Identifying the intrinsic biological factors of APOE risk and resilience across relevant iPSC-derived brain cell types

Brain resilience, the ability to withstand adverse outcomes despite significant risk factors, is crucial in late-onset Alzheimer’s disease (AD), where the Apolipoprotein E4 (APOE4) gene is a major risk factor. Carrying APOE4 increases AD risk up to 15-fold compared to the ApoE3 allele. Recent single-cell sequencing advancements reveal altered APOE4 expression in various brain cell types, reshaping understanding of its impact. Despite most APOE4 carriers developing AD, some exhibit resilience, showing normal cognitive function despite pathology. Yet, the cellular and molecular bases of this resilience remain unclear. To address this gap, this research team aims to develop human iPSC-derived CNS cell types from APOE4 donors and isogenic APOE3 controls to study both risk and resilience. This involves establishing cellular models representing diverse CNS cell types susceptible to neurodegenerative alterations. Through multiomic profiling, including transcriptomic, lipidomic, metabolomic, and proteomic analyses, the team will generate libraries corresponding to AD-relevant brain cell types. Leveraging existing cerebral spinal fluid (CSF) and blood proteomic data, they will validate enriched pathways and identifying underlying biological factors affected by APOE4 or related to resilience. These resources will accelerate in vitro research, benefiting the broader Stanford Knight Initiative community.