Proteomic Signatures of Neuropathological Alterations in Alzheimer’s Disease: Insights from the Bio-Hermes Study

Large-scale plasma proteomics can capture molecular changes across the Alzheimer’s disease (AD) continuum and provide insight into biological mechanisms associated with AD pathology. We analysed the Bio-Hermes cohort (n = 961), with participants enrolled across 17 sites in the United States from April 2021 to November 2022. Participants were stratified by clinical status and amyloid PET scan-based Core1 biomarker status (CN Core1 – , CN Core1 + , MCI Core1 + , and AD dementia Core1 + ). We performed differential abundance analyses across biologically defined contrasts, clustered proteins into co-expression networks, and evaluated protein panels to distinguish participants with biologically defined AD from amyloid-negative cognitively normal controls. We also used Mendelian randomization (MR) to assess genetic evidence for potential causal relationships with AD risk. The biologically defined contrast, Core1 + vs. CN Core1 – , identified 69 differentially abundant proteins. Across AD stages, eight core proteins were consistently dysregulated from preclinical through prodromal and dementia phases, and three additional proteins emerged at MCI Core1 + and remained altered in AD dementia Core1 + . We identified 29 co-expression modules, six of which varied significantly across the AD continuum. Among differential abundance proteins, ACHE ranked highest for distinguishing biologically defined AD from CN Core1 – . Stage-specific protein panels improved the discriminatory performance for MCI Core1 + (AUC = 0.850) and AD dementia Core1 + (AUC = 0.856). MR provided genetic evidence consistent with an association between plasma ACHE abundance and AD risk. Plasma proteomics delineated a stage-spanning core signature across the AD continuum. These findings nominate co-expression modules and candidate proteins for further validation in early detection and AD screening.