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Dr Alvaro Pascual-Leone Highlights Alzheimer Risk Factors, Disparities in Research


If clinicians empower individuals by giving them the appropriate tools and education to promote brain health, it can make a big difference, said Alvaro Pascual-Leone, MD, PhD.

Alvaro Pascual-Leone, MD, PhD

Alvaro Pascual-Leone, MD, PhD

In the first installment of this 2-part interview for World Alzheimer Day on September 21, 2023, Alvaro Pascual-Leone, MD, PhD, sat down with The American Journal of Managed Care® (AJMC®) to discuss racial and ethnic disparities he has seen in Alzheimer and dementia research, their potential drivers, and what clinicians can do to help mitigate these major disparities.

Pascual-Leone is a professor of neurology at Harvard Medical School, medical director of the Wolk Center for Memory Health at Hebrew SeniorLife Rehab Center, and cofounder and chief medical officer of Linus Health.

AJMC: What are some racial disparities that we are seeing in Alzheimer and dementia trials?

Pascual-Leone: One thing that oftentimes people don't think about is that scientific evidence from research and clinical studies is limited frequently by who chooses to participate in research studies, where those research studies are done, and how much representation of different racial groups and socioeconomic groups and minority patients are part of those studies. There is a lot of effort, because of awareness of this challenge, to try to counter the fact that oftentimes we do a lot of studies on a certain group of the population, and there are specific groups that are underrepresented. African Americans and Black individuals are often underrepresented in studies for many reasons, including the fact that we don't address their expectations and needs appropriately. The same is true for Hispanic patients, and the same is true for individuals with poor socioeconomic status in general regarding social background.

It turns out that is not just a limitation for research study results. It turns out that in many diseases there is a significant difference in how the disease plays out depending on your racial background and your socioeconomic status. In the case of dementia, which is the condition that I focus on, there are very significant gender and racial differences that, if you don't have appropriate representation of those groups in the studies, what you end up learning may not be fully applicable to everybody. Unfortunately, that's what we're faced with. We often have information that is true and valuable and important, but may not fully be applicable to some individuals because of their racial background and so forth. As a clinician, when you want to take scientific evidence, you don't want to treat a cohort of people, you want to use that evidence to help 1 individual you have in front of you. In order to do that, you need the studies to have full representation of those main characteristics that individuals will have. I think we have work to do as a community to ensure that that is the case.

AJMC: What specifically is keeping patients from racially and ethnically diverse populations out of these trials?

Pascual-Leone: It's often the case that it's not a problem of getting screened out of studies, but rather the recruitment efforts are not successful enough in attracting people of color and other minority patients into studies. That is in part because of the fact that we have a very sad history of the way some populations have been unethically misused in research studies and have been forced to participate in studies in inappropriate ways. Fortunately, we now have the regulations to ensure that is not the case, but there is a persistent mistrust born from that era in participation in studies, so there is a resistance for certain populations to participate in studies. In the case of dementia, in addition, there is a stigma of the recognition of dementia and what it means to have dementia, and that stigma is particularly strong in certain populations. For Hispanic and Latino patients, there is a particularly strong rejection to it.

And you don't want your loved one to be called stupid. Dementia doesn't mean that, but there is that stigma attached to it, so there is a resistance to reach out and look for help, and in doing so, to be identified as potential participants in studies. Finally, I think there is oftentimes a lack of awareness that the way to recruit individuals and make them aware of studies needs to be culturally, racially, and ethnically appropriate. The kind of response to a social media ad that may work well with young White Americans may not work well with older adults, particularly not of certain racial groups. How you approach people to make them aware and interested in participating in the study needs to be adapted to their particular cultural backgrounds that they bring to the table. So we need better ways to recruit and reach certain populations, we need to ensure that we set things up so that it generates trust and that there is a sense of value that comes to them, and we need to fight against the labels and biases that are attached to participating in studies because of the type of focus that they have, in this case dementia or Alzheimer disease.

AJMC: Some researchers are questioning whether the high rates of dementia in different racial and ethnic communities are due to causes other than Alzheimer disease. Can you discuss the potential reasons behind this?

Pascual-Leone: That's a great question. It is the case that dementias by different disease causes are associated with, frequently, multiple pathologies. The notion that dementia is just due to Alzheimer disease, or just due to vascular disease, or just due to diffuse Lewy body...that is becoming increasingly questioned, because evidence is building rapidly that there is very frequently mixed domains and mixed pathologies that there is Alzheimer and diffuse Lewy body and that there is vascular and Alzheimer disease. In different racial and ethnic groups, comorbidities of different pathologies play out differently. African American patients have increased risk of certain forms of vascular disease, women have increased risk of inflammatory cascade autoimmune diseases, and with that, their predisposition for a given combination of pathologies leading to dementia becomes different, and it's important to recognize it as such because the treatment targets become different.

That's the first reason, but the second reason is that, even for a given pathology and even for Alzheimer disease, we now know that there is a polygenic risk profile—the alignment of multiple genes—that define the risk of a given individual, and we know that those polygenic profiles differ by race and ethnicity. The polygenic profile that would apply to me as a White Hispanic person will turn out to be different than what applies to a White non-Hispanic person and, in turn, different from what applies to a non-White Hispanic person or an African American, non-Hispanic person. To realize that, because of those polygenic signatures being different by race we also need to realize that the symptoms and the manifestations of the disease may be different, is important. It's both the mixed pathologies and the specific characteristics of what leads to the disorder.

There's one final point which is often overlooked that is important, and that is that what we're really talking about is not the pathology alone, it is the manifestation of that pathology; it is the consequences, the symptoms, the disabilities caused by that pathology. Those depend very heavily on lifestyles, and cultural differences and racial differences oftentimes play out with different lifestyles. Hispanic people tend to have larger families, large family gatherings, a more supportive environment, and stay at home and all those things lead to different influences which, in turn, modify the clinical manifestations of the disease.

AJMC: Socioeconomic factors such as obesity and exposure to chronic stress have been mentioned as potential contributors to disparities in dementia risk. How do these factors intersect with racial and ethnic disparities in Alzheimer disease care and research?

Pascual-Leone: One of the most clear lessons learned over the past several years from dementia, regardless of its cause, is that we should not think of it as a disease of old age. Instead, we should think of it as the consequence of a lifelong process of impact on brain health in a disease that starts in middle age, even if it manifests in older age. What that means is that your entire life matters at the end of the day. It also means that when you have different racial groups, different socioeconomic groups, different backgrounds that impact your life, even if at a given point you are in the same situation, it is all that that you've lived that matters and that has an impact on you.

Midlife—not old age—obesity ends up being a risk factor for dementia. The amount of physical exercise, the amount of green in the surroundings where you live, and the density of populations all end up being risk factors, and they are risk factors that start playing a role in your 30s and 40s and 50s. And racial groups and socioeconomic groups particularly have great diversity and disparities in those regards. We need to learn from those epidemiologic data and from intervention studies and embrace a real effort in public health that minimizes those disparities for the sake of better overall population health, and with that, a reduction in dementia for specific groups.

One of the things that we know is that, with the increase in lifespan, there is a significant increase in the rate of dementia just because it manifests itself the longer we live. We now have the data to show that in certain countries—the United States among them—the current rate of increase in dementia is actually less than what one would predict because of lifestyle modifications. But those lessons and those policies that promote those lifestyle modifications haven't been applied in certain parts of the country and haven't been applied in other countries. For example, in South America, in Africa, or in some of our southern states, we're seeing a much higher rate of increase of dementia impacting particularly those most vulnerable and minority populations to a much higher degree than what would need to be based on what we know from other countries and latitudes. There are a lot of implications of this sort of lifelong emphasis on promotion of brain health–promoting lifestyles that are important. One particular impactful way to address this that we haven't fully embraced is to empower individuals. Empower you, empower me, empower each one of us to take charge of defining our brain health goals and have the tools to actually monitor if we are on target, if we are doing what we want to do, if it is deviating, and have our clinicians help us sort out the interventions to improve on it.

I think if we empower individuals by educating appropriately and having the appropriate tools, we can make a big difference.

This transcript has been edited lightly for clarity.

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