Apolipoprotein E (apoE) isoform has been identified as one of the major genetic risk factors for development of Alzheimer’s disease. Although the understanding of the underlying mechanisms is poor, the consensus view is that an increase the amount of apoE would be beneficial. In an attempt to identify novel targets that are involved in regulating the secreted levels of apoE, a phenotypic screen was performed. A highly bio-annotated compound set (~15K) was screened in an astrocytoma cell line for the capability to increase secreted levels of apoE. Compound hits were analysed, using the enrichment analysis method, to propose protein targets that affects apoE levels. Target hits were confirmed by expansion of compounds to cover analogues e.g. best in class, nearest neighbours and various chemical properties. Selected targets were further confirmed by siRNA knockdown and in primary and iPS derived astrocytes.