SMAD4 and Alzheimer disease: Although the plethora of biological pathways reflected in this large metagene precluded significant enrichment of an individual pathway after correcting for multiple testing, the upregulated arm of this metagene contains multiple heatshock and proteosome proteins such as HSP1A1, STIP1, HSP1B1, PSMB1/D6, and the TGFβ signaling proteins SMAD2 and SMAD4. The downregulated arm of NdStress is enriched in genes involved in folate metabolism, such as DHFRL1, MTR and FPGS, possibly related to the alterations in folate and homocysteine observed in AD patients [34], [35], [36] (Table 2, S2, Fig. S4).