Brain Transcriptome-Wide Association Study Reveals Selective Long-Term Potentiation Enrichment and Negative Directional Skew of Senescence-Regulation Pathways in Alzheimer's Disease

BackgroundAlzheimer’s disease (AD) has a strong genetic component, but most established risk loci fall in non-coding regions, which limits insight into the biological pathways through which inherited risk is expressed. Transcriptome-wide association studies (TWAS) help bridge this gap by imputing genetically regulated gene expression from genome-wide association study (GWAS) data. In this study, we used a brain-tissue TWAS framework to test whether AD genetic risk is enriched in pathways related to NAD metabolism, cellular senescence, GLP-1 and insulin signaling, synaptic plasticity, synapse pruning, complement biology, mitochondrial function, and glial cell identity.MethodsWe applied S-PrediXcan to the large European-ancestry AD GWAS meta-analysis reported by Bellenguez et al. (2022) across six brain tissues: amygdala, anterior cingulate cortex, caudate, frontal cortex, hippocampus, and nucleus accumbens. We then combined tissue-specific results with a Stouffer meta-analysis. Approximately 40 curated gene sets were tested, drawing on Hallmark, Reactome, KEGG, Gene Ontology, WikiPathways, and custom adult brain cell-type signatures. Enrichment was evaluated with Stouffer z-scores, Wilcoxon tests, and permutation-based p-values.ResultsThe strongest positive enrichment was observed for long-term potentiation, specifically KEGG LTP ALL, with a Stouffer z-score of +5.267. Astrocyte-expressed genes showed clear positive enrichment and outperformed microglial signatures. Complement cascade genes were also positively enriched, driven largely by CR1, whereas the synapse pruning set was negatively enriched. Insulin- and GLP-1-related pathways, together with PI3K–AKT–mTOR signaling, showed positive enrichment as well. In contrast, regulation of cellular senescence and oxidative phosphorylation displayed the strongest negative directional skews. NAD-related sets showed mixed, gene-specific effects rather than strong pathway-wide enrichment.ConclusionsThese findings suggest that AD genetic liability, as captured by brain TWAS, converges on glial-immune signaling, selective synaptic potentiation, and metabolic pathways, while canonical senescence regulation and mitochondrial oxidative phosphorylation show directional depletion. The overall pattern supports the use of pathway-based stratification tools to guide precision therapeutic approaches in AD, especially for glial-targeted and metabolic interventions.Keywords: Alzheimer’s disease, TWAS, long-term potentiation, senescence, complement, astrocytes, GLP-1, precision medicine