Analytical and Clinical Assessment of Plasma Phospho-Tau Isoforms in Alzheimer’s Disease (AD)
Ahmed Chenna1, Andreas Jeromin3, Brandon Yee1, Youssouf Badal2, Muriel Mendes4, Christos Petropoulos1, John Winslow1
1R&D, 2PDO, Monogram Biosciences Inc-LabCorp, 3Alzpath Inc, 4Quanterix Inc.
Objective:
Evaluate the analytical and clinical performance of four p-Tau assays using plasma from AD subjects and healthy controls, and determine correlative and discriminatory relationships for each assay and clinical diagnosis group.
Background:
Highly phosphorylated Tau protein is a major component of neurofibrillary tangles, a primary AD neuropathological cortical marker. Recently, sensitive immunoassays capable of measuring p-Tau isoforms p-Tau217 and p-Tau181 in blood have been developed, with promising diagnostic potential for AD.
Design/Methods:
AD plasma (n=64) and healthy control plasma (n=25) were analyzed with Simoa p-Tau217 developed by Alzpath, p-Tau181V2 and p-Tau181V2.1 (Quanterix) immunoassays using the HD-X analyzer, and the Lumipulse p-Tau181 (Fujirebio) immunoassay using the G1200 system. Plasma p-Tau levels were evaluated within AD sample groups consisting of mild (n=16, MMSE >23-30), moderate (n=20, MMSE=16-22) and severe (n=28, MMSE<16) cognitive impairment, and healthy controls (n=25).
Results:
P-tau levels were detectable by the four assays in >95% of all samples. Analysis by the three p-Tau181 and one p-Tau217 assays revealed significant increases in median p-Tau levels in the combined AD group (2.5-4.4-fold; p<0.0001, n = 64), relative to controls (n=25), and group discrimination (ROC-AUC=0.92). Significant median p-Tau elevations of 2.8-8.5 fold were observed in the moderate and severe dementia groups (p <0.0001) and 1.3-1.8 fold in the mild dementia group (p=0.0001-0.003), although distributions overlapped. Moderate or severe dementia group discrimination from controls was more pronounced (AUC>0.95) compared to mild dementia (AUC=0.75-0.84). Moderate to strong correlations between the p-Tau levels measured by the four assays were observed (Pearson r = 0.7-0.9).
Conclusions:
All p-Tau measurements were significantly elevated in the plasma of mild, moderate, and severe AD groups. All four p-Tau assays demonstrated robust analytical performance, and clinically differentiated AD plasma from healthy control plasma (p<0.0001). Plasma p-Tau181 and p-Tau217 biomarkers provide a practical diagnostic opportunity to identify AD patients.