APOE4 is the strongest genetic risk factor for Alzheimer’s disease (AD) and is also associated with poor recovery from traumatic brain injury (TBI) and increased risk of cognitive impairments following chemotherapy. Personalized genotyping products are increasingly enabling individuals to identify whether they are carriers of APOE4 or other genetic risk factors for cognitive impairments. However, we have limited understanding of how APOE4 increases the risk for cognitive impairments. As a result, there currently are no lifestyle or therapeutic interventions to minimize these known genetic risks. Here, we will investigate the relationship of APOE4 with the strongest pathological signature of cognitive impairment, neurofibrillary tangles composed of tau. Although AD, TBI and chemotherapy-induced cognitive impairments arise from very different causes, they all exhibit tau pathology, which strongly correlates with cognitive outcomes. Studies have demonstrated that APOE4 clearly increases the severity of tau pathology and cognitive impairments, but the mechanisms are unknown. We reason that further deciphering this relationship will uncover new therapeutic strategies for AD. To achieve this, we engineer human brain tissue from stem cells. Combining this technology with CRISPR/CAS9 genome editing, we generate genetically identical sets of human brain tissue that differ only by APOE genotype. This enables us to replay the biological events of AD, TBI and chemotherapy-induced cognitive impairments in a controlled laboratory setting to determine precisely how APOE4 influences the development of tau pathology. In addition to this, we have developed a novel drug screening platform that employs our engineered human brain tissue. We will deploy this technology to investigate how FDA-approved drugs interact with the human brain and APOE4 to further modulate tau pathology. We expect this to reveal adverse drugs that accelerate the development of tau pathology, and also drugs that reduce or prevent tau pathology that potentially could be repurposed to treat cognitive impairments. By integrating experimental and drug-screening approaches, we will gain an in-depth understanding of the relationship of APOE4 with tau, and uncover ways to modulate this connection that will accelerate our progress toward cures for Alzheimer’s disease.