Peripheral blood transcriptome signatures indicate environmental influences in monozygotic twins discordant for Alzheimer's disease

Abstract

Environmental factors have been proposed to contribute to the pathogenesis of Alzheimer's disease (AD). Because monozygotic (MZ) twins share identical genetic backgrounds, they provide a unique model to disentangle genetic and environmental contributions to disease-related molecular changes. Herein, we investigated MZ twins who lived distinctly different lives and became discordant for AD, and analyzed which transcriptome signatures were altered in the affected twin. We further examined whether these alterations paralleled those found in sporadic AD patients compared with individuals with normal cognition (NC). Whole transcriptome sequencing was performed on mRNAs isolated from peripheral white blood cells of the discordant MZ twins, and the results were compared with transcriptome datasets from blood cells and postmortem brains of sporadic AD patients and NC subjects. In the AD twin, transcripts associated with inflammatory and immune responses were up-regulated, whereas transcripts related to signal recognition particle–mediated protein targeting pathways were down-regulated. Biological network analysis revealed dense connectivity among up-regulated genes linked to cell chemotaxis, cytokine production, and inflammatory response. Heatmap analysis demonstrated differential expression of transcripts related to histone, DNA, and RNA modifications in the AD twin. Comparative analyses with transcriptome data from postmortem brains of sporadic AD patients confirmed similarly up-regulated inflammatory responses in both groups. Taken together, these findings suggest that environmental factors can shape transcriptome signatures related to inflammation and immune pathways, and that such gene expression alterations may ultimately contribute to AD development.