By Deborah Borfitz 

January 9, 2023 | Clinical trials for Alzheimer’s disease (AD) have a long way to go before they are properly inclusive of underrepresented populations, including Black and Latinx individuals who are up to twice as likely to develop dementias that come with a loss of cognitive functioning. The traditional way of conducting these studies results in “serious threats” to the validity of the findings, according to board-certified neuropsychologist Monica Rivera-Mindt, Ph.D., a tenured professor at Fordham University with a joint appointment at the Icahn School of Medicine at Mount Sinai. 

Rivera-Mindt, speaking at the recent Clinical Trials on Alzheimer’s Disease conference in Boston, points to an assortment of deficiencies in need of redress, including inadequate characterization of underrepresented groups, utilization of tests that may not always be making the intended measurements, and a paucity of sociocultural measures that are known to have significant associations with cognitive test outcomes. Change is certainly possible, she says, pointing to equitable and valid AD studies conducted during the pandemic.  

Often noticeably absent in Alzheimer’s and related dementia clinical trials are people with expertise in neuropsychology and other aspects of neuroscience who are best equipped to lead the charge, says Rivera-Mindt, drawing a parallel with running an MRI study without a radiologist. “It hurts the studies... with regard to structural/systemic levels of analysis... [as well as] threats to external validity.” 

Rates of individuals who have either been enrolled or screened for the Alzheimer’s Disease Neuroimaging Initiative (ADNI), like most other clinical trials for AD, fail to represent the real-world proportion of Latino, Black, and Asian populations affected by the condition. In a systematic review of over 100 AD clinical trials conducted between 2001 and 2019, Rivera-Mindt and her colleagues found that 95% of participants were non-Latinx Whites (Alzheimer’s & Dementia, DOI: 10.1002/alz.12433).  

“People have been talking about inclusion for a long time, so we hoped over time to see a trend of greater inclusion, but we didn’t see it,” she says. “It was flat over almost 20 years, and... a big driving force for that differential exclusion of underrepresented populations had to do with inclusion/exclusion criteria and other [research] methodology.” 

Unexplained Variance

Although sociocultural factors account for a significant amount of variance in cognitive outcomes, clinical trials typically don’t consider them, says Rivera-Mindt. The unexplained variance extends to MRI outcomes, including some functional imaging data. 

Among the most-studied Black and Latinx populations, AD not only has an earlier age of onset but a “greater severity of initial cognitive symptoms,” she says. By 2030, the two subpopulations will make up “nearly 40% of over eight million American families affected by Alzheimer’s disease and related dementias and that is simply unacceptable.” 

AD and related dementias among the U.S. Latinx population between now and the year 2060 is expected to grow “exponentially” with a price tag in the billions, reports Rivera-Mindt. This is a looming public health emergency in terms of the direct cost of care and hospitalizations and the indirect cost for the “countless caregivers and [their] lost wages,” she adds, highlighting the “urgent need to advance brain health equity.” 

Up to now, AD clinical trials have taken a “universalist... one-size-fits-all approach” to understanding brain-behavior relationships at the biological level of analysis, continues Rivera-Mindt. The studies tend to be focused on pathology where the findings “can be open to racist interpretation” if not properly contextualized. The trials often exclude underrepresented populations and, when they are included, typically don’t use evidence-based approaches to conducting research with those groups, she says. 

Amyloid PET imaging is an important tool for early detection and providing insights into treatments, but the cut-offs that have been applied in AD trials are based primarily on non-Latinx White samples. The body of literature on this point remains “equivocal,” she says, in some cases finding lower amyloid levels in Black and other minoritized populations and at other times suggesting there are no differences.   

The study methodology is part of the problem. “Even in studies where there has been greater inclusion of diverse populations, [they] have not always been well characterized,” making it difficult to draw strong conclusions, says Rivera-Mindt. Additionally, many of the samples have been comprised of cognitively unimpaired adults. 

‘Within-Group Heterogeneity’

Rivera-Mindt favors a “bio-psycho sociocultural” AD research framework that also embeds a structural/systemic level of analysis. It considers “within-group heterogeneity,” given that race is a population- or continentally based social construct and not based in genetics per se, she says. 

When looking at the Latinx population, research suggests that there is more within-group than between-group heterogeneity. Rivera-Mindt was an investigator on one study that subsequently found significantly greater cognitive impairment from AD among Puerto Rican and other Caribbean Latinx individuals than Mexican Americans. 

“In fact, the rates of impairment in this community sample from all over the country was similar to the non-Latinx Whites,” she points out. The finding is consistent with other research suggesting that when the broad Latinx population is examined at a more granular level, Puerto Ricans tend to experience more and worse disparities than other Latinx subgroups. 

Work out of her lab and others also suggests that researchers “should be paying attention to acculturation and other sociocultural factors such as area of nativity [and] social isolation” because they have a substantial impact on cognitive test outcomes, Rivera-Mindt says. Evidence points to effects on both global T scores (a metric of health standardized to the general population) as well as CES-D (a scale for detecting caregiver depression). 

Priorities, Prism, Process

Rivera-Mindt offers “three Ps” for moving forward based on the priorities, prism, and process of researchers working in the field. In terms of priorities, she references a special report published by the Alzheimer’s Association in 2021 focused on the need for providers prepared to work with diverse populations as well as increasing the diversity of dementia care and participants in clinical trials.   

But it would be irresponsible to simply increase the enrollment of underrepresented populations without giving them a “safe, prepared research environment” to enter, Rivera-Mindt says. To center clinical trials on brain health equity will require more time and money as well as expertise, and not only from someone like her “who happens to be Afro-Caribbean and indigenous.... We all need to become more culturally competent.” 

Principal investigators (PIs) and leaders also need to be “walking the talk... at the front of the pack pulling the weight, modeling and demonstrating how this is important,” she continues. It’s something that needs to start at the top rather than be “marginalized” to assistant professors or study coordinators. And it means, starting now, “training everybody from PIs to front line staff... on what it means to be culturally competent” and supporting health equity scholars. 

AD researchers are also invited to change their prism so that instead of acting as a “conquistador” intent on getting data from individuals and then returning to their ivory tower they position themselves as a partner forging a relationship based on what they can give—be it disclosure of study results, compensation, travel, or whatever else might be needed. Power and leadership must be shared with community members, Rivera-Mindt stresses. 

“The study and the team orientation are typically very vertical and patriarchal and as we move into more community-based contexts, we need to be okay with it being somewhat more lateral,” she continues.  “The [current] goal orientation tends to be mercenary... focused just on the metrics of the outcomes,” and, if knowledge is shared at all, tends to be done in “performative” rather than meaningful ways. 

Research must start moving “to the streets” both in person and digitally, which is another way to increase access, says Rivera-Mindt. “We need to earn the trust of community members, which means we need to be in it to win it in for the long haul. This is not a cup of noodles; this is gumbo... slow-cooking research.”  

Although inclusive science is new and growing, she continues, an evidence base exists for the process to follow. A systematic review of 22 AD studies has found that the community-engaged research approach increases the inclusion of minority, underrepresented populations (Alzheimer’s & Dementia, DOI: 10.1016/j.trci.2019.09.018). 

Success Stories

Best practices for working with individuals from minoritized backgrounds cover everything from trial initiation to dissemination of study results, says Rivera-Mindt. At each stage of a research endeavor there are opportunities “to partner with community members, be informed by them, and create a positive feedback loop.” 

An 18-month pilot study Rivera-Mindt conducted with Ozioma Okonkwo, Ph.D., with whom she co-led the ADNI Diversity Taskforce, succeeded in increasing the rate of enrollment of underrepresented populations from one to four per month, she reports. Overall, the participating sites moved from about 20% up to 40% representation of minoritized groups. The tactics are now being deployed across the ADNI team where the goal is between 50% and 60% representation of those populations, based on their ethnocultural, education and socioeconomic status (SES). 

A consistent, community-engaged approach similarly improved retention in the Community Engaged Digital Alzheimer’s Research (CEDAR) study, designed to increase research participation of Black American research participants in the Brain Health Registry across multiple metrics (The Journal of Prevention of Alzheimer’s Disease, DOI: 10.14283/jpad.2023.32). Engagement strategies included incentives for study task completion, culturally informed communications, resources about brain health, and video and written testimonials by CEDAR participants. 

The Biomarker Evaluation in Young Onset Dementia From Diverse Populations (BEYONDD) pilot study now underway likewise aims to make research more inclusive, culturally informed and community engaged—and, most importantly, accessible through plasma and digital biomarkers. The study includes the option of having blood and digital biomarkers collected at people’s home or community settings.  

In the United States, creating more equitable and valid AD clinical trials will require thinking not only about a more rapidly diverse and older populace, but “intersectionality,” Rivera-Mindt says. “How does age intersect with ethnocultural status, with SES, [and] with gender identity,” she offers as an example. 

“We just need to flip our lens, change our priorities, our prism, and our process from a deficit model to an empowerment and resilience model that is based on evidence and inclusion science and the broad cadre of cultural neuroscience available to us,” she concludes. “Through actions of change, including working together with cultural humility... we can increase access, we can diversify trials, and... transform this next chapter in clinical trials and Alzheimer’s research.”