Aging is the leading risk factor for most noncommunicable diseases such as cancer, diabetes and neurodegenerative diseases, including Alzheimer’s. Conversely, experimental interventions that can stave off the aging process—or even “reverse” it—protect against age-related maladies. We recently discovered that infusion of young plasma, which rejuvenates old brains, also may protect against Alzheimer’s disease. We propose here to identify a gene activity signature of rejuvenation in Alzheimer’s models. We show that such a signature enables the prediction of novel Alzheimer’s drugs in humans and propose an experimental pipeline to test candidate compounds in neurons from reprogrammed skin cells of Alzheimer’s patients. If successful, our study may provide a foundational pipeline to reverse-engineer the powerful capacities of rejuvenation into actionable targets for novel Alzheimer’s therapeutics.