Machine Learning Reveals a Multipredictor Nomogram for Diagnosing the Alzheimer’s Disease Based on Chemiluminescence Immunoassay for Total Tau in Plasma

Lingyu Zhang, Danhua Wang, Yibei Dai, Xuchu Wang, Ying Cao, Weiwei Liu, Zhihua Tao

Predicting amnestic mild cognitive impairment (aMCI) in conversion and Alzheimer's disease (AD) remains a daunting task. Standard diagnostic procedures for AD population are reliant on neuroimaging features (positron emission tomography, PET), cerebrospinal fluid (CSF) biomarkers (Aβ1-42, T-tau, P-tau), which are expensive or require invasive sampling. The blood-based biomarkers offer the opportunity to provide an alternative approach for easy diagnosis of AD, which would be a less invasive and cost-effective screening tool than currently approved CSF or amyloid β positron emission tomography (PET) biomarkers. We developed and validated a sensitive and selective immunoassay for total Tau in plasma. Robust signatures were obtained based on several clinical features selected by multiple machine learning algorithms between the three participant groups. Subsequently, a well-fitted nomogram was constructed and validated, integrating clinical factors and total Tau concentration. The predictive performance was evaluated according to the receiver operating characteristic (ROC) curves and area under the curve (AUC) statistics. Decision curve analysis and calibration curves are used to evaluate the net benefit of nomograms in clinical decision-making. Under optimum conditions, chemiluminescence analysis (CLIA) displays a desirable dynamic range within Tau concentration from 7.80 to 250 pg/mL with readily achieved higher performances (LOD: 5.16 pg/mL). In the discovery cohort, the discrimination between the three well-defined participant groups according to Tau concentration was in consistent agreement with clinical diagnosis (AD vs. non-MCI: AUC = 0.799; aMCI vs. non-MCI: AUC = 0.691; AD vs. aMCI: AUC = 0.670). Multiple machine learning algorithms identified Age, Gender, EMPG, Tau, ALB, HCY, VB12, and/or Glu as robust signatures. A nomogram integrated total Tau concentration and clinical factors provided better predictive performance (AD vs. non-MCI: AUC = 0.960, AD vs. aMCI: AUC = 0.813 in discovery cohort; AD vs. non-MCI: AUC = 0.938, AD vs. aMCI: AUC = 0.754 in validation cohort). The developed assay and a satisfactory nomogram model hold promising clinical potential for early diagnosis of aMCI and AD participants.