Two much-hyped new treatments for Alzheimer’s that work by removing a toxic protein called beta amyloid from the brain may benefit whites more than blacks – whose disease may be driven by other factors, and who appear to have lower levels of amyloid, say experts.
The two drugs, Leqembi, from partner biotech firms Eisai and Biogen, and an experimental treatment developed by Eli Lilly, called donanemab, are the first to offer real hope of slowing the fatal disease for the millions of Alzheimer’s sufferers.
However, although older black Americans have twice the rate of dementia as whites, they were screened out of the clinical trials at a higher rate, reports Reuters, after interviews with 10 researchers and four Eisai and Lilly executives revealed that prospective black volunteers with early disease symptoms did not have enough amyloid in their brain to qualify for the trials.
Hispanics, who experience dementia at one and a half times the rate of whites, were also excluded at a higher rate due to low amyloid, though the issue was not as pronounced as for black people, some 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 ageing research who leads clinical trial recruitment of the Rush Alzheimer’s Disease Research Centre in Chicago, asked: “Is this even applicable to those groups 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 question 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 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.
‘Not designed for specific ethnic groups’
Eisai said it was working to understand why so many black volunteers wanting to enrol in its clinical trial for Leqembi were screened out because of a lack of amyloid, and that 49% of them did not meet the amyloid threshold requirements, compared with 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, as the disease is most prevalent in black Americans, who comprise 13.7% of the US population.
Despite the amyloid screening failures, Hispanics made up 22.5% of the US arm of Eisai’s trial, an over-representation compared with the country’s 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 US head Ivan Cheung told Reuters. “We’re looking into it.”
Only people who are amyloid positive should get Leqembi, “irrespective of race and ethnicity”, Cheung added: “It was not designed to help specific ethnic groups or races.”
Tokyo-based Eisai is working with the US National Institutes of Health (NIH) to test Leqembi’s effectiveness in preventing Alzheimer’s among people with elevated amyloid but normal cognition, and is targeting black enrolment of at least 8% in the 1 400 person trial, said Shobha Dhadda, Eisai’s global head of biostatistics.
So far, 95% to 98% of black candidates are failing to meet the amyloid threshold, she added.
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 being reviewed by the FDA.
In the US, 4% of the participants were black and 6% Hispanic, Lilly said. The company acknowledged those numbers were low, despite its efforts to increase recruitment.
Lilly said the research into why black and Hispanic people were screened out of trials at higher rates is ongoing and 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 enrolment 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% were Asian, a 2022 study found.
In 96 dementia trials from 2000-2017, diverse populations made up only around 11% of enrolment, found a 2018 study.
Biological markers
Alzheimer’s researchers have shifted from using outward signs, like memory loss, for identifying patients with the disease, to instead, detecting Alzheimer’s-associated proteins in the body, including amyloid, which can occur long before dementia sets in.
Yet some tests used to identify these proteins may perform differently among black and white patients.
Differences in Alzheimer’s drivers 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 Centre, 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, like vascular disease.
Subsequent studies involving brain scans, spinal fluid and blood tests – many citing Barnes’ work – have also found differences.
Barnes has argued that scientists need a better understanding of Alzheimer’s in black people or else effective treatments will not be available to this at-risk, but under-represented population.
Dr Joshua Grill, a University of California-Irvine Alzheimer’s researcher, who collaborated with Eisai and other researchers to analyse two trials for Leqembi and two for an earlier anti-amyloid drug, also found that black, Hispanic and Asian people were likelier to be excluded from clinical trials because the amount of amyloid in their brain was below the trial’s threshold.
“Is it that it’s not Alzheimer’s? 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 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 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, says the National Institutes of Health (NIH).
Differences in APOE4 could help explain, then, why more black people fail to meet the amyloid thresholds required for trials, said Dr Reisa Sperling of Brigham and Women’s Hospital, who is leading the trial of Leqembi.
Other factors could also be at play, experts said.
In the US, 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. Socio-economic factors play a role in obesity, and may also play a role in dementia.
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