Deep Plasma Proteomics Reveals Shared and Disease-Specific Molecular Signatures in Alzheimer's Disease and Frontotemporal Dementia.

INTRODUCTIONAlzheimers disease (AD) and frontotemporal dementia (FTD) have considerable clinical and pathological overlap. While plasma proteomics has advanced in AD, deep comparative analyses with FTD-particularly in diverse, biomarker-confirmed Asian cohorts-remain limited. METHODSPlasma from 101 individuals with known pTau217 status was profiled using Olink Explore-HT. Differential expression-pathway enrichment, penalized regression-GLMNET, single-cell transcriptomic integration, associations with cognitive measures and, cross-platform validation were performed. RESULTSAmong 5,400-proteins, 1,168 were differentially expressed in AD and 370 in FTD (FDR<0.05). Distinct and overlapping proteomic signatures were identified in AD and FTD, reflecting gliosis, synaptic dysfunction, immune activation, and metabolic pathways. Prioritized proteins correlated with cognitive performance and plasma phosphorylated tau, A{beta}42, and neurofilament light chain, linking circulating proteins to disease severity. Cross platform validation revealed strong concordance with large independent datasets. CONCLUSIONComprehensive plasma proteomics in Asian cohort supports scalable framework for blood-based biologically informed targets for precision diagnosis and therapeutic stratification.