Plasma amyloid beta X‐42/X‐40 ratio and cognitive decline in suspected early and preclinical Alzheimer's disease

INTRODUCTION Blood‐based biomarkers are a cost‐effective and minimally invasive method for diagnosing the early and preclinical stages of amyloid positivity (AP). Our study aims to investigate our novel immunoprecipitation‐immunoassay (IP‐IA) as a test for predicting cognitive decline. METHODS We measured levels of amyloid beta (Aβ)X‐40 and AβX‐42 in immunoprecipitated eluates from the DELCODE cohort. Receiver‐operating characteristic (ROC) curves, regression analyses, and Cox proportional hazard regression models were constructed to predict AP by Aβ42/40 classification in cerebrospinal fluid (CSF) and conversion to mild cognitive impairment (MCI) or dementia. RESULTS We detected a significant correlation between AßX‐42/X‐40 in plasma and CSF ( r = 0.473). Mixed‐modeling analysis revealed a substantial prediction of AßX‐42/X‐40 with an area under the curve (AUC) of 0.81 for AP (sensitivity: 0.79, specificity: 0.74, positive predictive value [PPV]: 0.71, negative predictive value [NPV]: 0.81). In addition, lower AβX‐42/X‐40 ratios were associated with negative PACC5 slopes, suggesting cognitive decline. DISCUSSION Our results suggest that assessing the plasma AβX‐42/X‐40 ratio via our semiautomated IP‐IA is a promising biomarker when examining patients with early or preclinical AD. Highlights New plasma Aβ42/Aβ40 measurement using immunoprecipitation–immunoassay Plasma Aβ42/Aβ40 associated with longitudinal cognitive decline Promising biomarker to detect subjective cognitive decline at‐risk for brain amyloid positivity