it might operate through sort of cerebrovascular pathways and things like that. That said, as Lisa pointed out before, there is evidence to suggest that sleep in particular might have some kind of relationship with a beta through the lymphatic system. So I think it’ll certainly be worth pulling this apart and looking at individual components of it to see what might be driving it.

Because, I mean, will we deal with cognitive composites? We sort of see the same, right? Like of almost like a watering down effect of individual tests in some ways. But that said, I think working with modifiable risk factors with dementia, I think in general is complicated because in one way or another they’re so interrelated. Right. And so that was some of the impulse or the rationale behind putting it together or synthesizing it in this way in a sort of domain specific way, rather than I think we administer 14 different types of survey.

So kind of entering that into a statistical model would be really challenging even with the big sample size. And so we wanted a way to kind of synthesize. But I think in that synthesization we might be losing some important information as well.

Dr. Josh Fox-Fuller

Yeah, I think the approach makes perfect sense. I mean, given a very large and robust sample such as your own.

I think getting out much as a bunch of subgroups, right, of like who has, you know, five different cardiovascular risk factors, versus four, three and so on, probably creates losses to the challenges maybe in the future of combining datasets or things like that, we’ll be able to answer. But I guess kind of along that line, actually one of the questions that we had was we’re curious if you think that the number of individual modifiable risk factors, the type or severity of them or the type and number.

So essentially the combination, which one do you think would be most likely to be associated with risk of developing dementia? And do you think that would be based off of different social and cultural identities or biological factors like biological sex, that there’s sort of some implications there that you’d like to discuss?

Ms. Lisa Bransby

Yeah, no, it’s an interesting question, something that we think about quite a bit.

I think that it’s, again, probably all of the above and probably that is something to do with an accumulation of risk factors, also potentially a variety of different risk factors. You know, in this paper, in the supplementary materials, we also include an analysis where we just grouped participants based on the number of risk factors that they had, and we saw similar relationships but slightly weaker effect sizes.

So it’s possible that this suggests that by grouping people based on the different domains that we’re seeing, a little bit of the larger effects and maybe that does speak to the variety of risk factors.

Dr. Yen Ying

We also did an analysis, Lisa, I think where we just looked at cardiovascular risk factors or just lifestyle risk factors and that certainly didn’t produce the same kind of effect that we saw when we looked at a broader range of modifiable risk factors as well.

Ms. Lisa Bransby

Yeah, definitely. I think it also has a lot to do with socio cultural, socioeconomic factors. We weren’t able to look at that in this paper. That’s something we’re interested to do in the future. And yet we know that sex, especially female sex, is a risk factor for dementia as well. So it’s probably just a complicated formula of all those different things.

Dr. Yen Ying

And it’s an issue that I think female sex or biological sex is an interesting one, right? Because traditionally when you look at all the dementia risk scores and they classify male or female, males are given the risk because of cardiovascular conditions. Right. And so there is that. And I think it’s only kind of recently that we’re seeing this greater interest in this idea that perhaps female sex might be related to like increased tau pathology or other types of risk factors, particularly around menopause, that this sort of narrative is starting to change.

Dr. Josh Fox-Fuller

So definitely an area that we didn’t see in effect of sex here, but that doesn’t mean that there isn’t one. If we were to sort of dig a little bit more deeper Awesome. So I think for this last question, I’ll kind of put these two pieces together because as you know, neuropsychology trainees or clinical neuropsychologists, one of the sort of two things that we’re faced with often is, first of all, providing tangible feedback to patients we see in the clinic or recommendations to them in their care team about, okay, you know, you’re a 58 year old adult and you’re concerned about cognition. Like, what sort of things are you at a family risk of Alzheimer’s disease? What sort of things should you be doing to decrease your risk? But that being said, it can be hard to implement one intervention, much less two or three or five. But there’s five groups, right? So part one’s a little bit asking you what sort of interventions that may are your favorites or the ones that you think might cut across some aspects of modifiable risk for dementia?

And then kind of as a follow up part to that, we’re increasingly, you know, appreciating the role of advocacy as psychologists and neuropsychologists within governmental systems for how we can advocate for the public health care system and sort of broader changes in society. So I’d be curious to hear what you’d recommend. Similarly, we should be advocating to help maybe lower these modifiable risk factors and maybe perhaps the overall incidence of dementia.

Ms. Lisa Bransby

Yeah, what I would say is that probably small steps can hopefully still make a difference. I think that a lot of these risk factors are related to living a healthy life that is related to also cardiovascular health as well as being gauged and not being too stressed or getting enough sleep. And a lot of people find these things hard or struggle with a lot of these things, even not related to dementia risk.

So I think starting anywhere that they can is probably just a good idea. Research shows that literacy around dementia risk is very low in the community, so maybe could encourage people to learn or ask about risk factors for dementia from their doctors or wherever they’re getting their information. I think that there’s a lot of barriers to dementia risk reduction behavior.

That’s something that we’ve been looking at as well. So at the individual level, we see that behavior change for a lot of people is really hard. So what barriers are affecting the individual themselves? Is it commitment or motivation for behavior change? Do they have limited resources or time to dedicate to this? And then, as you said, in terms of advocacy, there are a lot of barriers at the population level.

So maybe we need to advocate for more, for example, greenspaces in the neighborhood to promote physical activity. Maybe there needs to be more funding for psychological therapy. There is a lot of things that need to be advocated for to give everybody the opportunity to reduce their dementia risk in some way.

Dr. Yen Ying

Just add to that. So I currently run a clinical trial that seeks to modify dementia risk factors in middle age adults called Better Brains and our experience from running that is that the best modifiable risk factor to target is the one that the person is ready to target.

Right? And so Better Brains kind of adopts this sort of person centered model in the sense that we look at their risk factors and then we say, Hey, these are your modifiable dementia risk factors, but like let’s target the one that you feel you’re ready to do whatever it’s going to be the most accessible for you. The hypothesis is that given that these modifiable risk factors are all inherently related in the sense that, you know, if you’re somebody who is obese or overweight, you’re also more likely to not do much physical activity, probably also going to experience some kind of like sleep disorder, probably not going to have the best mood either.

So which one do you start to address? And I think that, you know, if we can just get them to do something that would be probably better than doing nothing at all, feeling overwhelmed by the ginormity of it. So that’s sort of our kind of philosophy in some ways.

Dr. Josh Fox-Fuller

Yeah, I like that, of kind of starting small and starting with what people care about.

So sort of just overall picture for them. So I want to thank both of you for your taking the time to join us today, and especially given the time zone difference between Dr. Sperling, myself and you all. It’s challenging…

Dr. Yen Ying

Actually, it’s not too bad. It’s like 830 in the morning for us, so it’s not too bad… Yeah the one time of day.

Dr. Josh Fox-Fuller

But I appreciate getting to hear your perspectives. And really, you know, I think it helps bring this paper to life some. And I look forward to having it help supplement the reading experience for folks who are reading the paper as well. So I’ll pass this back to Dr. Sperling, who will wrap this up. I’d also like to thank you for putting out an absolutely fantastic and certainly timely paper.

Dr. Scott Sperling

Really wonderful addition to the literature and where we need to move the science and practice as we were just discussing. So on behalf of the Society for Clinical Neuropsychology and the Journal of Neuropsychology, again, just thank you for your great work and sharing your expertise with us today. And thank you, Dr. Fox-Fuller, for leading this podcast with us.

I wish you all well and appreciate your time, energy and expertise. Take care.

Ms. Lisa Bransby

Thank you so much.