Blood-based proteomic signature of amyloidosis: identification of novel regulators of amyloid load

INTRODUCTION: Cerebral amyloidosis is a defining feature of Alzheimer's disease (AD), yet the molecular heterogeneity among amyloidbeta-positive (Aβ+) individuals remains poorly defined. We aimed to map the proteomic correlates of cerebral amyloidosis and link them to clinical variability within Aβ+ individuals. METHODS: We integrated quantitative amyloid PET with large-scale plasma proteomics (∼7000 proteins; SomaScan version 4.1) in Knight Alzheimer's Disease Research Center and Bio-Hermes cohorts (n = 1429). Proteome-wide association analyses identified proteins associated with amyloid load, followed by unsupervised clustering and pathway enrichment analyses. RESULTS: We identified 454 amyloid-associated proteins, of which 54 replicated cross-cohort. A derived 54-protein proteomic score correlated with amyloid burden, AD biomarkers, and clinical severity. Pathway analyses of clinically distinct protein clusters revealed coordinated enrichment of intracellular signaling, immune, and proteostasis modules. DISCUSSION: These findings delineate the circulating proteomic signature of cerebral amyloidosis and support plasma proteomics as a complementary approach to phosphorylated tau at threonine 217 and amyloid PET for biological stratification and characterization of disease heterogeneity in AD.