Some of the populations with the highest risk for Alzheimer's disease remain greatly underrepresented in clinical trials—and a new study helps explain why. Researchers from the Keck School of Medicine of USC found that participants from these high-risk groups are less likely to have elevated amyloid in the brain based on blood levels of p-tau217. Elevated amyloid is a requirement for clinical trials of Alzheimer's disease treatments, and amyloid is known to accumulate in the brain years before any signs of cognitive decline.
The study, funded in part by the National Institutes of Health (NIH), builds on earlier research with similar findings , but leverages a new and improved blood test, p-tau217, that more accurately detects early signs of Alzheimer's disease. Rising levels of p-tau217 are strongly linked to the buildup of amyloid, which disrupts brain activity in Alzheimer's disease, and the p-tau217 test is increasingly used to determine who qualifies for treatment studies. Earlier this year, the U.S. Food and Drug Administration approved a similar test to help diagnose Alzheimer's disease in the clinic.
Researchers found that cognitively unimpaired individuals from African American, Hispanic and Asian participants were less likely to have levels of p-tau217 in the blood that indicate elevated amyloid in the brain, showing they lacked the early signs of Alzheimer's disease that would allow them to participate in a trial of lecanemab. The trial is testing whether the treatment can prevent symptoms of dementia related to Alzheimer's disease in individuals with biological evidence of the disease. These findings suggest that these groups may have a lower prevalence of amyloid and are not at sufficient level of risk to appropriately qualify for amyloid lowering trials. The results were just published in the journal Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring (DADM) .
"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.
In addition to helping explain the lack of diversity in Alzheimer's disease research, the findings raise questions about whether the disease progresses differently across racial and ethnic groups. To address these and other important questions, some individuals who did not qualify for the AHEAD Study were invited to participate in the Amyloid Plasma Extension Study (APEX). The study will follow the trajectories of these and other blood markers in these individuals 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 said. "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 included 6,437 adults, ages 55 to 80, recruited from 75 sites across the country for AHEAD 3-45 , a clinical trial designed to test the safety and efficacy of lecanemab, which removes amyloid from the brain. Of those, 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 participants were cognitively unimpaired.
Using blood tests for p-tau217, the 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. Those who identified as Hispanic Black, Hispanic white, non-Hispanic Asian and non-Hispanic Black were significantly less likely to qualify to participate.
In addition to blood tests, the researchers collected positron emission tomography (PET) scans from each participant to directly measure amyloid buildup in the brain. Among participants who qualified for the trials based on the p-tau217 test, all racial and ethnic groups were equally likely to meet the PET scan criteria. That suggests that the same blood test cutoff accurately identifies early signs of Alzheimer's disease pathology across racial and ethnic groups.
What drives 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 provides a valuable opportunity to better understand risk for future Alzheimer's disease related dementia across populations. Those insights have important implications for the development of prevention therapies that will be necessary to address the needs of all individuals at risk of dementia.
Blood-based testing also enables much 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 said. "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 will broaden their analysis of Alzheimer's disease trial eligibility to include more than 20,000 participants screened for the AHEAD 3-45 trials from around the world.
About the study
In addition to Molina-Henry, the study's other authors are 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.
