Fig. 6

Functional characterization of APOEε4 resiliency-associated proteins. A. GTEx database gene expression in brain, whole blood, and other tissues using data available from postmortem samples [57]. The expression of cognate genes coding for proteins associated with non-resilient versus resilient status are displayed in transcripts per million. Genes and tissues are grouped on the y- and x-axis based using hierarchical clustering. B. Brain and vascular cell-specific expression of genes coding for proteins associated with non-resilient versus resilient status [58]. Values are expressed in terms of average normalized counts. https://twc-stanford.shinyapps.io/human_bbb/. C-E. Brain and vascular cell-specific expression of genes coding for proteins associated with non-resilient versus resilient status. Expression values are presented stratified by Alzheimer’s disease verses control status [58]. F. Using Ingenuity Pathway Analysis (IPA), we identified molecules downstream of top candidate proteins associated with resilient versus non-resilient status among APOEe4 carriers. Relationships between molecules (edges) were defined based on activation, causation, chemical-chemical interactions, chemical-protein interactions, inhibition, modification, molecular cleavage, phosphorylation, protein-DNA interactions, protein-protein interactions, protein-RNA interactions, regulation of binding, RNA-RNA interactions, transcription, translocation, and ubiquitination. We identified the top three canonical pathways (based on number of overlapping molecules) among the candidate proteins and downstream molecules (left) and included three canonical pathways implicated in Alzheimer’s disease and related dementia (right). Bolded molecules are downstream of one or more candidate protein and implicated in AD. Abbreviations: aaSMC, Arteriolar Smooth Muscle Cell; ART, Arterial; aSMC, Vascular Smooth Muscle Cell; AST-Ctx, Astrocyte-Cortex; AST-Hpc, Astrocyte-hippocampus; CAP, Capillary; EPEN, Ependymal; M.FB, Meningeal Fibroblast; MCR, Motoric Cognitive Risk; MG, Microglia; M-PC, ECM-regulating Pericyte; NEU, Neuron; OL, Oligodendrocyte; OPC, Oligodendrocyte Precursor Cell; P.FB, Perivascular Fibroblast; PM, Perivascular Macrophage; TC, T-cell; T-PC, Solute transport-Pericyte; VEN, Venous; VINE, Vessel Isolation and Nuclei Extraction for Sequencing