Clinical performance of an antibody-free assay for plasma Aβ42/Aβ40 to detect early alterations of Alzheimer’s disease in individuals with subjective cognitive decline
Authors: Pascual-Lucas María , Allué José Antonio , Sarasa Leticia , Fandos Noelia , Castillo Sergio , Terencio Jose , Sarasa Manuel , Tartari Juan Pablo , Sanabria Ángela , Tárraga Lluís , Ruíz Agustín , Marquié Marta , Seo Sang Won , Jang Hyemin , Boada Mercè ,   on behalf of the FACEHBI study group, Aguilera N. , Alarcón-Martín E. , Alegret M. , Alonso-Lana S. , Berthier M. , Bojayrin U. , Buendia M. , Bullich S. , Campos F. , Cano A. , Cañabate P. , Cañada L. , Cuevas C. , de Rojas I. , Diego S. , Espinosa A. , Esteban-De Antonio E. , Gailhajenet A. , García-Sánchez A , García P. , Giménez J. , Gómez-Chiari M. , Guitart M. , Hernández I. , Ibarria M. , Lafuente A. , Lleonart N. , Lomeña F. , Martín E. , Moreno M. , Morera A. , Montrreal L. , Muñoz N. , Narvaiza L. , Niñerola A. , Nogales A. B. , Núñez L. , Orellana A. , Ortega G. , Páez A. , Pancho A. , Pelejà E. , Pérez E. , Pérez-Cordon A. , Perissinotti A. , Preckler S. , Pytel V. , Ricciardi M. , Rodríguez-Gomez O. , Roé-Vellvé N. , Ramis M. I. , Rosende-Roca M. , Seguer S. , Sotolongo-Grau O. , Stephens A. , Tejero M. A. , Torres M. , Valero S. , Vargas L. , Vivas A. 
Published: January 2023

Abstract
Background
Accessible and cost-effective diagnostic tools are urgently needed to accurately quantify blood biomarkers to support early diagnosis of Alzheimer’s disease (AD). In this study, we investigated the ability of plasma amyloid-beta (Aβ)42/Aβ40 ratio measured by an antibody-free mass-spectrometric (MS) method, ABtest-MS, to detect early pathological changes of AD.

Methods
This cohort study included data from the baseline and 2-year follow-up visits from the Fundació ACE Healthy Brain Initiative (FACEHBI) study. Plasma Aβ42/Aβ40 was measured with ABtest-MS and compared to 18F-Florbetaben PET as the reference standard (cutoff for early amyloid deposition of 13.5 centiloids). Cross-validation was performed in an independent DPUK-Korean cohort. Additionally, associations of plasma Aβ42/Aβ40 with episodic memory performance and brain atrophy were assessed.

Results
The FACEHBI cohort at baseline included 200 healthy individuals with subjective cognitive decline (SCD), of which 36 (18%) were Aβ-PET positive. Plasma Aβ42/Aβ40 levels were significantly lower in Aβ-PET positive individuals (median [interquartile range, IQR], 0.215 [0.203–0.236]) versus Aβ-PET negative subjects (median [IQR], 0.261 [0.244–0.279]) (P < .001). Plasma Aβ42/Aβ40 was significantly correlated with Aβ-PET levels (rho = −0.390; P < .001) and identified Aβ-PET status with an area under the receiver operating characteristic curve (AUC) of 0.87 (95% confidence interval [CI], 0.80–0.93). A cutoff for the Aβ42/Aβ40 ratio of 0.241 (maximum Youden index) yielded a sensitivity of 86.1% and a specificity of 80.5%. These findings were cross-validated in an independent DPUK-Korean cohort (AUC 0.86 [95% CI 0.77–0.95]). Lower plasma Aβ42/Aβ40 ratio was associated with worse episodic memory performance and increased brain atrophy. Plasma Aβ42/Aβ40 at baseline predicted clinical conversion to mild cognitive impairment and longitudinal changes in amyloid deposition and brain atrophy at 2-year follow-up.

Conclusions
This study suggests that plasma Aβ42/Aβ40, as determined by this MS-based assay, has potential value as an accurate and cost-effective tool to identify individuals in the earliest stages of AD, supporting its implementation in clinical trials, preventative strategies and clinical practice.