Cross-sectional transcriptomic analysis of the retina in 5XFAD mouse model identifies stage-specific gene expression differences and candidate hub genes with potential biomarker relevance in AD

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ABSTRACT Alzheimer's disease (AD) is the most prevalent form of dementia, with late diagnosis as a major contributor to its global burden . The retina, due to its physiological proximity to the brain, has been considerably studied as a potential site for early non-invasive AD biomarker changes. However, prior studies have been limited by single time-point design and the inability to identify specific genes associated with AD pathology in the retina. This study examined the retinal transcriptomic profiles of the 5xFAD mouse model through a cross-sectional analysis of RNA-sequencing data at early (1.5M) and late (6M) disease stages from the publicly available GSE274214 dataset, characterising stage-specific gene expression differences in retinal transcriptomic profiles at these two time points. Differential gene expression, functional and gene set enrichment, as well as Protein-Protein interaction analysis were performed to identify stage-specific transcriptomic signatures and hub genes. The cross-model expression overlap of the hub gene panel was then examined against an independent APP/PSEN1 dataset using PCA and ROC curve analysis. At 1.5M, DEGs were predominantly enriched for synaptic signalling and neuronal pathways. While at 6M, DEGs enrichment shifted toward mitochondrial dysfunction and glial activation, representing a pattern distinct from the early-stage profile. PPI analysis identified 20 hub genes associated with synaptic and mitochondrial activities, of which 16 were conserved in the APP/PSEN1 dataset and separated AD from wild-type samples in this small cohort (AUC = 1.0 in the 11-sample validation set); however, given the small sample size, this result should not be interpreted as evidence of diagnostic robustness. The findings of this study provide exploratory evidence of stage-specific gene expression differences in the 5xFAD retina and identify candidate hub genes warranting further investigation as molecular correlates of AD-associated retinal changes.

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