Proteogenomics captures a midlife biological state of Alzheimer’s disease susceptibility

Alzheimer’s disease (AD) develops over decades, but biological processes underlying susceptibility during midlife remain poorly understood. Using multimodal neuroimaging and plasma proteomics in UK Biobank participants, we identified circulating proteomic signatures of brain structure and organization. This ‘neurostructural proteome’ predicted future cognitive decline, incident dementia, and later-life AD pathology across independent cohorts spanning two decades of follow-up. Genetic and single-nucleus transcriptomic analyses demonstrated convergence of the neurostructural proteome and AD genetic architecture, highlighting enrichment in astrocyte, microglia, and endothelial pathways beyond the APOE region. Collectively, these findings identify a circulating neurostructural proteome detectable in midlife that captures molecular processes associated with future AD susceptibility and provide a framework for uncovering an early biological landscape of disease susceptibility that precedes conventional biomarkers and clinical onset.