Plasma Proteomic Signatures for Alzheimer's Disease: Comparable Accuracy to ATN Biomarkers and Cross‐Platform Validation

Background There is growing recognition of the potential of plasma proteomics for Alzheimer's Disease (AD) risk assessment and disease characterization. However, differences between proteomics platforms introduce uncertainties regarding cross‐platform applicability. Objective We aimed to identify a detailed plasma biosignature for distinguishing AD from cognitively normal (CN) and another signature for classifying mild cognitive impairment (MCI) decliners and non‐decliners. We also explored the cross‐platform applicability of these models between two proteomic platforms. Methods Elastic net was performed on 190 plasma analytes measured using the Luminex xMAP platform in 566 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to model MCI stable/decliner and AD/CN classification. MCI decliner was defined as progression to AD during follow‐up (mean 4.2 ± 3.2 years). External cross‐platform validation was conducted with 1303 participants from the Spanish Ace study, using the SOMAscan 7k platform. Results An 11‐analyte signature for distinguishing AD from CN achieved a 93.5% accuracy on ADNI and 95.2% on Ace. The ApoE and BNP proteins were the two most important contributors to the classifier. The MCI classification signature performed less well, with 65.9% accuracy on ADNI and 51.0% accuracy upon validation testing in Ace. Discussion Compared with prior proteomic‐based studies on the same dataset, our findings attained higher specificity and sensitivity for AD classification while utilizing a smaller panel of analytes. We also confirmed the reliability and consistency of this signature within a different population from a different platform. The plasma proteomic platforms explored were, however, not sufficient to determine MCI decliners versus non‐decliners.