Total Aβ42/Aβ40 ratio in plasma predicts amyloid-PET status, independent of clinical AD diagnosis

Abstract

Objective: To explore whether the plasma total β-amyloid (Aβ) Aβ₄₂/Aβ₄₀ ratio is a reliable predictor of the amyloid-PET status by exploring the association between these 2 variables in a subset of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging cohort.

Methods: Taking plasma samples at 3 separate time points, month 18 (n = 176), month 36 (n = 169), and month 54 (n = 135), we assessed the total Aβ₄₂/Aβ₄₀ ratio in plasma (TP42/40) with regard to neocortical Aβ burden via PET standardized uptake value ratio (SUVR) and investigated both association with Aβ-PET status and correlation (and agreement) with SUVR.

Results: The TP42/40 plasma ratio was significantly reduced in amyloid-PET-positive participants at all time points (p < 0.0001). Adjusting for covariates age, gender, APOE ε4 allele status, and clinical classification clearly affects the significance, with p values reduced and only comparisons at 54 months retaining significance (p = 0.006). Correlations with SUVR were similar across each time point, with Spearman ρ reaching -0.64 (p < 0.0001). Area under the curve values were highly reproducible over time points, with values ranging from 0.880 at 36 months to 0.913 at 54 months. In assessments of the healthy control group only, the same relationships were found.

Conclusions: The current study demonstrates reproducibility of the plasma assay to discriminate between amyloid-PET positive and negative over 3 time points, which can help to substantially reducing the screening rate of failure for clinical trials targeting preclinical or prodromal disease.

Classification of evidence: This study provides Class II evidence that plasma total Aβ₄₂/Aβ₄₀ ratio is associated with neocortical amyloid burden as measured by PET SUVR.

Figure 1. TP42/40 plots for Aβ-PET and clinical classification groups

Box and whisker plots of total plasma β-amyloid (Aβ)₄₂/Aβ₄₀ (TP42/40) ratio between the 3 time points and (A) PET Aβ groups or (B) clinical classification. Raw data are presented on a box-and-whisker plot background. Middle line of the box represents the median; lower and upper lines represent first and third quartiles, respectively. In panel A, blue represents those participants who are PET-Aβ−ve, and red represents those participants who are PET-Aβ+ve. In panel B, blue represents those participants who are in the healthy control (HC) group, orange represents those participants who are in the mild cognitive impairment (MCI) group, and red represents those participants who are in the Alzheimer disease (AD) group.

Figure 2. Correlation and agreement between model fitted values including TP42/40 and amyloid-PET SUVR

Correlation and threshold plot for the fitted values from the amyloid Aβ₄₂/Aβ₄₀ (TP42/40) model (generalized linear mixed model [GLMM]) including covariates as represented in table e-1 (available from Dryad, doi.org/10.5061/dryad.f300d56) (y-axis, inverse with values close to 1 indicating high probability that they are plasma Aβ-ve, and values close to 0 indicating high probability that they are plasma Aβ+ ve) vs standardized uptake value ratio (SUVR) (x-axis). (A– C) Relationships for all participants, and (D–F) relationships for healthy control (HC) participants only. (A and D) Relationships at 18 months, (B and E) relationships at 36 months, and (C and F) relationships at 54 months. Shown on each are the quadratic fit lines representing the relationship between fitted values from the TP42/40 model (from a full GLMM including adjustment for confounders) and SUVR. Spearman ρ value with associated p value from the same data is shown in the top right of each plot. Circles represent those participants from the HC group; squares represent those participants from the mild cognitive impairment group; triangles represent those participants from the Alzheimer disease group. Blue points represent those participants who are PET-Aβ-ve, and red points represent those participants who are PET-Aβ+ve.

Figure 3. ROC curves for the TP42/40 plasma ratio vs the base model

Plots show the receiver operating characteristic (ROC) curves from 2 models to predict PET β-amyloid (Aβ) status, the base model with covariates only, and the base model plus the total plasma Aβ₄₂/Aβ₄₀ (TP42/40) biomarker. (A, C, and E) ROC curves from all participants at 18, 36, and 53 months, respectively. (B, D and F) ROC curves from healthy control (HC) participants only at 18, 36, and 53 months. Shown on each panel are the ROC curves with the calculated area under the curve (AUC) value in the bottom right corner at 18 months (A and B) 36 months (C and D), and 54 months (E and F).