Parsing the role of race in Alzheimer’s biomarkers

Karen Titus

October 2021—It’s not quite six degrees of Kevin Bacon, but the connection between Alzheimer’s disease biomarkers and equity in medicine is real (and far more important).

It’s a trail researchers have been following for some time, but which has gained more prominence with the recent approval of a new drug for treating the disease (aducanumab) and the acknowledgment of racial disparities in CSF amyloid and tau biomarkers and their associated cutoffs.

Whitney Wharton, PhD, cognitive neuroscientist and associate professor of nursing and medicine, Emory University, has spent decades trying to unsnarl the threads. She recently spoke with CAP TODAY about the work she and colleagues in the field are doing and the impact it could have on clinical laboratories.

As she and others note, African American individuals are at an increased risk of Alzheimer’s disease but are underrepresented in most AD biomarker studies. At the same time, more recent studies have found that biomarker levels appear to be different in different racial groups.

In a sense, people like Dr. Wharton are pulling back the curtain on not one but two Wizards of Oz. Patients need to see what biomarkers mean for their health; physicians need to see the patients behind the biomarkers.

Since Dr. Wharton arrived at Emory some seven years ago, her focus on health disparities has been mostly through the lens of race. “That’s actually the reason I moved to Atlanta—from Wisconsin, which has a primarily non-Hispanic white population,” she says. She’s a clinical interventionist who designs lifestyle and pharmaceutical interventions to help prevent AD. Her investigations into the Alzheimer’s timeline is based on data showing blood and CSF biomarkers begin to accumulate in patients decades before clinical manifestations of the disease.

“My research is biomarker heavy,” says Dr. Wharton, “so in all of the clinical interventions I collect blood, spinal fluid, neuroimaging, and cognitive testing in people who are, as of right now, cognitively normal but at high risk, based on a number of factors,” such as gender and race. She does research with the LGBTQ community as well.

She also works closely with people like William Hu, MD, PhD, associate professor and chief of cognitive neurology at Rutgers, who is involved in research to establish fluid biomarkers to reflect the underlying pathology of AD. (See “CSF biomarkers in ‘a new era’ for Alz­heimer’s,” CAP TODAY, August 2021.)

Dr. Hu was the first to identify apparent differences in tau biomarker levels in African American/Black individuals versus non-Hispanic whites, with tau markers lower, on average, among those in the former group. These findings have since been replicated in patients as young as in their 20s, in studies done by Dr. Wharton and others.

“At first blush that would seem great,” says Dr. Wharton. But interventions that target tau might not be appropriate for every patient group, she says, if the disease in those patients is not marked by higher tau levels.

This was the work that led Dr. Hu and Dr. Wharton to contact the national bioethics center at Tuskegee University. Those conversations have helped researchers and physicians take a deeper look at race, equity, and biomarkers.

Dr. Wharton has also looked closely at other, independent biomarkers, primarily related to inflammation (e.g. IL-9). “What we found is that very subtle increases in IL-9 and brain inflammation in general in African Americans might be a bigger culprit and a bigger indicator of Alzheimer’s in comparison to tau. And we don’t currently have any therapeutics for Alzheimer’s disease that target inflammation.” No one, perfect biomarker for Alzheimer’s disease will cross all categories, including ancestry, sex, age, and disease status, she predicts. Instead, providers need to follow the science, she says. “We need to say, These seem to be, from the most recent studies, an indicator of brain health for African Americans. We need to take into account inflammation, like IL-9, as well as beta-amyloid and tau.”

While there’s nothing new about the need to identify biomarkers and establish cutoffs, Dr. Wharton sees an even older challenge embedded within that work. “Historically, there’s been such low representation of people in clinical research. And not just Alzheimer’s—childhood leukemia, breast cancer. . . .”

The link between history and biomarkers couldn’t be any more direct, in Dr. Wharton’s opinion: “We need to have equal representation of people of color in this clinical research, so we can find out what those biomarkers are.”

The primary patient cohorts in Atlanta are Black/African American and white. Other regional centers have different populations, of course, and can enroll other groups of patients; Dr. Hu intends to start biomarker studies looking at cohorts of Asian and Asian American patients (as he previously told CAP TODAY). “That will be exceedingly informative,” Dr. Wharton says.

Just as informative, she says, are the social determinants of health that may be linked to health disparities in people of color, and which may affect biomarkers.

Her work follows the community-based participatory research model. “That means I work very closely with community members, including Tuskegee,” she says, adding that her work is informed and driven by community, local, and national advisory boards. Outreach includes not only patients and their caregivers but also what she calls community gatekeepers, such as those who run health care organizations and those involved in the legal system. These are, in a sense, the earliest preanalytical variables. “We really try to say, How can we improve the representation of people of color in clinical research?”

That, in turn, has prompted her to take a closer look at why representation is so low. Historical harms might play a role—the infamous Tuskegee syphilis study, for instance, is routinely trotted out as a barrier.

As Dr. Wharton notes, however, current, real-life issues can prevent people from taking part in research. Lack of trust and trustworthiness are part of the picture as well—disparities that have been further exposed by the pandemic—but so are issues related to transportation and housing, she says.

While her biomarker research is translational, she also uses extensive questionnaires to collect data on access to health care, willingness to participate in clinical research, housing, criminal justice, transportation, and systemic, lifetime racism. The goal is to identify barriers, “and then see how they might influence things like inflammation that we know is a biomarker.”

Racism has physiological ramifications, she says. She refers to a tweet sent out this summer by one of her physician colleagues who was racially profiled while shopping and accused of stealing dress shirts, and who noted that the incident was interfering with his sleep and had raised his blood pressure. Asks Dr. Wharton: “What if it’s not just that one instance? What if that happens to someone over a lifetime? What does that do to someone’s health?”

There’s also room to wonder what this means, on a practical level, for clinical laboratories. “Sure,” she says. “I understand that. We all get very immersed in our primary and day-to-day work.

“But it is my strong opinion,” she continues, “that even if I’m looking at biomarkers, if we’re not understanding the mechanism, the root cause, by which these biomarkers influence disease—whether that’s kidney function, heart health, Alzheimer’s disease—then we’re not going to help anybody. I don’t always want to just give someone a pill to reduce blood pressure. I want to know why your blood pressure is high. Is that genetic? Is it because you’re stressed out all the time? What stresses you out about going to the doctor? Is it because you had to take off work and take two buses to get here? Is it the needles? Is it past atrocities? What is it?” There are, she says, “real clinical implications for all these structural inequities.” Not only can they affect mood and cognition, she says, but they are difficult to untangle from conditions such as high blood pressure and diabetes that are independent risk factors for Alzheimer’s disease.

None of this is easy work, she says, even among those who are committed to change. Investigators are sometimes not willing to collect data on structural inequities, either because it is a difficult topic for some or because they may not feel they have the time, given that their jobs are already overstuffed with obligations. Further complicating the disconnect between clinical research and health care and race-related issues is that people of color and others who’ve been disregarded by health care, such as those who are part of the LGBTQ community, may be hesitant to talk to medical professionals.

When conversation is constrained, it may feel more expedient to follow a speedy, rote script, Dr. Wharton says: You’re in here for blood pressure, so we’ll give you a pill to fix your blood pressure. “Instead of trying to understand what the root cause is and to look at the patient situationally and over a lifespan.”

If the culprit is genetic, medication alone might be fine, she acknowledges. “But is there something else we can do besides giving you medication? Can we help assuage other reasons that are contributing to high markers of inflammation?” Biomarkers alone aren’t enough for effective interventions, she argues, even if they meet the high bar clinicians typically set: that it has to be actionable. What happens after the results leave the laboratory and clinicians are acting? Can that be better? If not, she says, “you’re just kind of throwing buckets of water on a huge health fire.”