New Insights on Bridging Integrator 1 Protein Isoforms as a Risk Increasing Gene in Alzheimer's Disease

INTRODUCTIONGenome-wide association studies (GWAS) have identified Bridging Integrator 1 (BIN1) as the second-most significant genetic risk factor for Alzheimers disease (AD). We performed GWAS by proxy (GWAX) using UKBiobank and replicated this finding. However, the mechanism by which BIN1 impacts AD risk is largely unknown. METHODSTo address this, we first measured the expression of BIN1 isoforms in a human induced pluripotent stem cells (hiPSC) model and further evaluated whether the BIN1 risk loci associated with the expression of BIN1 isoforms in a Phase 2 AD clinical trial. RESULTSOur data indicated BIN1 isoform expression patterns associated with the differentiation of hiPSC into neurons or microglia and found the variant rs35103166 impacts the expression of the BIN1 microglia-specific isoforms. DISCUSSIONGiven the strong association 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. HighlightsO_LIBIN1 variants are significantly associated with AD risk in GWAX analysis from UKBB. C_LIO_LIBIN1 isoforms show a cell-type-specific expression pattern during hiPSC differentiation into neurons or microglia. C_LIO_LIBIN1 risk alleles associate with BIN1 isoform expression in a Phase 2 AD trial (NCT02880956). C_LI