Cdkn2a/p16INK4A Loss affects hippocampal transcription in Young Adult Mice Independently of Alzheimer ’s-Associated Genetic Pathways

We performed differential gene expression analysis, gene set enrichment analysis (GSEA), and interaction modelling to assess the molecular consequences of p16INK4A loss alone and in combination with amyloid pathology. Results –Transcriptomic analysis revealed that p16INK4AKO upregulated metabolic, mitochondrial, and translational pathways, while downregulating synaptic and cytoskeletal genes. In contrast, AppNL-G-F mice displayed strong immune activation.

The double mutants showed additive transcriptional changes, yet GSEA indicated non-linear interactions in synaptic and immune-related pathways. Unexpectedly, p16INK4A deletion alone enriched senescence-associated signatures, despite the loss of this canonical senescence gene. Conclusion – Constitutive p16INK4A loss causes broad transcriptomic remodelling in the adult hippocampus, independently of amyloid pathology.

These findings uncover non-canonical roles for p16INK4A in neuronal homeostasis and emphasise the need for temporally controlled models to better dissect the brain-specific functions of senescence regulators in ageing and neurodegeneration.