20 Nov 2024

Despite higher rates of clinically diagnosed dementia among people from non-white racial and ethnic groups, historically they have been underrepresented in AD clinical trials. Efforts are underway to boost recruitment among these populations into clinical studies. They are successful inasmuch as black and Hispanic people are showing up for trial screenings. However, as scientists reported at the CTAD conference held October 29 to November 1 in Madrid, current trials still end up with too few participants from underrepresented groups because scientists are finding that their prevalence of amyloid positivity is significantly lower than that of whites, rendering many eligible for trial enrollment.

New screening data reported from ongoing and past trials indicated that, across racial and ethnic groups, blood biomarkers were faithful predictors of amyloid plaques lurking in the brain. However, in both cognitively normal and impaired populations, non-Hispanic white volunteers consistently had higher amyloid prevalence, resulting in their overrepresentation in amyloid-targeted trials. AHEAD 3-45, TRAILBLAZER-ALZ2 and 3, and New IDEAS were the main studies presenting this finding at CTAD.

Other studies suggest that people from underrepresented groups tended to have more comorbidities, and to live with a higher burden of social and economic strain, both of which may contribute to health disparities. How this factors into amyloid prevalence remains unclear, noted Michael Weiner of the University of California, San Francisco. Because studies are prone to selection bias, he said, it is difficult to know if differences in amyloid prevalence reflect those found in broader ethnoracial populations. Others believe that the lower prevalence of amyloid in black and Hispanic communities implies that other underlying pathological processes—such as vascular dysfunction—drive higher dementia rates in them, and they called for more research on those processes. Scientists at CTAD sounded highly motivated to figure out which physiological factors underlie differences in the way dementia develops across populations (see also Nov 2023 conference news).

In Madrid, Doris Molina-Henry of the University of Southern California in San Diego presented biomarker screening data from AHEAD 3-45, a pair of AD prevention studies that are evaluating lecanemab in cognitively normal people with intermediate (A3) or elevated (A45) levels of amyloid accumulation at baseline (Nov 2024 conference news). The trial finished randomizing its 1,621 participants in October. Finding them was a tall order, requiring the screening of 20,721 people. Twenty-seven percent of those screened came from underrepresented ethnoracial groups, approaching the 2023 U.S. Census Bureau estimate of 33 percent of the U.S. population being black or Hispanic. This was progress. For comparison, the previous A4 prevention trial, which also attempted to diversify recruitment, netted 14 percent non-Hispanic white.

Alas, among those who were subsequently enrolled in A3 and A45, the percentage of people from these underrepresented groups was only 15 and 11 percent, respectively. In Madrid, Molina-Henry attributed most of these screen failures to volunteers having negative AD blood biomarker tests.

The trial aimed to enroll cognitively normal people with 20 to 40 centiloids of amyloid based on PET scans for A3, or greater than 40 centiloids for A45. The screening process took nearly four years. Initially, it started with blood collection and cognitive testing at the first visit, followed by an amyloid-PET scan at visit 2. Once AD blood biomarkers became validated, the researchers introduced a plasma prescreening step—first with Aβ42/40 and later adding in p-tau217—hoping to reduce the number of negative PET scans. In the final months of screening, to complete enrollment for A45, the researchers raised the plasma cut-off to let in more people with elevated amyloid (image below).

Stages of Screening. The early months of screening for AHEAD3-45 used cognition and amyloid-PET. Adding plasma screening—first with Aβ42/40, then also p-tau217—drove down the number of people who were subsequently shut out due to a negative amyloid PET scan. [Courtesy of Reisa Sperling, Brigham and Women’s Hospital.]

The scientists had previously reported outcomes of plasma prescreening based on the Aβ42/40 ratio, adjusted for age and ApoE4 status (Molina-Henry et al., 2024). During this phase of screening, they set the algorithm to select a plasma biomarker threshold predictive of at least 11 centiloids on amyloid-PET—an intentionally low bar to maximize recruitment for A3, Molina-Henry told Alzforum. That revealed that people self-identifying as non-Hispanic white were more likely to cross this threshold for amyloid positivity than people from any of the other ethnic or racial groups. Among those whose plasma biomarkers made them eligible to move forward to a PET scan, about half subsequently tested positive via amyloid-PET. This was true across all ethnic and racial groups, suggesting that the relationship between plasma Aβ42/40 and amyloid-PET positivity held across groups.

Who Gets In? Non-Hispanic whites (purple line) were less likely to be ineligible based on plasma biomarkers than were people from other ethnoracial groups. [Courtesy of Doris Molina-Henry, University of Southern California, San Diego.]

At CTAD, Molina-Henry showed results of the next phases of screening, which incorporated plasma p-tau217 along with Aβ42/40. For this, the scientists set the algorithm to select participants with blood biomarker levels predictive of at least 18 centiloid of amyloid. Adding this additional biomarker weeded out more people, further reducing the number of unnecessary PET scans. But again, non-Hispanic white people were more likely to have this much amyloid than any other group. While 27 percent of non-Hispanic whites were "plasma-eligible" to move forward with amyloid-PET, only 19 percent of Hispanic white, 11 percent of Hispanic black, 19 percent of non-Hispanic black, and 15 percent of Asian people were. Among those who moved forward with a scan, there were no differences across ethnoracial groups in how many would subsequently test positive for amyloid via PET.

Plasma Eligible? Measured by the same blood test, different ethnic and racial groups had different rates of amyloid positivity (orange, eligible; grey, ineligible). [Courtesy of Doris Molina-Henry, University of Southern California, San Diego.]

These findings show that the plasma thresholds are similarly effective across groups at predicting amyloid-PET positivity, Molina-Henry said. In other words, plasma screening does not disproportionately weed out potential participants from any group. The results also jibe with what others have found in the field: namely, that black, Hispanic, and Asian volunteers are less likely to have amyloid accumulation than their non-Hispanic white counterparts.

To Molina-Henry’s mind, this is striking given the higher prevalence of dementia among black and Hispanic people. Although AHEAD 3-45 enrolled cognitively normal people, 75 percent of those screened had a family history of dementia. Molina-Henry thinks that a higher prevalence of other diseases, including cardiovascular illness and diabetes, could drive this result of amyloid-independent forms of dementia among black and Hispanic communities. She emphasized that these comorbidities might in turn exacerbate amyloid-driven AD. These questions are ripe for study.

To do so, the scientists are enrolling people whose plasma or PET result kept them out of AHEAD3-45 into the Alzheimer Plasma Extension observational study. With 762 in it so far, APEX is 75 percent full, and more than half of the enrollees come from underrepresented racial or ethnic groups. It will track sociodemographic and health factors, as well as cognition and AD biomarkers. Molina-Henry hopes the data will reveal underlying causes of dementia and identify better biomarkers for them.

Another prevention effort, TRAILBLAZER-ALZ3, turned up similar results. In Madrid, Eli Lilly’s Karen Holdridge showed data of people who were screened in the trial, which is evaluating donanemab in cognitively normal people with brain amyloid based on plasma p-tau217. To expand its reach geographically and demographically, TRAILBLAZER-ALZ3 performed decentralized screening—ruling out cognitive impairment over the phone with the modified telephone interview for cognitive status (TICSm) and collecting blood for AD biomarker testing at third-party, often remote, sites. They screened 63,124 people in the U.S. and Japan, of whom 2,196 were randomized to drug or placebo. Of the more than 60,000 screen fails, 81 percent were due to low plasma p-tau217, 5.4 percent due to cognitive impairment.

Consistent with AHEAD 3-45, Holdridge reported greater ethnic and racial diversity among those who were screened than among those who were subsequently enrolled. For example, Hispanic/Latino people made up 13 percent of those who were screened, but only 8.2 percent of those randomized. For people identifying as black or African American, the differences were even greater, dropping from 10.5 to 2.6 percent from screening to enrollment. The opposite trend unfolded for white people, who went from 81.7 percent of the screened population to 93 percent of enrollees. Again, these differences were attributed to higher screen-fail rates among non-whites.

After Holdridge’s talk, Anton Porsteinsson of the University of Rochester, New York, noted that compared to the population screened for AHEAD3-45, where 75 percent had a family history of dementia, only 54 percent of participants screened for TRAILBLAZER-ALZ3 reported a first-degree relative with dementia. Similarly, while more than 70 percent of AHEAD3-45 participants were ApoE4 carriers, just over half of enrollees in TRAILBLAZER-ALZ3 were. Holdridge attributes this to a wider net cast during screening, by way of extensive community outreach with mobile research units and blood draws at health fairs. This made screening less reliant on self-selection. The different AD risk profiles of the two participant cohorts in these two prevention trials will make for a good comparison, Porsteinsson said.

Offering a potential counterpoint from a third population, Michael Hodsdon of Eli Lilly presented blood biomarker data from more than 2,000 people who were screened for the TRAILBLAZER-ALZ2 trial of donanemab in people with amyloid and mild cognitive impairment or mild dementia. While primarily about clinical validation of Lilly’s SPX p-tau217 assay, Hodsdon’s talk included a comparison of the assay’s performance across ethnoracial groups.

Nearly two-thirds of screened people were amyloid-positive according to the p-tau217 test, which in turn was more than 90 percent concordant with amyloid-PET, Hodsdon reported. At 65 and 61 percent, respectively, amyloid prevalence was similar between whites and non-whites. Hodsdon did not break down these racial groups by ethnicity, so both the white and non-white groups comprised Hispanic and non-Hispanic people. Likewise, Hodsdon did not report Aβ status for black/African Americans and Asians. In a separate comparison by ethnicity, Hodsdon found that only 37 percent of Hispanic people were amyloid-positive, compared to 80 percent of non-Hispanics. One clear finding from this cognitively impaired cohort was that Hispanic people had much lower rates of amyloid positivity than their non-Hispanic counterparts.

After Hodsdon’s talk, Charlotte Teunissen of Amsterdam University Medical Center noted that data from several studies are converging on the idea that people from underrepresented groups indeed have a lower prevalence of amyloid positivity. She wondered if there are better ways to identify people with underlying causes of cognitive impairment other than AD prior to trial screening. Others concurred, saying the field can now focus on understanding non-AD factors responsible for the higher rate of cognitive impairment in these groups. “Instead of squeezing them in to fit with what we do know about AD, we need to figure out what’s causing these impairments,” one audience member said.

APEX is attempting to do that. The study attempts to chronicle AD biomarkers along with various comorbidities such as cardiovascular disease, diabetes, and stroke, as well as sociodemographic factors in the development of cognitive impairment. “We think it’s disadvantage in these communities as a whole that makes them have higher rates of comorbidities,” Molina-Henry told Alzforum. Those comorbidities, she believes, influence what kind of dementia might develop.

Some of these social factors took center stage in a talk by Gil Rabinovici, University of California, San Francisco. He presented demographics and amyloid-PET results from New IDEAS. Similar to its predecessor, this study set out to test if amyloid-PET scans added enough value to clinical care to warrant coverage by Medicare. New IDEAS set the goal of enrolling at least 4,000 black/African American or Hispanic/Latino participants, among its target of 7,000 participants.

In Madrid, Rabinovici explained that the study fell short of those goals because it was terminated early. This happened in the wake of a decision in October 2023 by the Centers for Medicare and Medicaid Services to expand coverage for amyloid-PET, obviating the need to demonstrate that amyloid-PET warrants coverage. Rabinovici said they initially decided to continue anyway, using the newly expanded coverage to pay for their participants’ PET scans. Alas, problems arose once people’s scans were denied coverage, particularly by Medicare Advantage plans, which black and Hispanic participants were more likely to carry. Ironically, this recreated a disparity New IDEAS had set out to address, hence the scientists decided to stop, Rabinovici told Alzforum.

Even so, New IDEAS registered more than 6,000 people, of whom 4,845 received an amyloid scan at one of the 111 participating PET facilities. They averaged 75 years of age; 64 percent had MCI, 36 percent dementia. Non-Hispanic whites made up 60 percent of those scanned; black/African Americans and Hispanic/Latinos accounted for 21 and 18 percent, respectively.

While 68 percent of non-Hispanic whites were amyloid-positive, 60 percent of people from black and Hispanic groups were. Why is this difference smaller than in other cohorts? Partial reasons could be that New IDEAS reflects a real-world memory care population, not clinical trial volunteers, and also that more non-Hispanic white people saw dementia specialists and received their scans at earlier stages of impairment than did black or Hispanic volunteers, Rabinovici said.

The study also captured differences in sociodemographic and health variables across ethnoracial groups. On average, black and Hispanic people had less formal education than non-Hispanic whites, and more of them were unmarried and living alone. They were less likely to live in a “prosperous/comfortable” neighborhood, as gauged by area deprivation index, a measure of neighborhood disadvantage. For example, while 65 percent of non-Hispanic whites lived in such neighborhoods, 55 percent of Hispanic/Latinos and 42 percent of black/African Americans did.

The prevalence of comorbidities was also higher among black and Hispanic groups. For example, 73 percent of black and 61 percent of Latino people had hypertension, compared to 54 percent of non-Hispanic whites. Diabetes affected nearly 30 percent of people who were black or Latino, but only 16 percent of non-Hispanic whites. Black people had higher rates of stroke, chronic kidney disease, and cerebrovascular disease as well. How these disparities relate to one another, and to prevalence and types of cognitive impairment that arise across groups, is being investigated in ongoing analyses of New IDEAS data, to be published early next year. Blood biomarkers will be measured among a subset of volunteers who opted to give blood, Rabinovici said.—Jessica Shugart

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References

News Citations

1. From St. Louis to Boston, Scientists Grapple with Ethnoracial Divide in AD Biomarkers 5 Nov 2023
2. Fully Loaded: Secondary Prevention Studies of Lecanemab, Donanemab 15 Nov 2024

Paper Citations

1. Molina-Henry DP, Raman R, Liu A, Langford O, Johnson K, Shum LK, Glover CM, Dhadda S, Irizarry M, Jimenez-Maggiora G, Braunstein JB, Yarasheski K, Venkatesh V, West T, Verghese PB, Rissman RA, Aisen P, Grill JD, Sperling RA. Racial and ethnic differences in plasma biomarker eligibility for a preclinical Alzheimer's disease trial. Alzheimers Dement. 2024 Jun;20(6):3827-3838. Epub 2024 Apr 17 PubMed.

Further Reading

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