Plasma Proteomic Networks Reveal Shared Biology with Brain Linked to Alzheimer’s Disease Pathology

Alzheimer’s disease (AD) drives widespread molecular changes beyond the brain that are increasingly detectable in plasma. To map plasma proteomic signatures of AD in a broadly unbiased manner with high depth and reproducibility, we profiled plasma from 214 individuals spanning cognitively normal controls, mild cognitive impairment, and AD using microbead-based enrichment and data-independent acquisition mass spectrometry (DIA-MS). We reliably quantified 5,823 proteins across samples, and network analysis identified 29 plasma modules enriched for functions related to lipid metabolism, extracellular matrix remodeling, immune signaling, mitochondrial function, and proteostasis. Several modules were associated with cognition, APOE4, sex, race, and cerebrospinal fluid (CSF) amyloid and tau biomarkers. Among 129 individuals with paired CSF and plasma biomarker measurements, over 1,500 proteins differed between CSF biomarker–positive and –negative groups, including amyloid-linked matrisome proteins such as SMOC1, FRZB, SPON1 and CTHRC1. A 10-protein plasma panel classified CSF biomarker positivity with performance similar to plasma pTau217 (AUC = 0.91), and combining both improved accuracy (AUC = 0.99). Integration with a human brain proteomic network revealed that two-thirds of plasma modules were preserved in brain, with many AD-altered modules changing concordantly across compartments. This study establishes a scalable DIA-MS plasma proteomics platform that captures systemic and brain-linked AD biology and identifies complementary biomarkers beyond phosphorylated tau.