Some of the populations at the highest risk for Alzheimer’s disease remain significantly underrepresented in clinical trials, and a recent study sheds light on the reasons behind this disparity. Researchers from the Keck School of Medicine of USC discovered that participants from these high-risk groups are less likely to exhibit elevated amyloid levels in the brain, as indicated by blood levels of p-tau217. Elevated amyloid is a critical requirement for participation in Alzheimer’s disease treatment trials, as it accumulates in the brain years before cognitive decline becomes apparent.
This study, partially funded by the National Institutes of Health (NIH), builds on previous research with similar findings but uses a more advanced blood test, p-tau217, which accurately detects early signs of Alzheimer’s disease. The p-tau217 test, which the U.S. Food and Drug Administration approved earlier this year, is increasingly employed to determine eligibility for treatment studies. The study’s findings were published in the journal Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring (DADM).
Underrepresentation in Clinical Trials
Researchers found that cognitively unimpaired individuals from African American, Hispanic, and Asian backgrounds were less likely to have blood levels of p-tau217 indicating elevated amyloid in the brain. This suggests these groups lack the early signs of Alzheimer’s disease necessary to participate in trials like the one for lecanemab, which aims to prevent dementia symptoms related to Alzheimer’s in individuals with biological evidence of the disease.
“Using this new and more accurate marker, we confirmed our earlier finding and affirmed that we may be seeing differences in the prevalence of amyloid across some populations,” said Doris P. Molina-Henry, PhD, an assistant professor of research neurology at the Alzheimer’s Therapeutic Research Institute (ATRI) at the Keck School of Medicine and lead author of the study.
Exploring Disease Progression
In addition to highlighting underrepresentation in Alzheimer’s research, the findings raise questions about whether the disease progresses differently across racial and ethnic groups. To explore these questions, some individuals who did not qualify for the AHEAD Study were invited to participate in the Amyloid Plasma Extension Study (APEX), which will track these and other blood markers over time.
“It is somewhat paradoxical because the populations showing low levels of amyloid on biomarker assessments are also the groups that face the highest risk of dementia,” Molina-Henry explained. “If amyloid is not what drives disease risk in these groups, then we need to do our due diligence to find out what does.”
Eligibility for Clinical Trials
The study involved 6,437 adults aged 55 to 80, recruited from 75 sites across the United States for the AHEAD 3-45 clinical trial, which tests the safety and efficacy of lecanemab, a treatment that removes amyloid from the brain. Among these participants, 4,832 identified as non-Hispanic white, 877 as Hispanic white, 511 as non-Hispanic Black, 155 as non-Hispanic Asian, and 62 as Hispanic Black. All were cognitively unimpaired.
Using blood tests for p-tau217, researchers found that non-Hispanic white participants were more likely than other groups to meet the threshold for inclusion in Alzheimer’s disease clinical trials. Conversely, those identified as Hispanic Black, Hispanic white, non-Hispanic Asian, and non-Hispanic Black were significantly less likely to qualify.
In addition to blood tests, researchers collected positron emission tomography (PET) scans from each participant to directly measure amyloid buildup in the brain. Among participants who qualified for trials based on the p-tau217 test, all racial and ethnic groups were equally likely to meet the PET scan criteria. This suggests that the blood test cutoff accurately identifies early signs of Alzheimer’s disease pathology across diverse groups.
Understanding Dementia Risk
As one of the first and largest Alzheimer’s disease trials of cognitively unimpaired individuals to use blood-based biomarkers, the AHEAD study offers valuable insights into future Alzheimer’s disease-related dementia risk across populations. These insights are crucial for developing prevention therapies to address the needs of all individuals at risk of dementia.
Blood-based testing also allows for broader data collection than PET scans, which are more costly and burdensome. “The additional data is helping us paint a clearer picture of why these populations may be underrepresented in research,” Molina-Henry noted. “It may not be because of issues in recruitment, access, or interest, but simply that the lower frequency of elevated amyloid in some groups makes them less likely to qualify for anti-amyloid trials.”
Further research can help clarify whether the observed differences relate to Alzheimer’s disease development and progression and whether factors beyond amyloid—such as sociodemographic or genetic characteristics—contribute to dementia risk in these populations.
Next, Molina-Henry and her team plan to broaden their analysis of Alzheimer’s disease trial eligibility to include more than 20,000 participants screened for the AHEAD 3-45 trials worldwide.
About the Study
In addition to Molina-Henry, the study’s authors include Rema Raman, Andy Liu, Oliver Langford, Robert A. Rissman, and Paul Aisen from the Alzheimer’s Therapeutic Research Institute, Keck School of Medicine of USC, University of Southern California; Joel B. Braunstein, Philip B. Verghese, and Venky Venkatesh from C2N Diagnostics, LLC, St. Louis, Missouri; Shobha Dhadda and Michael Irrizary from Eisai, Inc., Nutley, New Jersey; Joshua D. Grill from the Institute for Memory Impairments and Neurological Disorders, University of California Irvine; Keith Johnson and Reisa A. Sperling from Mass General Brigham, Harvard Medical School, Boston, Massachusetts; and the AHEAD 3-45 Study Team.
The AHEAD 3-45 Study is conducted as a public–private partnership of the Alzheimer’s Clinical Trial Consortium, funded by the National Institute on Aging, National Institutes of Health, Eisai Inc., the GHR Foundation, and other philanthropists.
