Genetic and mechanistic overlap between Alzheimer’s disease and myasthenia gravis: insights into neuro-immune crosstalk

Alzheimer’s disease (AD) and myasthenia gravis (MG) are characterised by acetylcholine dysregulation, yet their epidemiological links remain inconclusive. We comprehensively assessed the genetic relationship between AD and MG, including early- and late-onset MG, using large-scale genome-wide association study data. We detected significant global genetic correlations between AD and MG, supported by concordance in polygenic SNP effects and gene-level overlap. Local correlation analyses revealed shared locus-specific associations between AD and MG, and MG subtypes. Mendelian randomisation (MR) suggested that genetic liability to MG modestly increases AD risk (not vice versa). Cross-trait meta-analysis and colocalisation highlighted several shared loci. Gene-based and summary-data-based MR analyses prioritised 32 genes, including canonical immune mediators, zinc finger genes, chromatin regulators, and putative novel candidates. Synaptic genes such as STX4 and transcriptional regulators, implicate neuronal–immune coordination bridging autoimmunity and neurodegeneration. Tissue- and pathway-specific analyses revealed shared immune mechanisms with disease-specific emphasis: innate immunity in AD, adaptive immunity in MG, converging on antigen presentation, T-cell, and interferon signalling. Gene–drug interactions identified candidate targets, including VKORC1 and NOTCH4 , suggesting avenues for therapeutic exploration. These results provide the first integrative evidence of shared genetic architecture and a putative causal effect of MG on AD, with translational relevance.