Annals of Clinical and Translational Neurology · Oct 13, 2025

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

By Hu M, Robinson O, Lill CM et al.

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.

doi.org/10.1002/acn3.70227Open accessPubMed 41083424Biomarkers