Fig. 7

Sex-specific resilient mechanisms are related to autophagy and interferon signaling. A PCA plot of our data without correcting for sex shows PC1 is driven by sex. m = males, f = females. B When removing all genes from the X and Y chromosomes, sex is no longer driving PC1 and PC2 in the PCA plot. m = males, f = females. C Venndiagram showing the DEGs specific for female resilience or males resilience, with females having more DEGs. D Pathways which are overrepresented in the female DEGs are related to metallothionein (response to metal ions), mitochondria and interferon signaling. E GSEA of male versus female resilient donors after removing the X and Y chromosomes, indicating enrichment of gene sets related to autophagy and translation in males and interferon signaling in females. F Quadrant plot of normalized enrichment scores (NES) after performing GSEA on sex-specific gene-expression to explore sex-dependent mechanisms. Our main findings seem to be independent of sex. Metallothionein signaling, oxidative phosphorylation and the TYROBP pathway are all either up or downregulated in resilient compared to AD. Processes related to autophagy and translation are enriched in male resilient donors but not in females. G–J Quantification of MT-1/MT-II and MT-CO1 on protein level show that both pathways behave similarly in each sex, although only metallothionein signaling is significantly increased in female resilient cases compared to female AD cases (F(3, 14) = 5.86 p = 0.018, AD versus control; p > 0.999, resilient versus control; p = 0.029, resilient versus AD; p = 0.029). Data of IHC is represented as average ± SEM