Blood Test May Detect Amyloid Plaques in the Brain

LONDON—Plasma β-amyloid concentrations may have sufficient specificity to screen for amyloid plaques in the brain, according to research presented at the 2017 Alzheimer’s Association International Conference. A blood test for CNS amyloidosis could accelerate clinical trial enrollment. It also could aid in Alzheimer’s disease diagnosis and be incorporated into regular patient screening if effective antiamyloid therapies are developed, said Randall Bateman, MD.

Randall Bateman, MD

Studies indicate that Alzheimer’s disease pathology occurs over 20 to 30 years. A presymptomatic stage is characterized by 15 to 20 years of amyloid deposition. Symptoms manifest in the last seven to 10 years, and this symptomatic stage is characterized by tau tangle pathology, said Dr. Bateman, Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University School of Medicine in St. Louis.

Although CSF testing and PET scans can detect brain amyloid deposition, researchers have sought more practical and less expensive tests to detect amyloid plaques in patients who have or are at increased risk of Alzheimer’s disease.

Seeking a Blood Biomarker

To investigate the potential of a plasma-based β-amyloid biomarker, Dr. Bateman and colleagues adapted their Stable Isotope Label Kinetics (SILK) protocol to analyze the turnover kinetics and absolute amounts of β-amyloid 38, β-amyloid 40, and β-amyloid 42 in blood plasma. Dr. Bateman has equity in a company, C2N Diagnostics, that has licensed the assay technology, and he receives royalty income from its use.

The researchers included 41 older adults in the study. Participants had clinically diagnosed late-onset Alzheimer’s disease or were cognitively normal age-matched controls. All participants underwent brain PET amyloid imaging or CSF amyloid measurement to detect brain amyloidosis.

Eighteen patients were amyloid positive, and 23 patients were amyloid negative. The majority of the participants were cognitively normal. Participants’ Clinical Dementia Rating scores ranged from 0 to 2, and the average Mini-Mental State Examination score was about 27.

Participants received a bolus of 13C6-leucine label and underwent blood sampling over 24 hours. Researchers blinded to participants’ amyloid status immediately processed blood samples to plasma. They immunoprecipitated β-amyloid isoforms with an anti-β-amyloid antibody and analyzed them using high-resolution liquid chromatography–mass spectrometry.

The turnover rate of β-amyloid 42, compared with that of β-amyloid 40, in blood was faster in participants with β-amyloid plaques than in participants without β-amyloid plaques. This difference in turnover rate is the same characteristic signature of amyloidosis that appears in CSF, Dr. Bateman said. In blood, however, the turnover occurs more rapidly, and the magnitude of the difference is less than that in CSF, he said.

In addition, the investigators compared the concentrations of β-amyloid isoforms. The ratio of β-amyloid 42 to β-amyloid 40 was lower in patients with amyloidosis than in patients without amyloidosis. “This [result] is consistent with what we see in CSF, again, at a lower magnitude of difference,” he said. An analysis indicated that there is an important physiologic relationship between amyloid measures in the CSF and those in blood.

High Sensitivity

The researchers then assessed the potential of using blood β-amyloid concentrations to distinguish between patients who are amyloid positive and patients who are amyloid negative. Using a blood β-amyloid 42:40 ratio of less than 0.1243 as a cutoff, the test provided an area under the receiver operating characteristic curve (AUC) of approximately 0.89, “which puts this potentially in the range of being a good screening test for amyloidosis,” Dr. Bateman said.

The test identified the vast majority of people who were amyloid positive and the majority of people who were amyloid negative. “However, there are some amyloid negative individuals who would be incorrectly classified as being amyloid positive, and so confirmatory tests would be needed if this [measure] were to be used as a screening test,” Dr. Bateman said.

Validation Cohort

The researchers conducted a double-blind validation study using 164 samples. The validation study identified a highly statistically significant difference between participants who were amyloid positive and participants who were amyloid negative. In the validation cohort, the test had an AUC of approximately 0.76.

The blood test requires validation in larger, multicenter studies, Dr. Bateman said. Amyloid buildup does not necessarily mean that a patient has or will develop Alzheimer’s disease, “but a test like this can help identify those who are at risk,” he said.

A plasma β-amyloid test could lead to shorter and less costly clinical trials and allow investigators to test more therapeutics, he said. In addition, a blood test someday could “facilitate widespread treatment when effective antiamyloid therapeutics are developed,” Dr. Bateman said. Similar to screening for and treating high cholesterol to reduce the risk of heart attack and stroke, “a person may … get a blood test to find out if the amyloid protein is building up in the brain, and then go on specific treatments to prevent the onset of Alzheimer’s disease dementia,” he said.

—Jake Remaly

Suggested Reading

Huang Y, Potter R, Sigurdson W, et al. β-amyloid dynamics in human plasma. Arch Neurol. 2012;69(12):1591-1597.

Ovod V, Ramsey KN, Mawuenyega KG, et al. Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement. 2017;13(8):841-849.

Patterson BW, Elbert DL, Mawuenyega KG, et al. Age and amyloid effects on human central nervous system amyloid-beta kinetics. Ann Neurol. 2015;78(3):439-453.