An integrated approach to identify sex-specific genes, transcription factors, and pathways in Alzheimer's disease

Background: Age is one of the bigger risk factors for developing Alzheimer's disease (AD). Still, in the last decade, several experimental studies and reviews document the role of sex in several features of AD. Understanding the impact of sex in specific molecular mechanisms in this disease is critical for tailored interventions. Methods: To explore sex differences impact disease (SDID) in AD, we conduct a systematic review during 2021 to select transcriptomic studies of AD with sex information data in public repositories in the 2002-2021 period. We focus on the main brain regions affected by AD; cortex (CT) and hippocampus (HP). Then, a differential expression analysis for each study and two tissue-specific meta-analyses were performed. Last, focusing on the cortex, where significant SDID were detected, we conducted a functional characterization: protein-protein network interaction (PPI), Over-Representation Analysis (ORA) to explore biological processes and pathways, and a VIPER analysis to estimate transcription factor activity. Results: A group of eight studies in CT and five in HP were selected from Gene Expression Omnibus (GEO) repository, for tissue-specific meta-analyses. We detected 389 significant SDID genes in CT. In general, females show more affected genes than males and the genes were grouped in six subsets according to the expression profile in females and males with AD. Only subset I (repressed genes in affected females) displayed significant results at functional profiling. Females.AD compared to males. AD showed a more significant impairment in biological processes related to the regulation and organization of synapsis, the pathways more impaired those linked to neurotransmitters (Glutamate and GABA) and several pathways related to protein folding, Abeta aggregation, and accumulation. This could explain, in part, why the cognitive decline is more pronounced in females.AD. Finally, we detected 23 TFs having different activation patterns by sex, some of them associated with AD for the first time. All results generated during this study are readily available through an open web resource. Conclusion: Our meta-analyses indicate differences in several mechanisms involved in AD between females and males. Such sex differences represent the base of new hypotheses and could importantly impact precision medicine, and improve diagnosis and clinical outcomes in AD for females and males.