biostudies-literatureUnknown24(8)Scalia EEuropean CommissionAlzheimer's disease (AD) is a multifactorial neurodegenerative disorder that presents with heterogeneous clinical and pathological features, necessitating improved biomarkers for accurate diagnosis and patient stratification. In this study, we applied a data-independent acquisition-based proteomics workflow to cerebrospinal fluid (CSF) samples from 138 individuals, including AD patients with high (Aβ+/tau+) or normal (Aβ+/tau-) CSF tau levels, and non-AD controls. Analysis using an Astral mass spectrometer enabled unprecedented proteome depth, identifying 2661 proteins with high data completeness. Comparative proteomic profiling revealed distinct protein signatures for Aβ+/tau+ and Aβ+/tau- subtypes. These findings were validated using an independent internal cohort and further corroborateMolecular & cellular proteomics : MCP101025https://www.ebi.ac.uk/biostudies/studies/S-EPMC12335992biostudies-literatureProteome Profiling of Cerebrospinal Fluid and Machine Learning Reveal Protein Classifiers of Two Forms of Alzheimer's Disease Characterized by Increased or Not Altered Levels of Tau.PMC12335992Piccoli TLo Pinto MIemmolo MScilabra SDGhersi GScalia ELo Re VCastelbuono SBivona GCalligaris MfalseProteome Profiling of Cerebrospinal Fluid and Machine Learning Reveal Protein Classifiers of Two Forms of Alzheimer's Disease Characterized by Increased or Not Altered Levels of Tau.Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that presents with heterogeneous clinical and pathological features, necessitating improved biomarkers for accurate diagnosis and patient stratification. In this study, we applied a data-independent acquisition-based proteomics workflow to cerebrospinal fluid (CSF) samples from 138 individuals, including AD patients with high (Aβ+/tau+) or normal (Aβ+/tau-) CSF tau levels, and non-AD controls. Analysis using an Astral mass spectrometer enabled unprecedented proteome depth, identifying 2661 proteins with high data completeness. Comparative proteomic profiling revealed distinct protein signatures for Aβ+/tau+ and Aβ+/tau- subtypes. These findings were validated using an independent internal cohort and further corroborate2025-01-01T00:00:00Z2025 Aug2026-07-06T03:14:35.998Z2026-07-06T03:08:38.668ZS-EPMC123359924060252810.1016/j.mcpro.2025.101025