A Cross-sectional Study of Plasma Aβ42/40 Ratio, pTau217, pTau181, GFAP and Nf-L in an Alzheimer’s Disease Clinical Cohort Characterized by Amyloid PET Imaging
John Winslow1, Ahmed Chenna1, Youssouf Badal1, Mintzu Lo1, Brandon Yee1, Bryan Lim1, Andreas Jeromin2, Christopher Fowler3, Robert Martone4, Christos Petropoulos1
1Labcorp/Monogram Biosciences, 2ALZpath, Inc, 3Florey Institute of Neuroscience and Mental Health, 4Labcorp Drug Development
Objective:

We detail a cross-sectional, multi-plasma biomarker characterization of the AIBL cohort samples using plasma Aβ42/40 ratio, pTau217, pTau181, GFAP, and Nf-L assays across the Alzheimer’s disease (AD) continuum, and determine discriminatory performance with CNS amyloid PET imaging status.

Background:
Recent advances in automated immunoassays have enabled sensitive detection of Aβ42/40, pTau181, and pTau217 in plasma, components of AD neuropathological markers.  Further characterization of possible increased diagnostic accuracy in pre- and symptomatic AD subjects is needed. 
Design/Methods:
Two hundred participants of the AIBL cohort were selected representing a cross-sectional population of four clinical and amyloid PET subgroups: cognitive normal (CN) Aβ- (n= 75), CN Aβ+ (n= 50), mild cognitive impairment (MCI) Aβ+ (n=25), and AD Aβ+ (n= 50).  EDTA-plasma samples were analyzed with the Lumipulse Aβ42/40 assay, the Simoa Neuro-4-plex E assay (Aβ42, Aβ40, GFAP, Nf-L), the ALZpath Simoa pTau217 assay, and the Simoa pTau181 v2 assay.
Results:

Lower Lumipulse and Simoa Aβ42/40 ratios were observed in Aβ+ vs Aβ- groups (p<0.0001), with differences across the four clinical subgroups (p <0.0001).  Aβ42/40 ratio ROC-AUC vs amyloid PET status was 0.88 and 0.85, respectively, consistent with moderate Spearman correlations between Aβ42/40 ratios and amyloid PET centiloids (R = -0.53; -0.49, (p<0.0001).  Simoa pTau217 and pTau181 levels were elevated in Aβ+ vs Aβ- groups (p<0.0001), increasing with disease severity (4.0- and 1.9-fold, respectively).  ROC-AUC vs amyloid PET status was 0.95 and 0.81, respectively. Multivariable models combining Lumipulse Aβ42/40 ratio and demographic base model improves the AUC to 0.913, whereas Aβ42/40 + pTau217 + base model results in an AUC = 0.978.

Conclusions:

A plasma biomarker study of a clinically well-characterized cohort revealed an improved association of Aβ42/40 ratios and pTau217 levels with CNS amyloid PET, as measured by recently developed immunoassays. These results support further validation toward AD drug development and patient management.  

10.1212/WNL.0000000000205336