Early plasma proteomic alterations precede amyloidosis diagnosis, reflecting cardiac and immune dysregulation

Abstract

Systemic amyloidosis is typically diagnosed only after irreversible organ damage has occurred, limiting the effectiveness of available therapies. Whether the disease is preceded by detectable molecular changes long before clinical presentation has remained unclear. Here, we leveraged population-scale plasma proteomics and longitudinal follow-up from the UK Biobank to investigate early circulating protein signatures associated with future diagnosis of amyloidosis. Among approximately 53,000 participants with proteomic profiling, we identified 61 individuals who developed amyloidosis up to 14 years after protein assessment. Differential expression and correlation analyses identified a seven-protein panel, including MYL3, MYBPC1, NT-proBNP, NPPB, FCRLB, IGFBP1, and FABP1, consistent with early cardiac stress and immune dysregulation. Time-to-event modelling demonstrated robust stratification of amyloidosis risk and timing. Importantly, a parsimonious subset of these proteins retained strong predictive performance, indicating that a reduced set of biologically informative markers is sufficient for risk stratification. Furthermore, these proteomic signals were not explained by pre-existing cardiac disease, clonal haematopoiesis, or related plasma cell disorders, indicating that they capture disease-specific biological processes preceding clinical diagnosis. Together, these findings show that amyloidosis is preceded by persistent plasma proteomic alterations, providing a framework for early risk stratification and insight into the preclinical biology of this under-recognised disease.