Synaptic Plasticity Fragility Underlies a Microglial Pruning Continuum in Major Depressive Disorder and Amyotrophic Lateral Sclerosis

Background: Major depressive disorder (MDD) and amyotrophic lateral sclerosis (ALS) are clinically distinct yet show intriguing comorbidity, with depression affecting 10–34% of ALS patients, often early in the disease course. We hypothesized a shared microglial-mediated synaptic pruning vulnerability, amplified differently by disorder-specific pathways—autophagy collapse in ALS versus RNA processing and immune dysregulation in MDD—creating a biological continuum. Methods: Using large-scale GWAS from the PGC (MDD, N=829,249) and Project MinE (ALS, effective N=87,381), we applied MAGMA for gene- and set-level associations, GSEA/DGSEA for pathway enrichment and differentials, S-PrediXcan TWAS across 14 GTEx tissues, and LDSC for partitioned heritability and cross-trait genetic correlation. Eight gene sets (housekeeping controls, monoaminergic, neurosteroid, glutamatergic, synaptic pruning, autophagy/protein quality, RNA processing, immune/neuroinflammation) were tested for convergence and divergence. Results: Synaptic pruning emerged as the sole consistent cross-disorder signal, with robust enrichment in MDD (LDSC 1.32×, GSEA NES=1.42, p=0.001) and nominal but consistent signals in ALS (GSEA NES=1.40, p=0.011; TWAS HLA-B). Autophagy dominated ALS (LDSC 2.20×, TWAS C9orf72 Z=13.43, GSEA NES=1.94) but was depleted in MDD. RNA processing and immune pathways were prominent in MDD (LDSC 1.48× and 1.89×) with only nominal ALS signals. Overall genetic correlation was near-zero (rg=–0.044, p=0.196). Conclusions: These findings support a microglial pruning continuum model: shared pruning liability as the foundation, with autophagy failure driving ALS neurodegeneration and RNA/immune dysregulation shaping MDD stress sensitivity. The low rg explains the modest overlap, while pathway specificity accounts for comorbidity and divergent progression. This framework offers testable predictions for PRS stratification, complement modulators in ALS mood subsets, and microglial therapies in treatment-resistant MDD.