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

INTRODUCTION Genome-wide association studies (GWAS) have identified Bridging Integrator 1 (BIN1) as the second-most significant genetic risk factor for Alzheimer’s 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.

To 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.

Our 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.

Given 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. Highlights BIN1 variants are significantly associated with AD risk in GWAX analysis from UKBB. BIN1 isoforms show a cell-type-specific expression pattern during hiPSC differentiation into neurons or microglia. BIN1 risk alleles associate with BIN1 isoform expression in a Phase 2 AD trial (NCT02880956). Competing Interest Statement The authors have declared no competing interest. Footnotes Abbreviations - GWAS - Genome-wide association study - AD - Alzheimer’s disease - BIN1 - Bridging integrator 1 - SAIGE - Scalable and Accurate Implementation of Generalized Mixed Model - hiPSC - Human induced pluripotent stem cells - SNP - Single nucleotide polymorphism - NPC - Neural progenitor cells - PB - Peripheral blood