The medications have not been widely tested in Black people with the disease,
underscoring stark — and persistent — disparities
By Laurie McGinley, January 29, 2024 at 6:00 a.m. EST
ABINGTON, Pa. — Wrapped in a purple blanket, Robert Williford settles into a quiet corner of a
bustling neurology clinic, an IV line delivering a colorless liquid into his left arm.
The 67-year-old, who has early Alzheimer’s disease, is getting his initial dose of Leqembi. The drug is
the first to clearly slow the fatal neurodegenerative ailment that afflicts 6.7 million older Americans,
though the benefits may be modest. The retired social worker, one of the first African Americans to
receive the treatment, hopes it will ease his forgetfulness so “I drive my wife less crazy.”
But as Williford and his doctors embark on this treatment, they are doing so with scant scientific data
about how the medication might work in people of color. In the pivotal clinical trial for the drug,
Black patients globally accounted for only 47 of the 1,795 participants — about 2.6 percent. For U.S.
trial sites, the percentage was 4.5 percent.
The proportion of Black enrollees was similarly low for Eli Lilly Alzheimer’s drug, called donanemab,
expected to be cleared by the Food and Drug Administration in coming months. Black people make
up more than 13 percent of the U.S. population.
HEALTH
The paltry data for the new class of groundbreaking drugs, which strip a sticky substance called
amyloid beta from the brain, has ignited an intense debate among researchers and clinicians. Will the
medications — the first glimmer of hope after years of failure — be as beneficial for African
Americans as for White patients?
“Are these drugs going to work in non-Whites? And particularly in Blacks? We just don’t have enough
data, I don’t think,” said Suzanne E. Schindler, a clinical neurologist and dementia specialist at
Washington University in St. Louis. “In general, the default is that they will work the same in
everybody, but we don’t really know that for sure.”
The situation casts a spotlight yet again on the decades-long failure of researchers to reflect the
increasingly diverse character of the patient population in the United States, and underscores the
stark disparities in Alzheimer’s treatment and care. Black Americans develop the disease and related
dementias at twice the rate of their White counterparts, but are less likely to receive specialized care
and are diagnosed at later stages, studies show. That’s an urgent problem considering that the new
drugs must be used early to have an effect.
In addition, a perplexing new issue appears to be contributing to low Black enrollment in trials and is
fueling a debate among experts about the role of race, genetics and other factors. To qualify for the
main trial for Leqembi — developed by the Japanese pharmaceutical giant Eisai and the
biotechnology company Biogen of Cambridge, Mass. — participants were required to have elevated
levels of brain amyloid, a defining characteristic of Alzheimer’s, and symptoms such as memory loss.
But brain scans showed that the African American volunteers were less likely to have excess amyloid
than White patients and thus were excluded from the trial at higher rates. Almost half of Black
applicants failed to meet the amyloid threshold, compared with 22 percent of White volunteers,
according to Eisai. A similar pattern occurred with the Lilly drug and in some other studies, and
sometimes involved other people of color, including Hispanics.
Experts are baffled by the findings. Why would amyloid levels — thought to be a key driver of
Alzheimer’s — be different in people with similar cognitive problems?
“Is it the color of someone’s skin? Almost certainly not,” said Joshua D. Grill, an Alzheimer’s
researcher at the University of California at Irvine. “Is it a difference in genetics? Or other health
conditions, like cholesterol, blood pressure or vascular health? Or is it something else, that we
haven’t measured?”
While the biology of Alzheimer’s is almost surely the same regardless of race, some researchers say
the patients themselves might be different because of underlying health conditions. Some older Black
patients diagnosed with Alzheimer’s, they say, might actually have vascular dementia stemming from
heart disease, hypertension and diabetes — all conditions more prevalent among African American
patients.
The risk of vascular damage also could be increased by a lack of access to health care and years of
exposure to racism, as well as genetics, some experts say. And many patients could have a
constellation of pathologies driven by other factors, they add.
Whatever the cause, experts say, the bottom line is the same: Patients who do not have excessive
amounts of the sticky brain protein should not be treated with the amyloid-targeting drugs because
the therapies are unlikely to work and pose substantial risks, including potentially deadly bleeding in
the brain.
But that raises the specter of another disparity. If it turns out that a lower proportion of Black
dementia patients and other people of color have excess amyloid, they could be left behind as the
drug industry races to develop amyloid-reducing treatments. To counter that, experts are urging
companies to accelerate work addressing other potential drivers of cognitive decline and to develop
combination drugs with multiple targets.
“If we are just targeting amyloid, we can just miss a large potential population that might benefit
from treatment,” said Lisa L. Barnes, a neuropsychologist at Rush University in Chicago.
‘A brain is a brain’
For now, the question remains: What should Black patients and their doctors think about the anti-
amyloid drugs?
The answer, experts say, depends largely on the level of amyloid in their brains.
More than a year ago, Williford was diagnosed with early Alzheimer’s by David C. Weisman, a
neurologist at Abington Neurological Associates, a large practice north of Philadelphia that treats
patients and conducts clinical trials for drug companies. The clinic was one of the test sites for
Leqembi.
After Leqembi received full FDA approval last summer, Williford underwent tests to determine
whether he was a good candidate for the drug. One test — a lumbar puncture, sometimes called a
spinal tap — showed elevated amyloid in his brain. That means Williford and similar patients are
likely to benefit from an anti-amyloid medication regardless of their race or ethnicity, Weisman and
several other experts said.
“A brain is a brain is a brain, whether it is Asian, Hispanic, African American or White,” Weisman
said. “A patient is either a good fit or a bad fit, and Robert is a good fit.”
Williford, who spent years working with troubled families in Philadelphia, began having memory
problems a few years ago, said his wife, Cynthia Byron-Williford, 59.
“You could tell him almost anything, and he would almost immediately forget,” she said. “If I asked
him to make a peanut butter sandwich for our grandson, he would come back three times and say,
‘What am I supposed to do?’”
With few treatment options, many physicians say they will offer anti-amyloid therapy to any patient
who has elevated levels of the substance and passes safety tests.
Barry W. Rovner, a neurology professor at Thomas Jefferson University in Philadelphia, said he
would not hesitate to offer Leqembi to African American patients who tested positive for amyloid.
But, he added, because of the low numbers of Black individuals in the Leqembi trial, “I would say,
‘Look, this has not been tried in many Black people, so we don’t know precisely how it is going to
work. But you don’t know precisely how it will work in any person.’”
From a research perspective, “You could say, as a group we don’t know if Black individuals respond
the same way to anti-amyloid drugs because we don’t have the data,” Washington University’s
Schindler said. “But on an individual level, it is different. If I had a Black patient who was amyloid-
positive, I would start him on these drugs.”
But some Black patients might not be comfortable with the medication.
Zaldy S. Tan, director of the memory disorders center at Cedars-Sinai Medical Center in Los Angeles,
said when African American patients are informed about the risks and benefits of Leqembi, and
about the sparse data available for Black individuals, some will “take a pause and question whether
they are willing to accept the uncertainty” and challenges of receiving the every-other-week infusion
and multiple follow-up tests.
A promise of diversity
The best way to know for sure how drugs for Alzheimer’s — and other diseases — affect different
populations is to have more diversity in trials, experts agree. But research participation by Black
Americans and other people of color has been held down for years for several reasons.
The 20th century’s infamous Tuskegee syphilis study created long-standing mistrust about trials
within the African American community. Men were left untreated to suffer and die even after an
effective treatment emerged for the bacterium.
Alzheimer’s research, meanwhile, has long been centered in memory clinics at elite academic
institutions, which tend to attract well-heeled patients with health insurance and other resources.
The clinics have served as effective recruiting grounds for trials that end up with a predominantly
White enrollment.
“We have done a poor job of making African American Alzheimer’s research inclusive,” said John
Morris, a neurologist at Washington University in St. Louis. More than two decades ago, he created
an African American advisory board at the school’s Knight Alzheimer Disease Research Center after
realizing only 3 percent of trial participants were Black.
Others also are redoubling efforts to increase diversity. John Dwyer, president of the Global
Alzheimer’s Platform Foundation, a nonprofit that runs trials, said the organization has sharply
increased participation by people of color by sending dedicated teams of African American and
Latino professionals into communities to build relationships with physicians and personnel at health
centers, senior centers and places of worship. They stress to the communities how much they can
benefit from the studies, he said.
Stephanie Monroe, vice president and senior adviser of health equity and access at the advocacy
group UsAgainstAlzheimer’s, noted that low Black enrollment is not limited to Alzheimer’s trials. If
all the drugs that have not been tested on people of color were eliminated, the shelves of pharmacies
would be nearly empty, she said.
“That doesn’t work when you are almost a 50-50 minority/majority population,” Monroe said.
The FDA has issued guidelines for industry designed to bolster diversity in studies, while the National
Institute on Aging recently pledged to prioritize funding requests that are “appropriately inclusive.”
The low Black enrollment in studies is just the latest controversy involving the anti-amyloid drugs.
For years, earlier versions of the drugs failed repeatedly in trials. By contrast, Leqembi, in an 18-
month trial, showed unambiguous, if modest, benefits, slowing disease progression by about 27
percent, or roughly five months. The drug, administered every other week, carries a list price of
$26,500 a year.
In July, Lilly reported that its anti-amyloid drug, donanemab, was even more effective at removing
amyloid. But like Leqembi, it can cause serious side effects, including brain hemorrhages. Some
doctors think the drugs will provide bigger benefits when taken for a longer period or earlier in the
disease, but others say the medications, which require repeated MRIs to check for side effects, leave
much to be desired.
Both Eisai and Lilly said they are working hard to increase diversity in clinical trials. In the
meantime, they said, patients with elevated amyloid should benefit from the anti-amyloid drugs,
regardless of race or ethnicity.
“We have no pathophysiological reason to expect different efficacy between races and ethnicities for
Alzheimer’s treatments that remove amyloid,” Lilly said in a statement.
Eisai acknowledged that the Leqembi trial was not designed to test the drug in individual racial and
ethnic subgroups. But it said in a statement that the totality of the evidence indicated that “all
patients, regardless of ethnicity, benefited from treatment” with the drug.
“We and the U.S. FDA — as evidenced by the agency’s approval of Leqembi — believe that the
benefits and risks in these patient populations and races has been established,” the company added.
Eisai said volunteers who did not pass the amyloid threshold did not have Alzheimer’s and should be
assessed for other conditions.
In an interview, Teresa Buracchio, acting director of the FDA’s Office of Neuroscience, said the
agency “did not see a notable difference by race” in safety and effectiveness in the limited data
available on subgroups in the Leqembi trial.
But other experts were skeptical, saying the number of Black patients in the Leqembi trial was too
low to know whether the medication is safe and effective for African Americans. “Without having a
representative population, it is impossible to assess,” said Barnes, of Rush University. Some
researchers suggested that patients in underrepresented populations should wait for future advances
in treatment.
‘We just want to get going’
On a recent day, nurse Christine Besso bustled in and out of Williford’s infusion room at the
neurology clinic, taking his vital signs and inserting an IV line. “Let’s get this party started,” she said.
Byron-Williford, watching the process from a nearby couch, said she was not concerned about the
low numbers of African Americans in the Leqembi trial.
“I think it will work or not work based on the individual,” she said, adding with a laugh, “and if it
doesn’t work for him, it is because he is ornery.”
Byron-Williford said her husband’s health problems accelerated a few years ago after his son, who
was in his early 20s, died unexpectedly. Williford became depressed and lost his appetite. Last
summer, when he went to pick up his wife at a nearby hair salon, he drove around, lost. She later
confiscated his car keys.
In the clinic, shortly after Williford’s infusion began, Weisman stopped in to check on him and
discuss possible side effects. When Williford asked him how long he would be on the drug, Weisman
shrugged, saying it depended on how he did on the drug and on test results.
“We are getting on an airplane, and we don’t even have a destination airport yet,” Weisman said. “We
just want to get going.”