Alzheimer’s disease (AD) has become a significant public health problem, but the therapeutic options are limited. Recently, ADUHELM® (Biogen) has been conditionally approved as a new AD drug targeting pathogenic amyloid beta in the patient’s brain. However, there is still an urgent need for affordable and more effective AD drugs. Therefore, we aim to accelerate AD drug discovery using our three-dimensional Alzheimer’s in a Dish™ (ADiD) model as a drug screening platform. Using our 3D AD cellular models, we identified and validated novel AD drug candidates derived from unbiased natural products library screening and transcriptomic data analysis with AD patient brains. We also found that a group of anti-malarial drugs alters aggregation of the amyloid beta 42 isoforms, a major pathogenic molecule found in AD patient brains. Our findings are expected to accelerate AD drug discovery.