The two cut-offs approach for plasma p-tau217 in detecting Alzheimer's disease in subjective cognitive decline and mild cognitive impairment

Abstract

Background: The study aimed to explore the applicability of plasma phosphorylated tau (p-tau)217 in identifying patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) carrying Alzheimer's disease (AD) pathology in real-world settings.

Methods: Fifty SCD, 87 MCI, and 50 AD-demented patients underwent blood collection to dose plasma p-tau217 with a fully automated Lumipulse G600II assay. Patients were classified according to the Revised Criteria of the Alzheimer's Association Workgroup as Core1+ or Core1- (based on amyloid positron emission tomography, cerebrospinal fluid [CSF] amyloid beta [Aβ]42/Aβ40, CSF p-tau181/Aβ42).

Results: Plasma p-tau217 was accurate for discriminating between Core1+ and Core1- patients (area under the curve = 0.92) with an optimal cut-off value of 0.274 pg/mL, revealing good accuracy (86.29%), positive predictive value (PPV; 88.18%), and negative predictive value (NPV; 83.09%). The two cut-offs approach (0.229-0.516 pg/mL) showed higher accuracy (91.11%), a PPV of 96.25% and a NPV of 83.63%.

Conclusion: The two cut-offs approach provides for stronger accuracy, PPV, and NPV than a single cut-off, making reliable the clinical application of plasma p-tau217 for early detection of AD in real-world settings.

Highlights: Plasma phosphorylated tau (p-tau)217 was highly accurate in detecting Alzheimer's disease (AD) pathology.The two cut-offs approach increased plasma p-tau217 accuracy for AD diagnosis.Even when measured with immunoassay, p-tau217 is a good biomarker for AD diagnosis.Transition of p-tau217 from research setting to clinical practice seems feasible.

Keywords: Alzheimer's disease; mild cognitive impairment; plasma biomarkers; plasma phosphorylated tau 217; subjective cognitive decline.

FIGURE 1

Plasma p‐tau217 levels according to clinical and clinical–biological diagnosis. A, Plasma p‐tau217 levels across diagnostic groups. Values quoted in the y axis indicate plasma p‐tau217 levels. Horizontal bars indicate significant differences between groups. B, Plasma p‐tau217 levels across diagnostic/Core1 groups. Values quoted in the y axis indicate plasma p‐tau217 levels. Horizontal bars indicate significant differences between groups. *p < 0.05; **p < 0.01; ***p < 0.001. AD, Alzheimer's disease; MCI, mild cognitive impairment; p‐tau, phosphorylated tau; SCD, subjective cognitive decline

FIGURE 2

Correlation matrices. A, Correlations in entire cohort. B, Correlations in SCD subgroups. C, Correlations in MCI subgroups. D, Correlations in AD dementia subgroups. Values quoted in the correlation matrix are Spearman ρ correlation coefficients. Statistical significance: P < 0.05. Color maps represent Spearman ρ correlation coefficients. *p < 0.05; **p < 0.01; ***p < 0.001. Aβ, amyloid beta; AD, Alzheimer's disease; CSF, cerebrospinal fluid; MCI, mild cognitive impairment; SCD, subjective cognitive decline; p‐tau, phosphorylated tau

FIGURE 3

ROC curves for accuracy of plasma p‐tau217 in distinguishing Core1+ from Core1– patients. AUC, area under the curve; CI, confidence interval; ROC, receiver operating characteristic; p‐tau, phosphorylated tau

FIGURE 4

Single cut‐off approach in discriminating Core1+ from Core1– patients. Dot plot illustrating distribution of patients based of plasma p‐tau217 levels categorization according to single cut approach. The x axis represents Core1 status, the y axis represents plasma p‐tau217 levels. Blue dots: patients with plasma p‐tau217 levels above the cut‐off. Red dots: patients with plasma p‐tau217 levels below the cut‐off. p‐tau, phosphorylated tau

FIGURE 5

Two cut‐offs approach in discriminating Core1+ from Core1– patients. Dot plot illustrating distribution of patients based of plasma p‐tau217 levels categorization according to two cut‐offs approach using three different combinations of sensitivity and specificity: both sensitivity and specificity fixed at 95% (95/95; left); sensitivity fixed at 92% and specificity at 96% (92/96; middle); both sensitivity and specificity fixed at 90% (right). The x axis represents Core1 status, the y axis represents plasma p‐tau217 levels. Blue dots: patients with plasma p‐tau217 levels above the upper cut‐off (clearly positive). Red dots: patients with plasma p‐tau217 levels below the lower cut‐off (clearly negative). Gray dots: patients with intermediate values of plasma p‐tau217 (gray zone). p‐tau, phosphorylated tau