The BRAIN miniseries | Investigating the link between vascular health and neurodegeneration in underrepresented populations

In our second episode of the BRAIN (Black Researchers Addressing Inequalities in Neuroscience) podcast miniseries, we explore the lab techniques and interdisciplinary approaches being leveraged to understand how vascular health impacts neurodegeneration, particularly in underrepresented populations. 

[1:15] What made you want to pursue neuroscience research, specifically looking at the intersection of brain and vascular science?

Yes, it’s a long story, but to start out, I grew up in rural Mississippi, and starting college – I’m a first-generation college student – I needed a work-study job, and I had planned on going to medical school. So, I figured I should kill two birds with one stone, and I got a work-study job working in a research laboratory, because you need research to increase your chances of getting into medical school. It kind of just started out as me needing a job and fulfilling a requirement in Nicole Ashpole‘s laboratory at the University of Mississippi (MS, USA) as a sophomore undergraduate student, and from there, I just really liked the research I was doing. I was relatively good at handling the animals and this type of inquiry of studying neurodegeneration and thinking about cognition from a vascular and blood-based biomarker or hormones level. I kind of looked around and thought, okay, what affects people from my community and, primarily, my family members, and it was diabetes, hypertension, stroke, and if you live long enough past having a cardiovascular disease or hopefully not having one, then you get dementia.

And so, once I started looking into the literature, I realized that a lot of these risk factors for cardiovascular disease are the same exact risk factors for dementia. From doing basic science during my doctoral studies, I decided to switch gears for my postdoc training and to lean more so into the neuroepidemiology of human populations, where I could feel like I could have a greater impact and look at the nuances between these disorders across multiple different communities and the etiology. So, I would say it’s a mix between both personal motivations and, I guess, historical relevance. Just in the United States, we see that the majority of people do have at least one comorbid condition, like diabetes or hypertension. Those are risk factors for a bunch of different things that has an economic impact, a lifestyle impact, a healthcare impact. So, just trying to understand these things better to hopefully stave off dementia and cognitive decline could actually be a benefit for all.

[3:38] Please walk me through your research. How does vascular health impact neurodegeneration, particularly in underrepresented populations?

That is a really challenging question to get to the bottom of. If we think about cognition and dementia, previously, especially for Alzheimer’s disease, you could only diagnose Alzheimer’s disease with an autopsy. And it’s really characterized by these two pathologies or these two proteins that we see accumulate in the brain. One is amyloid, and the other is tau. We have this huge resource called the National Alzheimer’s Coordinating Center (NACC; WA, USA) in the United States, and it basically collects autopsy results from people that donate their brains to science. However, this cohort of about 9000 people is about 98% white.

Over the last 20 years, they’ve actually realized that when individuals die and they present an autopsy, they don’t only have Alzheimer’s disease pathology, they also have at least three vascular pathologies. So, in general, most people are receiving a single diagnosis, but inside their brains, you have at least three things going on, with vascular being the most common.

So, you can have up to six or seven vascular pathologies on top of having Alzheimer’s disease pathology. And then if we take a step back and think about, okay, the vascular system is essential for brain health. That’s how we get the vessels to our brain, and that’s how we get blood flow. And we think about conditions that affect those, diabetes, hypertension, high cholesterol, smoking, obesity; those are more prevalent in underrepresented populations. So, you have the increased prevalence in the risk factor that is hypothetically going to increase prevalence of the pathology, leading to more cognition and an earlier onset of cognitive decline and impact.

But the huge limitation is, like I said, the NACC cohort is composed of 98% white participants or European participants. So, we actually don’t have a lot of strong evidence of the mixed pathology of underrepresented populations because those communities don’t choose to donate their brains to science. Some of the studies out of Rush University (IL, USA) have actually shown that Black participants do have more vascular pathology compared to white participants at autopsy.

So, we are starting to get more support showing this, but we don’t know the direction. Does vascular pathology cause more Alzheimer’s disease or more Alzheimer’s disease cause more vascular? And that’s a lot of the nuances within my research of trying to basically look in midlife, early adulthood, at these risk factors and correlate them to the plasma biomarkers, the way that we can diagnose Alzheimer’s disease. Now, looking at different cognitive outcomes, but there’s still a lot of gaps.

Even if we think about the concept of genetic risk, the strongest genetic risk for Alzheimer’s disease is apolipoprotein E4. So, that’s APOE. If you are white or European and you have two copies of your E4, you get one from your mom, one from your dad, you have about a tenfold increase of getting Alzheimer’s disease. Whereas if you are Black or Hispanic, that risk dramatically drops. Even with something as hardcore as genetics, you have these genes from birth, we see these genetics being associated with our disease outcomes in one population, but in the population that is at risk or has more prevalence of the disease, you don’t see the same genetic risk.

Now, we get to the concept of how do we go beyond genetics and pathology? Is it the actual structural systems in place that affect our health, such as food intake, nutrition, the type of education you have, the amount of healthcare that you have, the opportunity to receive all those things? So, it’s really a mixed picture and all those things really affect vascular health, which is not even arguable as the most common pathologies across all populations.

[7:51] As BioTechniques is dedicated to life science methods, I’m particularly interested in hearing about what imaging and omics techniques you use in your research, and more broadly as well, how you incorporate interdisciplinary approaches into your research.

I’m a neuroscientist by training, which has turned epidemiologist, therefore I’m a neuroepidemiologist now. I would say my research uses what we call multimodal approaches. If we have a hundred people and they enroll in a study, depending on the type of study, we will get their clinical information, their demographics – age, sex, gender, education – their family history, all their comorbid conditions. Oftentimes people bring in their medications to see which medications they’re on, and then different studies have different requirements. So, the most common imaging is an MRI, and the unique things about MRI is that we can actually use MRIs to look at the structural integrity of the brain. So, as you get older, your brain actually gets smaller, and we call that atrophy, but you can also see things like white matter hyperintensities, which is arguably one of the most common vascular conditions in the aging population, which is about 20% prevalent when individuals are age 60, and then by the time you reach age 90 in those populations, we see almost 100% prevalence. So, it’s extremely common, and we actually don’t even know the underlying etiology or what truly causes it, even though it is assumed vascular.

Other neuroimaging techniques include PET, so positron emission topography, where you can use a ligand or basically a compound, and you receive an injection, and that compound will bind to the amyloid or the tau, or if there’s another signal, and you basically can quantify the pathology in vivo versus 25 years ago, we could only do that during autopsies.

The other gold standard is cerebrospinal fluid (CSF). However, that comes with a lumbar puncture. So, we can measure these same proteins, amyloid and tau, in the CSF, but with underrepresented populations, we actually see that those groups don’t like to willingly agree to spinal taps or lumbar punctures, so that creates this dissonance of trying to quantify pathology, which is where my research has led into maximizing plasma-based biomarkers. So, imagine a world where you could diagnose Alzheimer’s disease, vascular disease, Parkinson’s disease, with blood. That would be revolutionary.

CSF has a huge participant-patient burden of laying there and receiving that spinal tap. A PET scan exposes you to radiation, so we don’t want to have to get those every single year, and they’re super expensive, anywhere ranging from US$4–8000, depending on where you are, and you need something called a cyclotron near that facility because the ligands will degrade, so they just can’t be stored in a warehouse. So, for places like rural Minnesota or North Dakota, if there’s no major hospital around, they won’t even have access to that PET scan. That leads us to even going broader beyond the United States to other countries: how do we diagnose disease worldwide? Blood is relatively easy to get, whether that be from the vein or capillary. So, that’s been a huge part of what I’ve been expanding into.

We have something called multiomics, and now we actually have different platforms/assays/tests where we can actually measure a lot of these proteins in the blood. Now, we’re at the stage of trying to use blood to quantify brain-derived blood-based biomarkers and plasma biomarkers, but there’s a lot of expansion. So, there’s some proteomic groups and platforms where, with blood, we can actually measure 5000 proteins in an aliquot of blood, which is amazing. We’re still at the discordance that we have blood-based biomarkers for Alzheimer’s disease, but we don’t have any for Parkinson’s disease or Lewy body dementia, and we don’t have one that’s extremely specific towards a subtype of vascular disease. So, we don’t have a general biomarker for arterial atherosclerosis, cerebral amyloid angiopathy, and white matter hyperintensities. So, that’s a big push in the field of even trying to use nonspecific blood-based biomarkers. If we can basically create a threshold of things that are nonspecific with the Alzheimer’s disease ones and figure out if people are in this specific window, we can ask, do they have a certain level of vascular disease?

So, I would say my research integrates kind of the genetics part, the clinical demographics part, and the imaging and the blood-based biomarkers to try to get a complete picture. The primary cohort that I’ve begun working in is the Health and Aging Brain Story – Health Disparities based in Dallas (TX, USA), with over 5000 participants included and processing blood to measure all these plasma-based biomarkers to get at these underlying questions.

[13:10] What aspects of your research are most challenging? How do you approach those challenges?

Previously, in the government, studies basically enrolling people in ages 30 to 50 were almost impossible to get funded because people in the 30 to 50 age range don’t have Alzheimer’s disease. So, we spent all this time enrolling individuals over the age of 65 in studies. But by age 65, what we realized over time is that, there’s something called a preclinical or prodromal phase. At age 40, individuals start accumulating Alzheimer’s disease pathology and white matter hyperintensities and different vascular conditions. So, a lot of our research is built on these older adult cohorts, but we don’t have the preclinical or the midlife adulthood trajectories.

So, that’s one of the most challenging things to get at – causation – because we only have a snapshot, if it’s cross-sectional, of an individual age 65 coming in and trying to give us their life history. And then the other aspect is just the majority of major institutions are not near underrepresented communities. Underrepresented communities often have a lower socioeconomic status, so when enrolling in research studies, you often have to take off work or if you have caring responsibilities, these create barriers to actually enrolling and doing all the things a study requires. So, that’s extremely challenging.

The lack of control from the study design, if you’re a junior investigator or an early career postdoc like me hoping to start their own lab, is tough. You’re kind of tied to what data were collected 10 years ago, so you have to come up with an interesting research question. And as time moves on, then we try to get better about that. There are studies now and the government and different agencies that have gotten a lot better at trying to look at this preclinical window, because we’re realizing at age 65 when you have a certain level of amyloid and you’re already on that trajectory, it’s almost too late. So, we kind of think about the midlife trajectory in that way of when someone is 40 years old, you want to basically lower their high cholesterol levels. You want to try to control their diabetes and their insulin resistance. You want to prevent hypertension because those are modifiable risk factors for late life dementia and vascular disease and pathology. So, other things like exercise and increased sleep are super non-pharmacological interventions that we are targeting when people are in the middle of their life, oftentimes the prime of their life. And we want to basically home in on those because we know that if we target that area around that time, we can push out the window of you accumulating pathology, having earlier onset of cognitive impairment decline, and just overall better general health.

I would say the global modifiable risk factors, we assume that about 40% of dementia is attributed to these 12 risk factors, and this is worldwide. So, this is not just a United States focus or a region focus, but the interesting thing I think about the United States is that if you take a map of the United States and you look where people live, so this concept of race, place and space, African Americans or Black individuals primarily reside in the South. A lot of Hispanic individuals reside in Texas, New Mexico and California. So, if you just take a map of where people live and you overlay that map onto a prevalence from the CDC or the government of the prevalence of cardiovascular disease and stroke, the same hotspots of where people live exist. And then if you overlay the same exact map for dementia and Alzheimer’s disease, it’s a hotspot of where people live. So, even just geographically where people live, the distribution of race and ethnic groups, you can see the hotspots for cardiovascular disease and dementia.

If you put all three of those maps side by side, the highest prevalence of the diseases that we say are affecting communities, that’s also where people live. But then you have these nuances. For example, Hinds County (MS, USA) has the fifth highest rate of dementia and Alzheimer’s disease in the entire United States. Yet, the entire state of Mississippi does not have an Alzheimer’s research center. So, the state is 50% Black, and you have a county with the fifth highest rate of dementia in the country, but the resources are going other places. So, then you have to partner with other places.

I personally believe that if we figure out how to treat these diseases in the underrepresented or minoritized populations, everybody will be benefited, both health-wise and economically, because it is very expensive to be poor, and especially expensive to be poor with a health condition. So, I think it’s just super challenging that a lot of the work that I do want to do, I feel like sometimes it’s almost impossible to do, even though there are now amazing resources. But I think the advancements could help, like blood-based biomarkers.

If we end up being able to diagnose Alzheimer’s disease and track Alzheimer’s disease really accurately with the blood, and it can be widespread beyond the United States, I think that’ll open up a lot of doors of figuring out where and how and when we treat and the type of treatments that people will need, because it won’t be a one-size-fits-all.

[18:53] What kind of interventions do you hope to develop to address the biological and social contributors to neurodegenerative disease?

I think the concept of a combinatorial therapy is going to be transformative, and we are moving into that space. So, now the new criteria for Alzheimer’s disease, we use something called the ATN framework. That’s A for amyloid, T for tau, N for neurodegeneration – and within neurodegeneration, that includes neuroinflammation as well. So, just say if we end up developing multiple types of drugs, I envision someone that has Alzheimer’s disease, or if we’re trying to stave off Alzheimer’s disease, if they’re in the earlier stages of development, they will be on a vascular drug or a vascular pharmacological intervention. They will be on a neuroinflammatory intervention, and they could be on an amyloid or a tau intervention, just based on their brain health. So, some people, they get a lot of amyloid, and for some reason, they don’t get a lot of tau. So, they wouldn’t need the tau drug.

We did an interesting study in the autopsy cohort, basically trying to see for individuals that don’t have any amyloid or very low amyloid, but they have high tau, which vascular conditions were contributing to cognition while they were alive, because we measure all these things in our brains at autopsy. So, you have to use statistical techniques to basically map on what we find at death when people were alive, and we actually found that microinfarcts, which you can see on MRIs for this specific phenotypic group, were super, super important for memory and executive function and language. So, I think that’s a really key part of identifying what type of brain and the types of diseases that people have to stratify them in these groups, which will make our treatments more efficacious, because it will be that, even within a Black population, some people don’t even accumulate as much vascular pathology, and why is that the case?

It’s also this weird underlying concept that Black and Brown individuals get more Alzheimer’s disease in general, but if Black and Brown people have not historically enrolled into autopsy studies, so we could not confirm the disease when they died; with clinical trials, they make up only about 2% of the clinical trial populations; and they don’t enroll in research studies at the highest rate. So, how do people have a disease and disorder, but they aren’t in any of the things that support how we diagnose these diseases? So, is this also a case of overdiagnosis? Some people hypothesize that the way that we diagnose disease, just looking at neuropsychology, the tests are flawed, in the way that they have cultural content. Just think about fruits and vegetables. I can’t ask the same fruits and vegetables and animals to people in Australia that I can in the United States. That goes the same way for different communities. So, if that cultural competence for certain communities and certain groups is not there with the test that we use to track cognition, then we also have an issue there because the tests are flawed. We’re actually getting some evidence that way using the plasma biomarkers, saying that the Black and Hispanic groups actually have more mild cognitive impairment and diagnosed dementia. However, they don’t have the same amount of amyloid and tau being measured in their blood and brains. So then, what is the underlying cause?

There’s a lot of discrepancies in how we diagnose disease, treat disease and then think about it from a cultural content perspective. So, we have the discrepancy between the outcomes we measure and then the biological mechanisms, and we have to do a better job at recruiting more participants and retaining more participants because one thing that works for one group may not work for another one. But I think it’ll end up being a combinatorial therapy based on precision medicine approaches.

[23:10] You’ve been involved in numerous DEI-focused publications and initiatives. Please can you tell me about your efforts in this space and the programs you’re a part of that provide mentorship and resources to Black and underrepresented scholars? 

I guess regarding my DEI efforts and publications, once I started college, I kind of looked around, and I felt this aspect of isolation just because if you’re in a lab class and you have to pick (23:42) partners, it was my experience of almost being picked last every single time until you’re further along in your education and you know everyone in the class. So, it was just looking around that way and realizing I’d never had a Black doctor. I’m in a state that’s 50% Black, and I don’t have any Black professors. And I look around and there are no Black professors in the STEM departments. So, that was kind of my motivation of how do you become something when you cannot see that it is even a light or a pathway that is feasible. So, I think that was my inherent motivation behind it. And it just kind of transformed of starting out as an undergrad, of being in certain organizations and then going into graduate school and saying, oh, we don’t have a graduate school organization focused on minoritized individuals with completely different unique needs for our education. Oftentimes, our K-12 educations aren’t as strong just because we went to public schools. We don’t have the familiarity of education of being able to go to a family member or a cousin and ask, what resource helped you with this? So, it became that type of space.

And then also bringing in outside speakers to just show that someone is out there doing what I think I can envision myself doing, but I’ve never seen anyone do. I would say the first time I ever really saw a Black male scientist speak in a room full of non-Black people, I was in my third year of graduate school. So, by that time, I was 25 years old, and I had never saw another Black man stand in front of a room of people that are not Black and talk about his science. And I would say it was transformative in that way of saying, all these people are in awe of his science, and I’m in awe that this is someone that looks like me. He had on the same type of shoes as me. He had on a pair of Jordans. And it was just amazing to have that feeling.

So, I think that’s transitioned more as I completed my PhD and being a postdoc and hopefully starting my own lab soon of just being involved in different groups and finding a way to pay it back because academic training and science is very hidden curriculum –  that’s what we like to call it – of how you progress to the next stage. What are the most strategic mechanisms to do this? If you have a smaller community to rely on, how do you find all of these opportunities? So, I think that’s been a large focus of participating in all types of groups that I have access to.

One was – since 2020, when I was in grad school – the Black in Neuro organization. Another one that’s been around for 30 or 40 years is the Neuroscience Scholars Program sponsored by the Society for Neuroscience and the NIH, and I was a part of that program for 4 years. It really helped me and offered this external community of like-minded scientists, both from Black and Brown disadvantaged groups. Even if they were white, we had similar things in common. For example, being first-generation college students, which was enough of a challenge in itself to basically find common ground and understand that we have a lot more things in common. Other ones, the way that I received my postdoc position at Stanford was I did a program called PRISM. It actually actively recruits senior level graduate students to come to Stanford to interview at different labs, which is especially important for students that attend things like Historically Black Colleges and Universities that don’t have as many resources. You may not have this super, super outstanding or most competitive CV to get a person to fly you across the country to come interview with them because it is a metric-based environment, but this program offered me the opportunity to come to Stanford and interview and receive a postdoc position.

I think the biggest one that’s been extremely transformative has been the internet and social media. Just being in Mississippi, being my first year, being the only Black student in the program. And by the time I completed, I was actually the first Black person to complete the degree, which has been around since the 1970s. And even applying for grants, we have a huge grant called the NIH F31 that grad students compete for and it’s almost like the highest honor you can get as a doctoral student in the United States as far as a fellowship or grant. My first year of grad school, I said I wanted to apply for this grant. Nobody at my school had applied for it. Nobody had gotten it in 30-some years after the program started, two years after it started in the 1960s. Through the internet, through social media, I was able to reach out to so many other scientists to learn how they conveyed their story and their science in a way that showcased me as a human, as a trainee as well as my strong and rigorous science.

So I would say the internet has been transformative in me creating a community. Three months ago, I went to a conference in Boston and someone grabbed me and was like, thank you so much for always updating your website with the things that you apply to and the different application types and making it all accessible. I’ve been following your social media for three or four years and you don’t even know it and I use all your stuff and all your templates.

That brings me a lot of joy of just going to a conference in a random city and meeting other people that are having access to the stuff and they’re sharing it with their friends. It’s a low-hanging fruit of my way of being able to give back just because if you’ve never written a grant before, if you’ve never applied for this program, how do you write the application if you don’t have friends that’s done it, if you don’t have a boss that has experience doing it. This is my way of overcoming a lot of those hurdles that come with imposter syndrome and psyching yourself out of even applying for opportunities because you’re truly starting from scratch.

We wrote a publication on the social ecological construct of strong post-doctoral training that is not just about science, it’s about a supportive institution, a supportive mentor, supportive peers that look like you and sound like you and face some of the same challenges as you. I’ve been in a situation where I didn’t feel supported, and it was a struggle and I had to switch laboratories and I wouldn’t have been able to do it without some of my friends and associates that had gone through similar experiences. I think overall it’s just a way to give back. It’s important to disseminate science, but if you aren’t able to get the different types of people to do the science and stay in the programs and maneuver through, then that’s a fault within itself. I think retention is extremely, extremely important, and the only way we get more underrepresented people to not only enroll in the programs but retain, is providing specific level support the same way that we would do for biological disorders and disease.

Everything requires a combinatorial approach in my opinion, and it just looks different for education. It’s asking, how do you study? What’s your experience doing this? Do you have any experience with scientific writing? That comes up a lot with minoritized trainees: writing and publications. If you went to a poor k-12 education like me, the first time I wrote an essay or research paper I was 16 years old, whereas I have peers who were 12 years old and their school required them to write those things. Then, once you start your undergraduate training, if you’re a science major, you don’t write essays, we only take multiple choice tests. But, so much of grad school and science as a career is writing; you get to this point and people have literally outwritten you, and they have more experience than you across the last 15 years, so I think that’s been a big part of like offering different workshops. I also get so many emails to read people’s grants, fellowship applications, all those things, and I – pretty much 98% of the time – say yes because I know that’s the huge gateway to science because that is our metric of success in this community, and I think the publications help do that, so we try to culminate all these different hidden curriculum and resources into a couple of publications to basically give back. These last, even if someone doesn’t know me, they can read one of my papers and it can help them in some type of way.

The interviewee has no competing interests.

The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of BioTechniques or Taylor & Francis Group.