Fig. 2. Longitudinal associations of VAT gene expression at baseline and the scores in different cognitive domains later in life.

Volcano plots of differentially expressed genes in the VAT at baseline associated with (A) the STROOP color word tests (STROOPCW), (B) the TMTA, and (C) the Forward Digit Span scores 2 to 3 years later in the validation cohort (INTESTINE, n = 22) identified by limma-voom analysis controlling for age, BMI, sex, and education years. The log₂ fold change associated with a unit change in the cognitive test score and the log₁₀ P values adjusted for multiple testing (pFDR) are plotted for each gene. Differentially expressed genes (pFDR < 0.05) are colored in red and green indicating down-regulation and up-regulation, respectively. (D) Manhattan-like plot of pathways significantly associated (q < 0.1) with the TMTA in the VAT identified from a pathway overrepresentation analysis mapping significant genes to the Reactome and WikiPathways databases. (E) Dot plot of pathways significantly associated (q < 0.1) with the STROOPCW and (F) the Forward Digit Span in the VAT identified from a pathway overrepresentation analysis mapping significant genes to the Reactome database. The x axis in the dot plots and the bubble size in the Manhattan-like plots represent the ratio of input genes that are annotated in a pathway (GeneRatio). Dots are colored by the q value. NAD, nicotinamide adenine dinucleotide; TYROBP, Transmembrane Immune Signaling Adaptor TYROBP; SLIT, Slit Guidance Ligand; ROBO, Roundabout Guidance Receptor.