By Julie Steenhuysen
NEW YORK (Reuters) - Groundbreaking treatments for Alzheimer's disease that work by removing a toxic protein called beta amyloid from the brain may benefit whites 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 and Biogen (NASDAQ:BIIB), and an experimental treatment developed by Eli Lilly (NYSE:LLY), donanemab - are the first to offer real hope of slowing the fatal disease for the 6.5 million Americans living with Alzheimer's.
Although older Black Americans have twice the rate of dementia as whites, they were screened out of clinical trials of these drugs at a higher rate, according to interviews with 10 researchers as well as 4 Eisai and Lilly executives.
Prospective Black volunteers with early disease symptoms did not have enough amyloid in their brain 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 excluded at a somewhat higher rate due to low amyloid, though the issue 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, is raising questions among some scientists 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 expert in equity in aging research who leads clinical trial recruitment of the Rush Alzheimer's Disease Research Center in Chicago, asked: "Is this even applicable to the groups that are most at risk?"
About 20% of older Black people are estimated to have Alzheimer's or another dementia, twice the rate of white people and above the 14% of Hispanics.
Some researchers are asking whether Black patients are experiencing dementia due to causes other than Alzheimer's or whether the disease manifests differently in diverse populations who have higher rates of chronic conditions.
The disparity in beta amyloid is adding to evidence that some health metrics may not work the same in diverse populations as they do in white people.
Leqembi is being launched at a price of $26,500 per year after it received full US regulatory approval this month.
A US Food and Drug Administration spokesperson said the agency was aware of the potential exclusion of some African Americans from the new treatments due to insufficient amyloid levels.
The spokesperson said the FDA encourages companies to increase enrollment of diverse populations in their ongoing trials. In April of 2022, the FDA recommended 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 trial for Leqembi were screened out due to a lack of amyloid. The company told Reuters that 49% of Black volunteers did not meet the trial's amyloid threshold requirements compared to 22% for whites and 55% for Hispanics.
That left just 43 Black participants out of 947 people enrolled in the US portion of the trial, or 4.5% of the total - a stark under-representation since the disease is most prevalent for Black Americans and they make up 13.7% of the U.S. population.
Despite the amyloid screening failures, Hispanics made up 22.5% of the U.S. arm of Eisai's trial, an overrepresentation compared to the US population.
"Is it because MCI (mild cognitive impairment) or early dementia type-symptoms in Blacks are caused by other reasons more so than Alzheimer's?" Eisai's U.S. head Ivan Cheung told Reuters in an interview. "We're looking into it."
Only people who are amyloid positive should get Leqembi "irrespective 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 targeting 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 are failing to meet 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 for neuroscience research and development. The drug is currently being reviewed by the FDA.
In the US, 4% of the participants were Black and 6% were Hispanic, Lilly said. The company said it recognized those numbers were low despite its efforts to increase recruitment and that it aims to have enrollment in its US trials overall reflect the make-up of the population.
Lilly said the 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 in an earlier phase 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 US trials that reported race and ethnicity, about 80% of participants were white, 10% were Black, 6% were Hispanic and 1 percent were Asian, a 2022 study found. In 96 dementia trials from 2000-2017, diverse populations only made up around 11% of enrollment, according to a 2018 study.
BIOLOGICAL MARKERS
Alzheimer's researchers have moved away from using outward signs, such as memory loss, for identifying patients with the disease towards detecting Alzheimer’s-associated proteins in the body, including amyloid, that can occur long before dementia sets in.
Yet some tests that are used to identify these proteins may perform differently among Black and white patients.
Differences in the drivers of Alzheimer's were noted in a small 2015 study comparing brains of Black and white individuals 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 driver of their dementia. Among Black people who died of Alzheimer's, their dementia was more likely to result from multiple causes, such as vascular disease.
Subsequent studies involving brain scans, spinal fluid and blood tests - many citing Barnes' work – have also found differences.
In a 2021 paper published in Nature Reviews Neurology, Barnes argued that scientists need a better understanding of Alzheimer's in Black people or else effective treatments would not be available to this at-risk, but under-represented 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's threshold. The researchers intend to submit the findings for publication.
"Is it that it's not Alzheimer's disease? Is something else 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're not able to measure?" Grill said.
Two researchers told Reuters one possible explanation for the differences in amyloid is APOE4, a variant of a gene that regulates amyloid deposits in the brain and that 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 those of Asian or European ancestry and lower in people of African and Hispanic ancestry, according to the National Institutes of Health (NIH).
Differences in APOE4 could help explain why more Black people are failing to 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 could be at play, experts said.
In the United States, more than 75% of Black Americans are overweight or obese, increasing their risk of hypertension, high cholesterol, type 2 diabetes and sleep apnea - factors that raise the risk of vascular dementia, according to US government data. Socioeconomic factors play a role in obesity, and may also play a role in dementia.
A number of recent studies are finding that racism, and resulting inequities in income, access to high-quality medical care and healthy food, exposure to pollution and chronic stress affect the health and possibly the underlying biology of different populations.