PHILADELPHIA – Tests measuring certain beta-amyloid and tau biomarkers from blood draws are able to discern which older patients have a buildup of plaque in their brains, researchers from Washington University School of Medicine in St. Louis reported this weekend at the Alzheimer's Association International Conference.
Sticky protein clumps that accumulate and form into beta-amyloid plaque are a hallmark of Alzheimer's disease and a therapeutic target for a growing class of drugs.
Neurologists historically haven't needed to test for beta-amyloid accumulation, but that's changing as new drugs like Eisai and Biogen's Leqembi (lecanemab) and Eli Lilly's Kisunla (donanemab) have entered the market. These drugs are designed to slow progression of Alzheimer's by targeting beta-amyloid and are specifically indicated for early-stage disease patients with evidence of beta-amyloid pathology. Many doctors want accurate blood tests as a convenient and cost-effective alternative to the standard methods of PET imaging or cerebrospinal fluid (CSF) analysis they currently use to gauge beta-amyloid in their patients.
Guidelines bodies are also starting to support the move to blood tests in Alzheimer's diagnosis. Last month, a workgroup organized by the Alzheimer's Association published updated criteria for diagnosing and staging Alzheimer's, in which it said certain blood tests proven to be at least as accurate as approved CSF assays could be used for diagnosing Alzheimer's.
At the AAIC conference on Sunday, Randall Bateman, a professor of neurology at WashU, presented results from a study seeking to identify blood-based biomarkers that can predict when patients have beta-amyloid deposits in their brains. Based on the findings, Bateman's team hopes to develop a blood test for Alzheimer's.
Bateman launched the study, dubbed the Study to Evaluate Amyloid in Blood and Imaging Related to Dementia, or SEABIRD, at his lab in 2019. About 300 patients participating in SEABIRD have been evaluated with the Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR) scale, and PET imaging and have provided blood samples. Patients must be 60 years of age or older to participate in the study, and researchers sought to recruit a cohort of patients that varied in cognitive symptoms, APOE4 genotype, and demographic factors.
In the study, investigators compared results from multiple blood-based biomarkers against results from standard PET imaging. They found that the accuracy of testing for the percentage of phosphorylated-tau (p-tau) 217 was "excellent" and had a high correlation with the presence of beta-amyloid plaque in the brain, Bateman said. The percentage of p-tau 217 boasted a correlation of 96 percent with PET imaging, and positive-predictive value of 85 percent and negative-predictive value of 96 percent. "This indicates that these blood biomarkers can be used to confirm the presence of amyloid plaques for diagnosis, without the need for additional tests," he said during a presentation of the data.
Another blood-based biomarker, amyloid-beta 42/40 ratio, was also determined to be predictive of beta-amyloid plaque. Bateman characterized amyloid-beta 42/40 ratio as "largely a binary detector," with a correlation of 88 percent to PET imaging. The biomarker also had a positive-predictive value of 68 percent and a negative-predictive value of 91 percent.
By contrast, biomarkers like percent of p-tau 205 and percent of p-tau 181 had lower accuracy: 71 percent and 69 percent positive-predictive value, and 87 percent and 84 percent for negative-predictive value, respectively.
These results and others presented at the conference add to a body of evidence on p-tau 217 and amyloid-beta 42/40 ratio as promising blood-based biomarkers that predict beta-amyloid positivity. In a separate session Sunday, researchers from Lund University in Sweden presented results on a blood test they developed incorporating both percentage of p-tau 217 and amyloid-beta 42/40 ratio, which they said can detect Alzheimer's disease in patients better than doctors' diagnoses.
As a next step, the Bateman lab is recruiting patients for a new study, called SUNBIRD, to validate the diagnostic and prognostic performance of blood-based biomarkers and investigate the relationship between the protein biomarkers and cognitive decline in patients. Investigators will also evaluate blood-based biomarkers for tau pathology in the brain, in addition to beta-amyloid.
Investigators are enrolling in the new trial certain participants from the SEABIRD study and recruiting additional patients at least 60 years of age from primary and specialty care clinics. Patients with clinical cognitive impairment will undergo evaluation for beta-amyloid through either blood, PET, or CSF tests. They will also undergo tau PET imaging and receive annual evaluations on the electronic CDR scale, the MoCA tool, and blood-based tests.
This information may be used to inform care management, such as referrals or treatment. If patients are not cognitively impaired, they'll undergo those same assessments every year or every two years, unless they begin exhibiting symptoms, at which point they'll switch to the other study group.
SUNBIRD is a longitudinal study that will run for up to five years. However, almost all of the research will be performed in the clinical setting and likely won't require separate follow-up research visits from participants, Bateman noted.
Results from the SEABIRD study so far suggest blood-based biomarker testing is feasible, efficient, and cost-effective for identifying and quantifying beta-amyloid plaque, Bateman said. Adoption of the Alzheimer's Association's guidelines, he hopes, will enable the use of accurate blood-based biomarkers that help doctors confirm beta-amyloid pathology in their patients. "There are many thousands of people who today could benefit from [anti-amyloid] treatment, but do not have access because they don't have accurate diagnoses," he said.