Research Article
Integrated Transcriptomic and Genetic Analyses Identify Four Candidate Genes in Alzheimer’s Disease
Issue:
Volume 14, Issue 6, December 2026
Pages:
116-123
Received:
9 September 2026
Accepted:
4 October 2026
Published:
10 November 2026
DOI:
10.11648/j.ajbls.20261406.11
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Abstract: Alzheimer’s disease (AD) involves convergent neuronal, metabolic, vascular, and immune disturbances, yet reproducible genes linking tissue-level dysregulation to genetic liability remain incompletely defined. This study integrated three human hippocampal bulk-transcriptome datasets, two-sample Mendelian randomization (MR), and single-nucleus transcriptomic data to identify and characterize candidate AD genes. Differential expression was analyzed separately in GSE29378, GSE36980, and GSE48350, and ranked gene lists were combined by robust rank aggregation (RRA). Genetically supported genes were obtained using expression-associated variants as exposures and FinnGen AD summary statistics as the outcome. RRA genes were intersected with directionally concordant MR results. Human hippocampal nuclei from GSE163577 were processed with Seurat and Harmony and annotated using SingleR with marker-based review. The three bulk datasets were then merged after ComBat batch correction for gene set enrichment analysis (GSEA), CIBERSORT immune deconvolution, gene-immune correlation analysis, and construction of a four-gene nomogram with decision curve analysis (DCA). RRA and MR converged on four genes: HVCN1 and LAPTM5 were upregulated and associated with increased AD odds, whereas GAS7 and PARM1 were downregulated and associated with reduced odds. Single-nucleus mapping localized HVCN1 and LAPTM5 predominantly to microglia, while GAS7 showed broader neuronal and oligodendroglial expression. GSEA separated immune/complement programs from neuronal and bioenergetic pathways across the four genes. Gene expression also correlated with selected immune-cell fractions, and the combined model showed positive net benefit across a broad range of threshold probabilities. These findings nominate HVCN1, LAPTM5, PARM1, and GAS7 as biologically coherent candidate markers connecting genetic susceptibility, cell-type specificity, immune remodeling, and hippocampal dysfunction in AD. Independent cohorts and experimental studies are required before clinical translation.
Abstract: Alzheimer’s disease (AD) involves convergent neuronal, metabolic, vascular, and immune disturbances, yet reproducible genes linking tissue-level dysregulation to genetic liability remain incompletely defined. This study integrated three human hippocampal bulk-transcriptome datasets, two-sample Mendelian randomization (MR), and single-nucleus transc...
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,
Yingxin Qiu
