Alzheimer’s disease (AD) involves a complex cascade of pathologies, yet current drug discovery initiatives are predominantly centered around reducing amyloid beta levels. Identifying effective targets across the broader AD pathological cascade remains challenging. In this proposal, we will combine unbiased integrated pathway analyses and validation in various three-dimensional (3D) human neural-glial AD cellular models to identify novel drug candidates that can effectively reduce multiple AD pathology. We will systematically characterize novel AD drug candidates and therapeutic pathways identified from a previous Cure Alzheimer’s Fund Alzheimer’s Disease Drug Discovery & Development (AD4) 3D drug screening consortium, transcriptomic/machine learning, and our novel Integrated Pathway Activity Analysis (IPAA) platform, which identifies high-fidelity AD drug targets. By comparing post-mortem AD brains and 3D human neural cell culture models of AD, we have successfully pinpointed high-fidelity pathway drug targets that exhibit consistent dysregulation in the same direction. If successful, our study will yield novel clinical drug candidates that can be directly translated into clinical trials for AD patients.