Extended Data Fig. 2. Detection-tier architecture and six biological classes of the core CSF proteome.

(a) Classification of 12,606 proteins across 21 informative MS studies through initial coverage-aware tiering, leave-one-study-out reassignment, minimum-support filtering and final tier assignment. (b) Protein-by-study detection matrix. Proteins are ordered by the pooled lower 95% confidence bound and studies by proteomic depth; marginal tracks, number of informative studies, pooled lower 95% bound and final tier. (c,d) Pooled CAD estimates (c) and between-study heterogeneity, τ² (d; logarithmic scale), across Tiers A–D. Violin plots, distributions, boxes, median and IQR (Kruskal–Wallis: c, P < 2.2 × 10⁻¹⁶; d, P = 1.86 × 10⁻²⁰⁸). (e) Cross-tabulation of primary and secondary Core Class assignments among the 747 Tier A/B proteins. (f) PCA of the 747 proteins in latent-class probability space. Points, protein; colour, core class (CC1–CC6). PC1 and PC2 separate extracellular-matrix (ECM)/barrier, pan-CNS and metabolic/intracellular families. (g) Representative pathways enriched in each core class. (h) Sample-level core class abundance across 10,560 paired CSF profiles. Kruskal–Wallis P = 7.0 × 10⁻⁷. (i) Brain-protein half-lives for 232 mapped proteins in external stable-isotope-labelling-by-amino-acids-in-cell-culture (SILAC) data. Kruskal–Wallis P = 1.8 × 10⁻⁴. (j) Enrichment of core classes by protein origin, release mechanism and subcellular compartment. Fill, Fisher’s-exact-test enrichment score.