{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T13:12:22Z","timestamp":1783775542369,"version":"3.55.0"},"reference-count":47,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer's Disease Reports"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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\u2013AKT\u2013mTOR 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\u2013AKT\u2013mTOR as the most robust signals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/25424823261468711","type":"journal-article","created":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T12:34:01Z","timestamp":1783773241000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Brain transcriptome-wide association study reveals selective long-term potentiation enrichment and negative directional skew of senescence-regulation pathways in Alzheimer's disease"],"prefix":"10.1177","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3481-893X","authenticated-orcid":false,"given":"Ngo","family":"Cheung","sequence":"first","affiliation":[{"name":"Independent Researcher, Hong Kong SAR, 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