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

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 (A beta)42/A beta 40 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 Fundacio ACE Healthy Brain Initiative (FACEHBI) study. Plasma A beta 42/A beta 40 was measured with ABtest-MS and compared to F-18-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 A beta 42/A beta 40 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 A beta-PET positive. Plasma A beta 42/A beta 40 levels were significantly lower in A beta-PET positive individuals (median [interquartile range, IQR], 0.215 [0.203-0.236]) versus A beta-PET negative subjects (median [IQR], 0.261 [0.244-0.279]) (P < .001). Plasma A beta 42/A beta 40 was significantly correlated with A beta-PET levels (rho = -0.390; P < .001) and identified A beta-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 A beta 42/A beta 40 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 A beta 42/A beta 40 ratio was associated with worse episodic memory performance and increased brain atrophy. Plasma A beta 42/A beta 40 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 A beta 42/A beta 40, 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.

Automated summary

This study investigates the ability of plasma A beta 42/A beta 40 ratio measured by an antibody-free mass-spectrometric method to detect early pathological changes of Alzheimer's disease (AD). The results show that plasma A beta 42/A beta 40 is significantly correlated with A beta-PET levels and can accurately identify individuals in the earliest stages of AD. Additionally, lower plasma A beta 42/A beta 40 ratio is associated with worse episodic memory performance and increased brain atrophy, and can predict clinical conversion to mild cognitive impairment and longitudinal changes in amyloid deposition and brain atrophy at 2-year follow-up.