Plasma amyloid β 42/40 ratios as biomarkers for amyloid β cerebral deposition in cognitively normal individuals

Abstract

Introduction: Plasma amyloid β (Aβ) peptides have been previously studied as candidate biomarkers to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease.

Methods: Free and total Aβ42/40 plasma ratios (FP42/40 and TP42/40, respectively) were determined using ABtest assays in cognitively normal subjects from the Australian Imaging, Biomarker and Lifestyle Flagship Study. This population was followed-up for 72 months and their cortical Aβ burden was assessed with positron emission tomography.

Results: Cross-sectional and longitudinal analyses showed an inverse association of Aβ42/40 plasma ratios and cortical Aβ burden. Optimized as a screening tool, TP42/40 reached 81% positive predictive value of high cortical Aβ burden, which represents 110% increase over the population prevalence of cortical Aβ positivity.

Discussion: These findings support the use of plasma Aβ42/40 ratios as surrogate biomarkers of cortical Aβ deposition and enrichment tools, reducing the number of subjects submitted to invasive tests and, consequently, recruitment costs in clinical trials targeting cognitively normal individuals.

Keywords: Amyloid β; Biomarker; Clinical trials; Plasma amyloid β ratio; Positron emission tomography; Preclinical Alzheimer's disease; β-Amyloid imaging.

Fig. 1

Box-and-whisker plots of plasma markers with regards to categorical Aβ-PET status (Aβ+ or Aβ−) measurements at each visit. (A) TP42/40, for visualization purposes three outliers (of the 236 valid measurements) with TP42/40 values between 0.19 and 0.54 were discarded. (B) BP42/40. (C) FP42/40, for visualization purposes three outliers (of the 217 valid measurements) with FP42/40 values between 0.19 and 0.29 are not shown. See data in Table 1. Abbreviations: BP, amyloid peptide bound to plasma; FP, free in plasma; TP, total amyloid β in plasma.

Fig. 2

Box-and-whisker plot of changes in the SUVR/BeCKeT along the follow-up for subjects with low or high baseline TP42/40 plasma ratio. Each point represents the change in each individual in SUVR/BeCKeT at visit month 18 (m18, blue), m36 (green), m54 (red), or m72 (cyan), with respect to the baseline SUVR/BeCKeT in APOE ε4 noncarriers (A) and APOE ε4 carriers (B). In (A or B), left panel contains the individuals with low (<the population median) TP42/40 levels at baseline (m18) and right panel the individuals with high (≥the population median) TP42/40 levels at baseline (m18). Note that in those individuals with low baseline TP42/40, average change in SUVR/BeCKeT significantly increased over visits, whereas in those with high baseline TP42/40 there was almost no change in the SUVR/BeCKeT during the follow-up. Similar figures are also obtained for the other markers FP42/40 and BP42/40 (see Table 3). Abbreviations: APOE, apolipoprotein E; BP, amyloid peptide bound to plasma; FP, free in plasma; TP, total amyloid β in plasma.

Fig. 3

Comparison of the performance on PPV for three different classifiers as a function of the threshold value. In red, classifier including only the plasma marker log(TP42/40). In blue, classifier including age + APOE ε4 variables. In pink, classifier with all previous variables. The thick line represents the median value of the performance, and the thin dashed lines represent the 5th and 95th percentile values. Abbreviations: APOE, apolipoprotein E; PPV, positive predictive value; TP, total Aβ in plasma.