Pioneering treatments for Alzheimer’s disease that work by removing a toxic protein called beta-amyloid from the brain may benefit white Americans more than black Americans, whose disease may be driven by other factors, leading Alzheimer’s experts told Reuters.
The two drugs — Leqembi, from partner biotech firms Eisai ( 4523.T ) and Biogen ( BIIB.O ), and an experimental treatment developed by Eli Lilly ( LLY.N ), donanemab — are the first to offer real hope of slowing deadly disease for the 6.5 million Americans living with Alzheimer’s.
Although older black Americans have twice the rates of dementia as their white peers, they were screened out of clinical trials of these drugs at a higher rate, according to interviews with 10 researchers as well as four Eisai and Lilly executives.
Potential black volunteers with early disease symptoms did not have enough amyloid in their brains to qualify for the trials, the 10 researchers explained.
Hispanics, who experience dementia at one and a half times the rate of whites, were also ruled out at a somewhat higher rate because of low amyloid, although the problem was not as pronounced as for black people, five of the researchers said.
The growing evidence of a disparity around amyloid, a defining characteristic of Alzheimer’s, raises questions among some researchers about who will benefit from the two new treatments — the first ever proven to slow the rate of cognitive decline, the researchers said.
Referring to Leqembi, Dr. Crystal Glover, a social psychologist and aging justice expert who directs clinical trial recruitment for the Rush Alzheimer’s Disease Research Center in Chicago: “Does this even apply to the groups most at risk?”
About 20% of elderly blacks are estimated to have Alzheimer’s or another dementia, twice as many as whites and over 14% of Hispanics.
Some researchers question whether black patients experience dementia due to causes other than Alzheimer’s, or whether the disease manifests differently in different populations that have higher rates of chronic conditions.
The difference in beta-amyloid adds to evidence that some measures of health may not work the same way in different populations as they do in white people.
Leqembi will be launched at a price of $26,500 a year after it received full US regulatory approval this month.
A spokesman for the US Food and Drug Administration said the agency was aware of the potential exclusion of some African-Americans from the new treatments because of insufficient amyloid levels.
The spokesman said the FDA is encouraging companies to increase enrollment of different populations in their ongoing trials. In April 2022, the FDA recommended that companies submit a diversity plan for enrollment.
“Not designed for specific ethnic groups”
Eisai said it is working to understand why so many black people seeking to enroll in its clinical trials for Leqembi were screened out due to lack of amyloid. The company told Reuters that 49% of black volunteers did not meet the trial’s amyloid threshold requirements, compared with 22% for whites and 55% for Hispanics.
That left only 43 black participants out of 947 people enrolled in the American portion of the trial, or 4.5% of the total trial — a significant underrepresentation, since the disease is most prevalent in black Americans, who make up 13.7% of the US population.
Despite the amyloid screening errors, Hispanics made up 22.5% of the US portion of Eisai’s trial, an overrepresentation compared to the US population.
“Is it because MCI (mild cognitive impairment) or early dementia symptoms in blacks are caused by other causes more than Alzheimer’s?” Eisai’s American boss, Ivan Cheung, told Reuters in an interview. “We’re looking into it.”
Only people who are amyloid-positive should get Leqembi “regardless of race and ethnicity,” Cheung said: “The drug was not designed to help specific ethnic groups or races.”
Eisai, which is based in Tokyo, is working with the National Institutes of Health (NIH), a US government health research agency, to test Leqembi’s effectiveness in preventing Alzheimer’s dementia among people with elevated amyloid but normal cognition.
The company is aiming for black enrollment of at least 8% in the 1,400-person trial, Shobha Dhadda, Eisai’s global head of biostatistics, told Reuters. So far, 95% to 98% of black candidates have not reached the amyloid threshold required for inclusion, she said.
Eisai’s partner Biogen did not participate in Leqembi’s development, but has rights to sell the drug.
Black people and Hispanics were also screened out at somewhat higher rates in the trial for Lilly’s experimental drug donanemab, said Dr. Mark Mintun, Lilly’s group vice president of neuroscience research and development. The drug is currently being reviewed by the FDA.
In the United States, 4% of participants were black and 6% were Hispanic, Lilly said. The company said it acknowledged those numbers were low despite its efforts to increase recruitment, and that it aims for enrollment in its US trials to generally reflect the makeup of the population.
Lilly said research into why black and Hispanic people were screened out of trials at higher rates is ongoing and that there were many hypotheses, including that their dementia is not caused by Alzheimer’s or that they are at an earlier stage of Alzheimer’s, but that their disease is complicated by other factors such as small strokes.
Clinical trials typically have low enrollment of diverse populations: Among U.S. trials that reported race and ethnicity, about 80% of participants were white, 10% were black, 6% were Hispanic and 1% were Asian, a 2022 study found. 96 dementia trials from 2000-2017, diverse populations accounted for only about 11% of enrollment, according to a 2018 study.
Alzheimer’s researchers have moved away from using outward signs, such as memory loss, to identify patients with the disease to detecting Alzheimer’s-associated proteins in the body, including amyloid, which can occur long before dementia sets in.
Still, some tests used to identify these proteins may work differently among black and white patients.
Differences in the causes of Alzheimer’s were noted in a small 2015 study that compared the brains of black and white people who died of the disease.
The study, led by Dr. Lisa Barnes, who is also at the Rush Center, found that white people were more likely to carry Alzheimer’s-associated proteins as the primary cause of their dementia. Among black people who died of Alzheimer’s, their dementia was more likely to be due to multiple causes, such as vascular disease.
Subsequent studies involving brain scans, spinal fluid and blood samples — many citing Barnes’ work — have also found differences.
In a 2021 paper published in Nature Reviews Neurology, Barnes argued that researchers need a better understanding of Alzheimer’s in black people or effective treatments would not be available to this vulnerable but underrepresented population.
“We’re seeing that come to light with this recent drug,” Barnes said in an email to Reuters, referring to Leqembi.
“We need to know what the other pathologies are beyond amyloid that lead to dementia in black people and how risk factors, especially socially constructed risk factors, relate to those pathologies,” Barnes said.
Dr. Joshua Grill, a University of California, Irvine, Alzheimer’s researcher who collaborated with Eisai and other researchers to analyze two trials for Leqembi and two for an earlier anti-amyloid drug also found that black, Hispanic and Asian people were more likely to be screened out of clinical trials because the amount of amyloid in their brain was below the trial threshold. The researchers intend to submit the results for publication.
“Is it that it’s not Alzheimer’s disease? Is there something else that’s causing their cognitive problems across all these studies? Is it that the biomarkers don’t quite work the same in those communities, or is it something else that we don’t able to measure?” Grill said.
Two researchers told Reuters that one possible explanation for the differences in amyloid is APOE4, a variant of a gene that regulates amyloid deposits in the brain and is associated with a greater risk of late-onset Alzheimer’s. The risk of developing the disease among people with the variant is higher in people of Asian or European descent and lower in people of African and Hispanic descent, according to the National Institutes of Health (NIH).
Differences in APOE4 may help explain why more black people do not meet the amyloid thresholds required for recent drug trials, said Dr. Reisa Sperling of Brigham and Women’s Hospital, who is leading the trial of Leqembi to prevent Alzheimer’s dementia. Other factors may be at play, experts said.
In the United States, more than 75% of black Americans are overweight or obese, which increases their risk of hypertension, high cholesterol, type 2 diabetes and sleep apnea – factors that increase the risk of vascular dementia, according to data from the US government. Socioeconomic factors play a role in obesity, and may also play a role in dementia.
A number of recent studies show that racism and resulting inequalities in income, access to quality medical care and healthy food, exposure to pollution and chronic stress affect the health and possibly the underlying biology of different populations.