Fig. 3: DSAD CSF protein co-expression network.

A–C About 1116 proteins measured across control, DS, and AD cases were used to construct a CSF protein co-expression network (A). Modules were annotated with their primary ontologies. Module eigenproteins were correlated to CSF total tau (tTau), pTau181, pTau217, pTau231, Aβ42/40, Aβ42/tTau, neurofilament light polypeptide (NEFL), chitinase-3-like protein 1 (CHI3L1), CamCog score (higher scores reflect better cognitive function in DS), age of controls (CT), age of DS cases, sex in CT (1 = male), sex in DS (1 = male), and APOE ε4 risk (ε2/2 = –2, ε4/4 = +2). Red indicates positive correlation; blue indicates negative correlation. Differences in module eigenprotein levels were assessed between AD and control (AD-CT), asymptomatic DS and control (AsymDS-CT), demented DS and control (DemDS-CT), demented DS and asymptomatic DS (DemDS-AsymDS), all DS and control (allDS-CT), and symptomatic DS (prodromal and demented) and AD (SymDS-AD) using a two-sided t-test without correction for multiple comparisons. Green indicates increased levels; blue indicates decreased levels. Brain cell type enrichment in each module was performed for neurons, oligodendrocytes (oligo), astrocytes (astro), microglia (micro), and endothelia (endo) using one-tailed Fisher’s exact test with Benjamini–Hochberg correction. Only cell type overlaps that reached statistical significance are colored. Module ontologies highlighted in bold demonstrated strong associations with AD traits, with modules highlighted in red showing the strongest associations. Module protein memberships are provided in Supplementary Data 5. Heatmap values are provided in Supplementary Data 6. B Protein members of the M8 14-3-3/MAPT/Mixed module, which was the module most strongly correlated to CSF AD biomarkers. Circle size indicates the strength of correlation to the module eigenprotein. Transparent blue lines represent human protein-protein interactions as provided in the BioGRID database. Gray lines represent top-ranked co-expression network edges. C Differences in M8 eigenprotein levels among groups (boxplot; control n = 72, preclinical AD n = 8, AD n = 56, other DS n = 14, Asym DS n = 96, prodromal DS n = 47, dementia DS n = 72), and correlation of the M8 eigenprotein to age in DS cases, CSF tau phosphorylated at residue 217 (pTau217), CSF amyloid-β 42/40 ratio (Aβ42/40), CSF neurofilament light polypeptide (NEFL) levels, and CSF chitinase-3-like protein 1 (CHI3L1, also known as YKL-40) levels. The difference between groups was assessed by one-way ANOVA and adjusted for age and sex. Correlations were performed using midweight bicorrelation. Boxplots represent the median, 25th, and 75th percentile extremes; thus, hinges of a box represent the interquartile range of the two middle quartiles of data within a group. The farthest data points up to 1.5 times the interquartile range away from box hinges define the extent of whiskers (error bars). Plots for other modules are provided in the Supplementary Information.