Deep Plasma Proteomics Reveals Shared and Disease-Specific Molecular Signatures in Alzheimer's Disease and Frontotemporal Dementia.
Tan, Y. J.; Chauhan, M.; Chakravarty, S.; Timsina, J.; Ali, M.; Tan, N. I.; Zeng, L.; Tan, L. C.; Chiew, H. J.; Ng, K. P.; Hameed, S.; Ting, S. K.; Rohrer, J. D.; Cruchaga, C.; Ng, A. S. L.
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INTRODUCTION: Alzheimer's 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. METHODS: Plasma 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. RESULTS: Among 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. CONCLUSION: Comprehensive plasma proteomics in Asian cohort supports scalable framework for blood-based biologically informed targets for precision diagnosis and therapeutic stratification.
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