Indeed, only complete genetic knockout of brain ApoE (compared to 50% reduction with ASOs) in mouse models of Alzheimer’s disease (AD) resulted in pathology improvement.42, 43, 44, 45 Thus, the understanding of how cell identity and cell state may impact the response to these therapeutics is increasingly important and may have implications that reach further than cell-based screening studies and stretch throughout the drug-development process. This evidence concerns the gene APOE and early-onset autosomal dominant Alzheimer disease.