Black and Hispanic people are up to twice as likely as whites to develop Alzheimer’s disease, but they have a much lower chance of being included in clinical trials of Alzheimer’s treatments.
People of color made up only 20% of the participants in trials1 for the Alzheimer’s drug lecanemab, approved in July 2023, and less than 10% in the trial2 for donanemab. The 1,736-person donanemab trial – which was presented by Indianapolis, Indiana-based pharmaceutical company Eli Lilly at last month’s Alzheimer’s Association International Conference (AAIC) in Amsterdam – included only 19 black participants who received the drug.
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The low numbers have some researchers worried about whether these drugs — the first to show improvements in clinical outcomes for people with Alzheimer’s — will work for people of color, and whether these trials are fully addressing the causes of dementia, which can vary across demographics.
“I don’t think it should be acceptable for clinical trials to be so unrepresentative,” says neurologist Gil Rabinovici of the University of California, San Francisco. “This is a call to arms.”
In April 2022, the US Food and Drug Administration, based in Silver Spring, Maryland, introduced guidelines recommending that trials reflect the diversity of people who will use the drug — but that doesn’t always happen. The lack of diversity is particularly acute for Alzheimer’s disease. This is because participants in trials testing monoclonal antibodies such as lecanemab and donanemab must have sufficient levels of the sticky amyloid protein that accumulates in the brains of people with Alzheimer’s.
At the AAIC, neurologist Doris Molina-Henry, of the University of Southern California in Los Angeles, presented a study showing that having low amyloid levels made people of color two to four times less likely to qualify for an ongoing trial than their white counterparts. to test whether lecanemab could prevent Alzheimer’s. A study3 presented at the 2022 AAIC meeting found similar trends in data from nearly 11,000 people in the early stages of Alzheimer’s who underwent positron emission tomography (PET) scans to determine whether they could participate in four separate Alzheimer’s trials run by Eisai , a biopharmaceutical company. based in Tokyo.
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Qualifying for the latest donanemab trial was even more difficult, says Lilly’s senior medical director, John Sims, because the company screened for both amyloid and tau, another Alzheimer’s-related protein. Only one in eight black and one in 17 Hispanic volunteers qualified, he says, compared to one in four white applicants.
“The field really needs to understand why this keeps happening,” says Alzheimer’s researcher Joshua Grill at the University of California, Irvine. It is unclear why people of color would have lower amyloid or tau levels than their white counterparts with the same amount of cognitive impairment. Grill speculates that dementia in people of color may often be caused by other conditions such as vascular disorders or inflammation. External factors such as education level and stress may also contribute to dementia risk, and some evidence suggests that certain genetic variants involved in Alzheimer’s risk differ between people of European and African descent4,5.
Amyloid levels aren’t the only reason Alzheimer’s trials lack racial diversity, says Reisa Sperling, a neurologist at Harvard University in Cambridge, Massachusetts. People of color are less likely than whites to live near hospitals with PET scanners used to determine whether a drug is working, and recruitment campaigns typically target white communities. People of color also face higher rates of conditions that disqualify them from trials, such as cardiovascular disease and lupus. “We need to look at all of our inclusion and exclusion criteria: which ones are necessary and which contribute to inequities in who we bring in,” says Sperling.
Grill and others are concerned about whether lecanemab and donanemab will be safe and effective in different populations. Recent trials have shown that monoclonal antibodies can slow cognitive decline by about 30% in selected groups of people with Alzheimer’s who have mild cognitive impairment. But neither drug stops the progression of the disease, and both frequently cause brain abnormalities that can lead to bleeding, seizures or death. Sims says Lilly’s recent donanemab trial had too few participants of color to determine whether those risks, or even the drug’s effectiveness, differ by race.
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That worries Jennifer Manly, a neuropsychologist at Columbia University in New York City, who says she would hesitate to recommend monoclonal antibodies if a black family member had Alzheimer’s. “I want to know that the people in the clinical trials were as close to my family members as they can get — their lived experiences, backgrounds and health risks,” she says. “We don’t have that for black and Hispanic people right now.”
The lack of diversity in clinical trials is not only a justice issue, but also a scientific issue, Manly says, because it could prevent researchers from determining the causes of Alzheimer’s and other forms of dementia. The limited success of monoclonal antibodies against amyloid has made it increasingly clear that Alzheimer’s is not just driven by amyloid or tau, she says. If drugs are focused only on these proteins, it may miss other factors that contribute to the disease across populations. “It’s not just about developing the treatment, but about understanding the differences so they can inform the design of future studies,” says Molina-Henry.
Eisai is now working with community groups such as churches to advertise its trial more widely, said Shobha Dhadda, Eisai’s senior vice president of biostatistics and clinical development operations for neurology. The first step in the Alzheimer’s Prevention trial will screen potential participants for amyloid levels with a new blood-based test that should help weed out people who don’t qualify without forcing them to undergo cognitive tests or PET scans. Lilly is also ramping up similar recruitment strategies in its donanemab trials: Sims says it has doubled the number of people of color participating in a 1,000-person safety trial that ends later this year. It is also switching from PET scans to blood tests in an ongoing trial testing whether donanemab can prevent Alzheimer’s.
Grill would also like to see more infrastructure for Alzheimer’s registries that can direct disqualified people to other trials that can help them more. “I’m very worried that by rejecting them they will go back to their community and say, ‘They didn’t want me,'” he says. “We don’t want to add to the stigma of illness or lower trust in society.”