Fully automated and highly specific plasma β-amyloid immunoassays predict β-amyloid status defined by amyloid positron emission tomography with high accuracy

Abstract

Background Clinicians, researchers, and patients alike would greatly benefit from more accessible and inexpensive biomarkers for neural β-amyloid (Aβ). We aimed to assess the performance of fully automated plasma Aβ immunoassays, which correlate significantly with immunoprecipitation mass spectrometry assays, in predicting brain Aβ status as determined by visual read assessment of amyloid positron emission tomography (PET). Methods The plasma Aβ42/Aβ40 ratio was measured using a fully automated immunoassay platform (HISCL series) in two clinical studies (discovery and validation studies). The discovery and validation sample sets were retrospectively and randomly selected from participants with early Alzheimer’s disease (AD) identified during screening for the elenbecestat Phase 3 program. Results We included 197 participants in the discovery study (mean [SD] age 71.1 [8.5] years; 112 females) and 200 in the validation study (age 70.8 [7.9] years; 99 females). The plasma Aβ42/Aβ40 ratio predicted amyloid PET visual read status with areas under the receiver operating characteristic curves of 0.941 (95% confidence interval [CI] 0.910–0.973) and 0.868 (95% CI 0.816–0.920) in the discovery and validation studies, respectively. In the discovery study, a cutoff value of 0.102 was determined based on maximizing the Youden Index, and the sensitivity and specificity were calculated to be 96.0% (95% CI 90.1–98.9%) and 83.5% (95% CI 74.6–90.3%), respectively. Using the same cutoff value, the sensitivity and specificity in the validation study were calculated to be 88.0% (95% CI 80.0–93.6%) and 72.0% (95% CI 62.1–80.5%), respectively. Conclusions The plasma Aβ42/Aβ40 ratio measured using the HISCL series achieved high accuracy in predicting amyloid PET status. Since our blood-based immunoassay system is less invasive and more accessible than amyloid PET and cerebrospinal fluid testing, it may contribute to the diagnosis of AD in routine clinical practice.

The performance of plasma amyloid beta measurements in identifying amyloid plaques in Alzheimer’s disease: a literature review

“…A similar technique applied by some studies is known as immunoprecipitation-free liquid chromatography-mass spectrometry (IP-free LC-MS), which measures Aβ species with mass spectrometry, but without antibody purification prior to measurement by LC-MS [22,34]. Studies that use a bead-based immunoassay, for example, the SIMOA assay or some high-sensitivity chemiluminescence assays, use beads for specific Aβ species antibody binding and indirect quantification, sometimes after amplification [20,22,28,[35][36][37][38][39][40]. In contrast, other studies apply plate-based immunoassays (such as an ELISA assay), in which a binding antibody is adsorbed onto a plate where it binds the Aβ species, and a second antibody binds to another Aβ antigen, forming what is known as a "sandwich" between the two antibodies [22,25,28,36].…”

“…In general, the immunoassays displayed lower AUCs across most studies that used a PET reference standard. Studies using a SIMOA assay had a weighted average AUC value of 0.690 across ten cohorts [20,22,24,28,[35][36][37], chemiluminescence assays had a weighted average AUC of 0.818 across six cohorts [22,28,38,40], IP-free LC-MS assays had a weighted average AUC of 0.742 across five cohorts [22,34], and ELISA assays had a weighted average AUC of 0.734 across three cohorts [22,25,36] (Table 1, Fig. 3).…”

Assessment of Plasma and Cerebrospinal Fluid Biomarkers in Different Stages of Alzheimer’s Disease and Frontotemporal Dementia

“…The core AD biomarkers for amyloidosis (Aβ42 and ratio Aβ42/Aβ40) have been measured in plasma for the diagnosis of AD, even in the early stages [ 13 , 14 , 15 ]. A previous study showed the consistency of the plasma ratio Aβ42/Aβ40 as a predictor of AD [ 16 ], and plasma p-Tau181 has been studied as biomarker for the disease [ 17 , 18 , 19 ]. Moreover, these recent studies pointed to plasma p-Tau181 and other hyperphosphorylated Tau (p-Tau231, p-Tau217) as the most sensitive plasma biomarkers for AD diagnosis [ 18 , 19 ], even in the early stages [ 20 , 21 ].…”

A Perspective: Challenges in Dementia Research

“… What are the characteristics of the nervous system that are different (see Challenge 2) at the onset [ 113 ] of pathological aging? What is the detailed temporal relationship between amyloid and tau pathology, and the various biomarkers and behavioral changes in the database [ 114 , 115 , 116 ]? …”

“…What is the detailed temporal relationship between amyloid and tau pathology, and the various biomarkers and behavioral changes in the database [ 114 , 115 , 116 ]?…”