New insights on bridging integrator 1 protein isoforms as a risk increasing gene in Alzheimer’s disease

Introduction Alzheimer’s disease (AD) is a multifactorial, age-associated neurodegenerative disorder that leads to progressive declines in cognition, memory, and the capacity for independent daily living. Genome-wide association studies (GWAS) have identified Bridging Integrator 1 ( BIN1 ) as one of the strongest and most reproducible genetic risk factor for AD, which we replicated in our GWAS by proxy (GWAX) analysis on UKBiobank data. However, the mechanism by which BIN1 impacts AD risk is largely unknown and our work aims to uncover the underlying mechanism. Methods We generated human induced pluripotent stem cell (hiPSC)-derived neuronal and microglia cell models to evaluate cell-type specific BIN1 isoform expression using droplet digital polymerase chain reaction (ddPCR). We then extended our analysis to a Phase 2 AD clinical trial in which we evaluated the association of BIN1 isoform expression with the BIN1 genotype status. Results Our data indicated that BIN1 isoform expression patterns shifted with the differentiation of hiPSC into neurons or microglia. We also found that the SNP rs35103166 is associated with the expression of the microglia-specific BIN1 isoforms. Conclusion We demonstrate that BIN1 genotype is associated with isoform expression, which differs between neurons and microglia, enabling evaluation of disease-specific isoform effects. Given the strong association of BIN1 with susceptibility to AD, exploring the mechanisms of BIN1 genetic variants and their impacts on cell-type specific expression could serve as a valuable resource for novel drug discovery.