Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques

Abstract

Background and objectives: To determine the diagnostic accuracy of a plasma Aβ42/Aβ40 assay in classifying amyloid PET status across global research studies using samples collected by multiple centers that utilize different blood collection and processing protocols.

Methods: Plasma samples (n = 465) were obtained from 3 large Alzheimer disease (AD) research cohorts in the United States (n = 182), Australia (n = 183), and Sweden (n = 100). Plasma Aβ42/Aβ40 was measured by a high precision immunoprecipitation mass spectrometry (IPMS) assay and compared to the reference standards of amyloid PET and CSF Aβ42/Aβ40.

Results: In the combined cohort of 465 participants, plasma Aβ42/Aβ40 had good concordance with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.84, 95% confidence interval [CI] 0.80-0.87); concordance improved with the inclusion of APOE ε4 carrier status (AUC 0.88, 95% CI 0.85-0.91). The AUC of plasma Aβ42/Aβ40 with CSF amyloid status was 0.85 (95% CI 0.78-0.91) and improved to 0.93 (95% CI 0.89-0.97) with APOE ε4 status. These findings were consistent across the 3 cohorts, despite differences in protocols. The assay performed similarly in both cognitively unimpaired and impaired individuals.

Discussion: Plasma Aβ42/Aβ40 is a robust measure for detecting amyloid plaques and can be utilized to aid in the diagnosis of AD, identify those at risk for future dementia due to AD, and improve the diversity of populations enrolled in AD research and clinical trials.

Classification of evidence: This study provides Class II evidence that plasma Aβ42/Aβ40, as measured by a high precision IPMS assay, accurately diagnoses brain amyloidosis in both cognitively unimpaired and impaired research participants.

Figure 1. Plasma Aβ42/Aβ40 and PET-Positive Probability by Amyloid PET Status for the Combined Cohort

(A and B) The probability of amyloid PET positivity was estimated from a logistic regression model with amyloid PET status (positive or negative) as the outcome and plasma Aβ42/Aβ40 and APOE ε4 status as the predictors (see eTable 4, links.lww.com/WNL/B715, for parameter estimates). Filled circles represent cognitively unimpaired participants; open triangles represent cognitively impaired participants. Dashed gray lines represent the cut-off values shown in eTable 2, links.lww.com/WNL/B715.

Figure 2. Receiver Operating Characteristic Curves for Distinguishing Amyloid PET Status

Blue = plasma Aβ42/Aβ40 only; red = plasma Aβ42/Aβ40 and age; black = plasma Aβ42/Aβ40 and APOE ε4 status. ADNI = Alzheimer’s Disease Neuroimaging Initiative; AIBL = Australian Imaging, Biomarkers and Lifestyle Study; AUC = area under the curve.

Figure 3. Plasma Aβ42/Aβ40 as a Prescreening Test for Brain Amyloidosis

(A) The number of participants and amyloid PET scans needed to identify 1,000 amyloid PET–positive participants, with and without prescreening with a blood test. The amyloid PET positive rate was assumed to be 25% for the cognitively unimpaired group and 75% for the cognitively impaired group. Data provided in eTable 6, links.lww.com/WNL/B715, were used as the sensitivity and specificity of plasma Aβ42/40 test. (B) The time and cost savings associated with prescreening for brain amyloidosis with plasma Aβ42/Aβ40 were evaluated for an Alzheimer disease prevention trial similar to the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study. In the A4 study, amyloid PET scans were performed in 4,487 participants over a 3-year period, and 1,323 participants (30%) were classified as amyloid PET positive. The sensitivity of 0.80 and specificity of 0.83 based on cognitively unimpaired participants as shown in eTable 6, links.lww.com/WNL/B715, were used for the accuracy of the blood test. Costs were assumed to be $5,000–$8,000 per amyloid PET scan and $500 per blood test.