Web outline and results summary

Systematic Review

This section includes a step-by-step PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) diagram, showing the exclusion criteria applied during the systematic review. In addition, the characteristics of each of the selected studies for further analysis are presented.

The number of samples per selected study divided by sex, study, and experimental group is display in the following plot:

AD: Alzheimer’s disease, CT: cortex, HP: hippocampus

Individual Analysis of Selected Studies

This section focuses on evaluating the distribution of the data. For each study an exploratory analysis has been carried out, consisting of boxplots, PCA (principal component analysis) and clustering. In addition, differential gene expression analysis has been conducted by assessing the following comparisons:

  • IDF: impact of Alzheimer’s disease in females (case female - control female).

  • IDM: impact of Alzheimer’s disease in males (case male - control male).

  • SDID: sex-based differential impact on Alzheimer’s disease [(case female - control female) - (case male - control male)].

Gene Meta-analyses

In this section, based on the differential gene expression results obtained for each individual study, meta-analyses have been carried out by brain region (cortex and hippacampus) and comparison (IDF, IDM and SDID). A summary of the results is shown below.

Functional profiling

This section covers the functional characterization of the significant genes identified in each cortex meta-analysis through the following approaches:

  • Overrepresentation Analyses

  • Protein-Protein Interaction Networks

  • Transcription Factor Activity

For the first two instances, significant results have only been observed in the category of genes that are most repressed in Alzheimer’s disease females, corresponding to Subset I of the manuscript. The results of the over-representation analyses revealed 34 GO terms (Biological Processes ontology) and 20 Reactome pathways significant, whereas the protein-protein interaction networks grouped connected proteins in 10 different clusters.

Moreover, the transcription factor activity analysis identified 23 transcription factors with significantly altered activity in SDID comparison. Of them, 11 are activated in both sexes, 11 are repressed in both sexes, and 2 present divergent pattern.

Methods

Detailed description of the materials and methods employed to obtain the presented results.

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