Feb 28, 2024 | Jessica Kim Cohen
NEW YORK – Results from blood-based biomarker tests correlated with the presence of beta-amyloid detected using established Alzheimer’s disease diagnostics, according to a study published Wednesday.
PET scans and cerebrospinal fluid (CSF) analyses are highly accurate and established methods of identifying elevated levels of beta-amyloid, a hallmark of Alzheimer’s. However, these modalities have their drawbacks. For example, PET scans are expensive, and not all patients have access to healthcare facilities with the requisite equipment and specialists on staff. CSF analysis requires a lumbar puncture, which patients may consider invasive and be hesitant to receive.
Blood tests for specific protein biomarkers may have the near-term potential of prescreening individuals suspected of having Alzheimer’s before they undergo a confirmatory PET scan or CSF analysis, particularly in the context of clinical trials. Moreover, experts hope that one day, these blood tests could be standalone diagnostics for identifying which patients have Alzheimer’s and can receive anti-amyloid drugs like Biogen and Eisai’s Leqembi (lecanemab), which require patients to have a confirmed presence of amyloid pathology.
“Blood-based tests will be less expensive and much easier for patients to access,” said Richard Mohs, CSO at the nonprofit Global Alzheimer’s Platform (GAP) Foundation and first author on the paper, which was published in the journal Alzheimer’s & Dementia.
Identifying blood-based biomarkers for beta-amyloid has been a key area of interest in the life sciences industry, as the increasingly crowded market for anti-amyloid-targeted drugs is expected to drive demand for beta-amyloid testing.
Last year, the US Food and Drug Administration approved Leqembi, which is indicated for patients with early-stage Alzheimer’s, who are confirmed to have elevated levels of beta-amyloid plaque. Separately, Eli Lilly has said it is seeking FDA approval for its anti-amyloid Alzheimer’s drug donanemab.
The latest publication contains the first key analysis from the Bio-Hermes study, which the GAP Foundation and a consortium of about 20 biopharmaceutical, diagnostic, and nonprofit partners launched to research new biomarkers for diagnosing Alzheimer’s. The study comprises data from more than 1,000 people in the US with mild Alzheimer’s, mild cognitive impairment, and healthy cognition.
The analysis was funded by AbbVie, the Alzheimer’s Drug Discovery Foundation, Aural Analytics, Biogen, Cognivue, C2N, Gates Ventures, Linus Health, Merck, Quanterix, Retispec, and Roche.
In this study, researchers compared results of multiple blood-based biomarker tests to either results from brain PET scans with Eli Lilly’s Amyvid (florbetapir F-18) radiotracer or cerebrospinal fluid (CSF) assays that were sent to a CLIA-certified lab at Quest Diagnostics for analysis. The biomarkers from blood tests were also gauged at CLIA-certified labs operated by C2N Diagnostics, Quanterix, and Eli Lilly.
The study authors found a strong correlation between results from several blood tests and the presence of beta-amyloid plaque as determined by the standard testing methods.
In particular, blood tests for amyloid-beta 42/40 ratio, phosphorylated-tau 181, and phosphorylated-tau 217 predicted the likelihood that a patient would have beta-amyloid plaque in their brain as detected by conventional diagnostics. P-tau 217 had the strongest predictive value for amyloid-beta positivity, reaffirming other research that has identified it as a promising blood-based biomarker, and which some experts say may eventually be used as a standalone confirmatory test for brain amyloid positivity.
While p-tau 217 has emerging evidence that makes it one of the most promising blood-based biomarkers of brain amyloid positivity, researchers are still trying to better understand why this biomarker has such a correlation, Mohs said. One hypothesis is that the accumulation of beta-amyloid protein in the brain leads to abnormal formation and build-up of the tau protein.
“We don’t fully understand why p-tau 217 is so good at predicting brain amyloid deposits,” he said. “It seems likely that the overproduction of some forms of a-beta protein causes the production of p-tau 217, so any patient beginning to show a-beta deposits into amyloid will have elevated levels of p-tau 217.”
There was no significant relationship between amyloid-beta positivity and other biomarkers researchers studied, such as amyloid-beta 40 and total tau.
In light of their findings, the study authors suggested that blood tests, which are more convenient and less expensive than existing diagnostics, could be useful as a prescreening method before PET scans or CSF analysis to identify those likely to have elevated beta-amyloid. Such prescreening could help avoid costly or invasive procedures for patients who don’t have beta-amyloid deposits.
This is already being done within some clinical trials. For example, in Eisai’s AHEAD study, in which the drugmaker is investigating whether Leqembi can delay or prevent cognitive decline in those who are asymptomatic but have elevated levels of beta-amyloid, patients are first screened with C2N’s PrecivityAD blood-based test. Positive results are then confirmed with an amyloid PET scan.
In the Alzheimer’s & Dementia paper, study authors highlighted that their findings on the blood biomarkers were consistent across racial and ethnic groups, although the average values for amyloid-beta 42/40 ratio were slightly higher and p-tau 181 and p-tau 217 concentrations were lower in Black patients compared to their white counterparts. “Results indicate that A?42/A?40 ratio, p-tau181, and p-tau217 are good predictors of brain amyloid positivity in this clinical trial-ready population and suggest that further separate evaluation of biomarkers for Hispanic or non-Hispanic Black participants may be useful,” study authors wrote.
Recruiting diverse participants has been a focus for the Bio-Hermes study, since Black and Latino patients tend to suffer from Alzheimer’s at higher rates than white patients, study authors noted. Nearly one-quarter of the study population in Bio-Hermes was from historically underrepresented racial or ethnic groups.
While the initial adoption of these blood tests will likely be in the clinical trial space, Mohs said he envisions a time in the “near future” when patients will be able to prove evidence of amyloid pathology with only a blood-based biomarker test, without needing a PET scan or CSF analysis. “While the near-term use of these tests is likely to be for enrollment into clinical trials, the blood-based tests, particularly p-tau 217, are likely to be very useful in clinical practice,” Mohs said.