From GWAS to Mechanism: Immune-Excitotoxic Convergence via TRPM4 in Alzheimer's Disease Pathogenesis

Background: Alzheimer's disease (AD) progression involves excitotoxicity and synaptic loss downstream of amyloid-β pathology, potentially amplified by the NMDAR/TRPM4 death signaling complex. We hypothesized that genes related to synaptic pruning and TRPM4 pathways enrich for AD genetic risk, tested via pathway-based analyses of a large GWAS dataset. Methods: Using summary statistics from a meta-analysis of AD (N ≈ 74,000 effective samples), we applied Multi-marker Analysis of GenoMic Annotation (MAGMA) for gene-set enrichment, linkage disequilibrium score regression (LDSC) for partitioned heritability, and transcriptome-wide association study (TWAS) for imputed brain expression associations. Four curated gene sets were evaluated: housekeeping (negative control, n=184 genes), monoaminergic (control, n=104), pruning-related (n=262), and TRPM4-associated (n=140), allowing overlaps to reflect biological interconnectivity. Results: MAGMA showed nominal enrichment for pruning (p=0.020) and TRPM4 (p=0.146) sets, with seven and three genome-wide significant genes, respectively (e.g., ABCA7, APOE in pruning; FCER1G, PLCG2 in TRPM4). LDSC indicated heritability partitioning in TRPM4 (enrichment 1.08, Mann-Whitney p=2.92×10^{-22}) and controls, but not pruning (p=1.00). TWAS revealed stronger enrichments for pruning (1.40×, p=3.22×10^{-4}) and TRPM4 (1.27×, p=0.002) over background, with key genes like APOE (downregulated) and FCER1G (downregulated) implicating immune-excitotoxic convergence. Conclusions: These findings support pruning and TRPM4 pathways as modest amplifiers of AD genetic risk, suggesting the NMDAR/TRPM4 complex as a therapeutic target to complement amyloid-clearing approaches.