Journal of Alzheimer's Disease Reports · Published 2026-07-01 · DOI 10.1177/25424823261468711
Background Alzheimer's disease (AD) has a strong genetic component, but many risk loci are non-coding, limiting biological interpretation. Transcriptome-wide association studies (TWAS) help address this by imputing genetically regulated gene expression from genome-wide association study (GWAS) data. Objective To test whether AD-associated genetically regulated brain expression is enriched in pathways related to synaptic plasticity, glial-immune biology, senescence, mitochondrial function, nicotinamide adenine dinucleotide (NAD) metabolism, and metabolic signaling. Methods We applied S-PrediXcan to the European-ancestry AD GWAS meta-analysis from Bellenguez et al. (2022) across six brain tissues. Tissue-specific results were combined using Stouffer meta-analysis. Approximately 40 curated gene sets from public pathway databases and adult brain cell-type signatures were tested. Enrichment was assessed using Stouffer z-scores, Wilcoxon tests, and permutation p-values. Sensitivity analyses examined tissue consistency, top-driver removal, gene-level Z thresholds, gene-set overlap, and MHC/immune-gene exclusion. Results The strongest positive enrichment was long-term potentiation (LTP), particularly KEGG LTP ALL, with a Stouffer z-score of +5.267. Astrocyte-expressed genes were positively enriched and exceeded microglial signatures. Complement enrichment was largely driven by CR1, while synapse pruning was negatively enriched. Insulin, GLP-1, and PI3K–AKT–mTOR pathways also showed positive enrichment. Senescence regulation and oxidative phosphorylation showed the strongest negative skews. NAD-related sets showed mixed gene-specific effects. Sensitivity analyses identified senescence regulation, LTP, oxidative phosphorylation, and PI3K–AKT–mTOR as the most robust signals. Conclusions AD genetic liability captured by brain TWAS converges on glial-immune signaling, selective synaptic potentiation, and metabolic pathways, while senescence regulation and oxidative phosphorylation show directional depletion. These findings support pathway-based stratification to guide precision therapeutic approaches in AD.
Abstract from DOAJ. Public domain (CC0 1.0).
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Cheung, N. (2026). Brain transcriptome-wide association study reveals selective long-term potentiation enrichment and negative directional skew of senescence-regulation pathways in Alzheimer's disease. Journal of Alzheimer's Disease Reports. https://doi.org/10.1177/25424823261468711