Sex- and brain region-specific gene expression in Alzheimer's disease

Background Women with Alzheimer's disease (AD) have higher prevalence and more severe dementia syndrome than men with AD, and the brain regions are also affected differently. However, the underlying mechanisms are poorly understood. Objective To characterize the sex-dependent and region-specific gene expression in AD brain. Methods A previously published large scale bulk tissue gene expression dataset from postmortem brain samples across 19 cortical regions of normal control and individuals diagnosed with dementia and neuropathology of AD was used for differential gene expression analysis. Functional enrichment analysis was used to identify enriched biological functions or pathways related to selected genes. Protein expression level of a selected gene was validated by western blot. Results We identified 113 dysregulated genes in 11 AD brain regions (9 in men, 7 in women, and 5 shared between men and women). Notably, more dysregulated genes were found in women AD brain (77 genes) than in men (49 genes), and 13 dysregulated genes across these 11 brain regions were shared between women and men. Functional analysis further revealed the distinctive enrichment in categories of cellular component, biological process, and/or molecular function in these dysregulated genes. GPR34 gene expression was upregulated in the men AD brain across three different regions and a significant elevation of GPR34 protein level was confirmed in men AD brain. Conclusions These findings provide insight into sex- and brain region-specific gene expression dysregulation, which may indicate novel mechanisms underlying AD pathogenesis and will facilitate the development of personalized diagnosis and treatment strategies for AD.