Exploring the potential of fully automated LUMIPULSE G plasma assays for detecting Alzheimer's disease pathology

Abstract

Background: LUMIPULSE G-automated immunoassays represent a widely used method for the quantification of Alzheimer's disease (AD) biomarkers in the cerebrospinal fluid (CSF). Less invasive blood-based markers confer a promising tool for AD diagnosis at prodromal stages (mild cognitive impairment (MCI)). Highly sensitive assays for the quantification of amyloid-beta (Aβ) and phosphorylated Tau-181 (p-Tau181) in the blood are showing promising results. In this study, we evaluated the clinical performance of the recently available fully automated LUMIPULSE plasma marker assays for detecting brain AD pathology and for predicting progression from MCI to AD dementia stage.

Methods: A retrospective exploratory cohort of 138 individuals (22 neurological controls [NC], 72 MCI, and 44 AD dementia patients) was included. Data regarding baseline CSF concentrations of Aβ42, Aβ40, t-Tau, and p-Tau181 was available and used to establish the presence of AD brain pathology. Baseline Aβ42, Aβ40, and p-Tau181 concentrations were determined in stored plasma samples using high-throughput fully automated LUMIPULSE assays. Progression from MCI to AD dementia was evaluated during follow-up (mean 6.4 ± 2.5 years). Moreover, a prospective validation cohort of 72 individuals with memory complaints underwent AD biomarker quantification, closely mirroring typical clinical practice. This cohort aimed to confirm the study's main findings.

Results: In the exploratory cohort, correlations between CSF and plasma were moderate for p-Tau181 (ρ = 0.61, p < 0.001) and weak for Aβ42/Aβ40 ratio (ρ = 0.39, p < 0.001). Plasma p-Tau181 and p-Tau181/Aβ42 concentrations were significantly increased while Aβ42/Aβ40 was significantly decreased (p < 0.001) in patients with AD dementia and prodromal AD, as well as in individuals with CSF abnormal amyloid concentrations (A +). Plasma p-Tau181 showed a robust performance in differentiating patients clinically diagnosed as AD (AUC = 0.89; 95% CI 0.83-0.94); A + vs. A - (AUC = 0.84, 95% CI 0.77-0.91) and also in predicting conversion to AD dementia in MCI patients (AUC = 0.89, 95% CI 0.81-0.96). When tested in the validation cohort, plasma p-Tau181 displayed 83.3% of the overall percentage of agreement according to amyloid status.

Conclusions: Our results show that the measurement of p-Tau181 in plasma has great potential as a non-invasive prognostic screening tool for implementation in a clinical setting.

Keywords: Alzheimer’s disease; Automated; Early detection; Plasma biomarkers.

Fig. 1

Plasma amyloid and phosphorylated Tau concentrations in the exploratory cohort according to cognitive status and progression. Concentrations depicted A Aβ42/Aβ40 ratio, B p-Tau181, and C p-Tau181/Aβ42 ratio. Data is presented in points as individual values and the spread of the distribution with quartiles and median by a boxplot categorized by NC (n = 22), MCI-St (n = 36), MCI-AD (n = 36), and AD dementia (n = 44). Group comparison was performed by Kruskal–Wallis test with a Bonferroni correction showing a p-value label of significance: *p < 0.05; **p < 0.01; ***p < 0.001; n.s., not significant. Abbreviations: Aβ, amyloid beta; AD, Alzheimer’s disease; MCI-AD, mild cognitive impairment that progressed to AD dementia; MCI-St, stable mild cognitive impairment; p-Tau181, phosphorylated tau protein in the position 181

Fig. 2

Associations between CSF amyloid and phosphorylated Tau with corresponding plasma concentrations in the exploratory cohort. A CSF and plasma Aβ42/Aβ40 ratio. B CSF and plasma p-Tau181 concentrations. C CSF and plasma p-Tau181/Aβ42 ratio. Graphs are presented with a logarithmic transformed axis, except for the ratios. Data displays individual values with mean regression and 95% prediction lines, with shapes corresponding to the cognitive stage (• NC, ▴ MCI, and ■ AD). Spearman correlation coefficients and p-values are presented for each graph. Abbreviations: Aβ, amyloid beta; AD, Alzheimer’s disease dementia; CSF, cerebrospinal fluid; MCI, mild cognitive impairment; NC, neurological control; p-Tau181, phosphorylated tau protein in the position 181

Fig. 3

High diagnostic accuracy of plasma amyloid and phosphorylated Tau 181 in the exploratory cohort according to A amyloid status, B clinical condition, and C progression to AD dementia. Receiver operating curve (ROC) analyses presented with the area under the curve (AUC) with 95% confidence interval (CI) for plasma Aβ42/40 ratio, p-Tau181, and p-Tau181/Aβ42 ratio. Amyloid status was determined according to reference values of CSF Aβ42/Aβ40 ratio for dichotomization into negative (n = 58) and positive (n = 80). Clinical condition was determined according to their probable clinical diagnosis, grouped as NC + MCI-Stable (n = 58) vs. MCI-AD + AD (n = 80). MCI progression was determined, dividing patients into those who remained cognitively stable (MCI-Stable; n = 36) and those that developed AD-dementia (MCI-AD; n = 36). Abbreviations: Aβ, amyloid beta; AD, Alzheimer’s disease; CSF, cerebrospinal fluid; MCI, mild cognitive impairments; p-Tau181, phosphorylated tau protein in the position 181