ABSTRACT Abstract Figure Background Age represents a significant risk factor for the development of Alzheimer’s disease (AD); however, recent research has documented an influencing role of sex in several features of AD. Understanding the impact of sex on specific molecular mechanisms associated with AD remains a critical challenge to creating tailored therapeutic interventions. Methods The exploration of the sex-based differential impact on disease (SDID) in AD used a systematic review to first select transcriptomic studies of AD with data regarding sex in the period covering 2002 to 2021 with a focus on the primary brain regions affected by AD - the cortex (CT) and the hippocampus (HP). A differential expression analysis for each study and two tissue-specific meta-analyses were then performed. Focusing on the CT due to the presence of significant SDID-related alterations, a comprehensive functional characterization was conducted: protein-protein network interaction and over-representation analyses to explore biological processes and pathways and a VIPER analysis to estimate transcription factor activity. Results We selected 8 CT and 5 HP studies from the Gene Expression Omnibus (GEO) repository for tissue-specific meta-analyses. We detected 389 significantly altered genes in the SDID comparison in the CT. Generally, female AD patients displayed more affected genes than males; we grouped said genes into six subsets according to their expression profile in female and male AD patients. Only subset I (repressed genes in female AD patients) displayed significant results during functional profiling. Female AD patients demonstrated more significant impairments in biological processes related to the regulation and organization of synapsis and pathways linked to neurotransmitters (glutamate and GABA) and protein folding, Aβ aggregation, and accumulation compared to male AD patients. These findings could partly explain why we observe more pronounced cognitive decline in female AD patients. Finally, we detected 23 transcription factors with different activation patterns according to sex, with some associated with AD for the first time. All results generated during this study are readily available through an open web resource Metafun-AD ( https://bioinfo.cipf.es/metafun-ad/ ). Conclusion Our meta-analyses indicate the existence of differences in AD-related mechanisms in female and male patients. These sex-based differences will represent the basis for new hypotheses and could significantly impact precision medicine and improve diagnosis and clinical outcomes in AD patients. Highlights Female AD patients possess more affected genes than male AD patients. 389 genes from the sex-based differential impact on disease comparison significantly impact the cerebral cortex and suggest a more significant effect on cognitive function in female AD patients. The cluster of repressed genes in female AD patients functionally impacts glutamate and GABA neurotransmitters and Aβ deposition. Female AD patients exhibit several transcription factors with significantly different activity patterns compared to male AD patients. This work includes Metafun-AD, an open and interactive web tool to explore all generated data and results.

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