Antagonistic Pleiotropy in Inflammatory-Pruning Remodeling Explains Negative Genetic Correlation Yet Clinical Overlap Between Atrial Fibrillation and Alzheimer's Disease

Background: Alzheimer's disease (AD) and atrial fibrillation (AF) exhibit robust epidemiological comorbidity, with AF elevating dementia risk through vascular and inflammatory mechanisms. However, genome-wide analyses suggest limited or negative genetic correlation, raising questions about shared versus divergent pathways. We hypothesized differential contributions from synaptic pruning (microglial/complement-mediated) and TRPM4-related (conduction/calcium signaling) pathways, potentially reconciled by antagonistic pleiotropy. Methods: Using large GWAS summary statistics for AD (∼74,000 effective samples) and AF (>180,000 cases), we applied multi-method genetic analyses: competitive gene-set testing and gene-based association (MAGMA), brain transcriptome-wide association (TWAS with GTEx v8 MASHR models across eight regions), partitioned heritability (LDSC), rank-based enrichment (GSEA), differential GSEA, and bivariate genetic correlation (LDSC). Four curated gene sets (housekeeping and monoaminergic controls; expanded pruning-related; TRPM4-related) were tested, allowing overlaps. Results: Pruning pathways showed modest competitive and TWAS enrichment in AD (nominal MAGMA p=0.020; 7 FDR-significant associations, led by downregulated lipid genes like APOE/CLU/ABCA7), but stronger partitioned signals in AF (LD-adjusted 1.08-fold, Bonferroni-corrected). Conversely, TRPM4 pathways dominated AF (strong MAGMA/TWAS enrichment, 23 FDR hits including conduction genes SCN5A/TBX5) with weaker AD signals. Genome-wide correlation was negative (r_g = -0.058, p=0.0048). Differential GSEA highlighted pruning dominance in AD versus TRPM4 in AF. Conclusions: Pruning and TRPM4 pathways contribute complementarily yet divergently to AD and AF polygenic risk, yielding inverse correlation despite comorbidity. Antagonistic pleiotropy in shared inflammatory-pruning nodes—promoting cardiac remodeling in AF but restraining cerebral over-pruning in AD—offers a unifying model, overridden physiologically. Findings motivate AF-stratified AD subtyping for precision prevention and therapy.