The first and the largest group of about 2000 genes, further referred to as NdStress, was associated with various metabolic disruptions. This metagene contained some genes that were upregulated and others that were downregulated in AD samples. In normal brain samples with BioAge<0, the expression of these genes was maintained in a relatively stable narrow range with relatively low coherence. In AD samples, however, the expression of these genes varied dramatically and was highly correlated (Fig. 3). 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). Figure 4 includes the relationship between NdStress and BioAge, which moderately correlated in AD
