Large-scale Plasma Proteomic Profiling Unveils Novel Diagnostic Biomarkers and Pathways for Alzheimer's Disease

Alzheimer disease (AD) is a complex neurodegenerative disorder. Proteomic studies have been instrumental in identifying AD-related proteins present in the brain, cerebrospinal fluid, and plasma. This study comprehensively examined 6,905 plasma proteins in more than 3,300 well-characterized individuals to identify new proteins, pathways, and predictive model for AD. With three-stage analysis (discovery, replication, and meta-analysis) we identified 416 proteins (294 novel) associated with clinical AD status and the findings were further validated in two external datasets including more than 7,000 samples and seven previous studies. Pathway analysis revealed that these proteins were involved in endothelial and blood hemostatic (ACHE, SMOC1, SMOC2, VEGFA, VEGFB, SPARC), capturing blood brain barrier (BBB) disruption due to disease. Other pathways were capturing known processes implicated in AD, such as lipid dysregulation (APOE, BIN1, CLU, SMPD1, PLA2G12A, CTSF) or immune response (C5, CFB, DEFA5, FBXL4), which includes proteins known to be part of the causal pathway indicating that some of the identified proteins and pathways are involved in disease pathogenesis. An enrichment of brain and neural pathways (axonal guidance signaling or myelination signaling) indicates that, in fact, blood proteomics capture brain- and disease-related changes, which can lead to the identification of novel biomarkers and predictive models. Machine learning model was employed to identify a set of seven proteins that were highly predictive of both clinical AD (AUC > 0.72) and biomarker-defined AD status (AUC > 0.88), that were replicated in multiple external cohorts as well as with orthogonal platforms. These extensive findings underscore the potential of using plasma proteins as biomarkers for early detection and monitoring of AD, as well as potentially guiding treatment decisions.