Integrative machine learning reveals telomere-associated gene modules reflecting neuronal dysregulation in Alzheimer's disease
Syeda Ummul Khair Fatima, Abdul Jabber, Mosammat Halima Khanam, Jubayer Khan, Md. Mostafij Talukder, Mohammad Abul HasnatBackground
Telomere dysfunction contributes to cellular aging and genome instability, but telomere-associated transcription in Alzheimer's disease (AD) is poorly characterized. Telomere genes are commonly tested gene by gene, leaving it uncertain whether they organize into reproducible, disease-linked co-expression programs across cohorts.
Objective
To identify AD linked telomere gene modules and evaluate their diagnostic and biological relevance.
Methods
We curated 157 telomere maintenance genes and analyzed two GPL570-platform GEO Series datasets: GSE5281 (n = 161; AD = 87, control = 74) and GSE48350 (n = 253; AD = 80, control = 173). In GSE5281 hippocampus, RMA + age-adjusted limma identified 38 AD-associated telomere genes (FDR<0.05). Ward clustering (silhouette) defined two modules, summarized as eigengenes (module PC1). Eigengenes were evaluated across seven classifiers with nested stratified 5 × 5 cross-validation; Youden's J thresholds from out-of-fold predictions were fixed and applied to GSE48350 using frozen z-scoring (GSE5281 μ/σ) and fixed cutoffs. Robustness used 500-bootstrap stability; hub genes from the dominant module were interpreted with BRETIGEA and Reactome/GO enrichment.
Results
PCA and t-SNE showed AD-associated structure in telomere-gene expression. With only two module features, models achieved ROC-AUC 0.722–0.780 internally and 0.689–0.695 externally. Bootstrap resampling converged on one dominant axis: Cluster 2 was consistently the strongest feature and was reduced in AD (Cohen's d = −1.07; Welch p = 8.13 × 10 − 1 0 ). Hub genes (TSPYL5, TUBB3, PLCL2, NHP2) were downregulated, tracked neuronal signatures positively, varied inversely with microglial/astrocytic signatures, and mapped to telomere/chromosome maintenance, DNA repair, and cell-cycle regulation.
Conclusions
AD features a reproducible, resampling-stable telomere genome-maintenance module that provides an interpretable systems-level disease axis for mechanistic follow-up and integrative biomarker development.