Reproducibility-driven discovery and systematic benchmarking reveal a robust cerebrospinal fluid proteomic signature in Alzheimer's disease

Numerous cerebrospinal fluid (CSF) proteomic signatures for Alzheimers disease (AD) diagnosis and prognosis have been proposed. However, cross-cohort reproducibility and head-to-head comparison among signatures remain uncertain. We implemented a reproducibility-driven framework integrating systematic review, multi-cohort validation, and systematic benchmarking to prioritized robust biomarkers. Across eight discovery studies (n=759) we identified eleven consistently dysregulated proteins (termed PPAV11). In three independent validation cohorts (n=1,198), PPAV11 demonstrated high diagnostic accuracy (AUC>0.94) and significant prognostic capacity (CU to AT MCI HR>4.96, p=0.004; AT MCI to AT dementia HR>3.23, p=3.13x10-). Comparative benchmarking against thirteen published signatures revealed superior cross-context stability across diagnostic definitions, disease stages, and proteomic platforms. Biologically, PPAV11 captures synaptic, metabolic, immune, and vascular processes and correlates with cognitive decline and neurodegeneration. Together, these findings establish reproducibility as an important criterion for proteomic biomarker prioritization and define a stable molecular signature for integrated AD diagnosis and prognosis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/26351766v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1db1c5org.highwire.dtl.DTLVardef@1823918org.highwire.dtl.DTLVardef@7262b6org.highwire.dtl.DTLVardef@1aecf45_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIA reproducibility framework identifies stable CSF proteomic signature for AD. C_LIO_LIPPAV11 shows strong diagnostic accuracy across cohorts, platforms, and stratifications. C_LIO_LIPPAV11 levels correlate with cognitive decline and predict AD progression. C_LIO_LIPPAV11 unites synaptic, metabolic, immune, and vascular pathways in AD dynamics. C_LI