Targeting abnormal metabolism in Alzheimer's disease: The Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study

• Published in: Alzheimer's & dementia : translational research & clinical interventions Vol. 6; no. 1; pp. e12095 - n/a
• Main Authors: Desai, Rishi J., Varma, Vijay R., Gerhard, Tobias, Segal, Jodi, Mahesri, Mufaddal, Chin, Kristyn, Nonnenmacher, Edward, Gabbeta, Avinash, Mammen, Anup M., Varma, Sudhir, Horton, Daniel B., Kim, Seoyoung C., Schneeweiss, Sebastian, Thambisetty, Madhav
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 2020; John Wiley and Sons Inc; Wiley
• Subjects: Alzheimer's disease; Autopsies; Bias; Brain research; Candidates; Clinical medicine; Clinical trials; Dementia; Disease prevention; drug repurposing; Drugs; FDA approval; Gene expression; Health care policy; Hypotheses; Longitudinal studies; Medicare; Metabolic disorders; Metabolites; Neuropathology; Pathology; pharmacoepidemiology; Practice research; R&D; Research & development; Validity; United Kingdom > UK; United States > US; Baltimore Maryland; dementia; drug repurposing; Alzheimer's disease; pharmacoepidemiology
• ISSN: 2352-8737; 2352-8737
• DOI: 10.1002/trc2.12095

Drug discovery for disease‐modifying therapies for Alzheimer's disease and related dementias (ADRD) based on the traditional paradigm of experimental animal models has been disappointing. We describe the rationale and design of the Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study, an innovative multidisciplinary alternative to traditional drug discovery. First, we use a systems biology perspective in the "hypothesis generation" phase to identify metabolic abnormalities that may either precede or interact with the accumulation of ADRD neuropathology, accelerating the expression of clinical symptoms of the disease. Second, in the "hypothesis refinement" phase we propose use of large patient cohorts to test whether drugs approved for other indications that also target metabolic drivers of ADRD pathogenesis might alter the trajectory of the disease. We emphasize key challenges in population‐based pharmacoepidemiologic studies aimed at quantifying the association between medication use and ADRD onset and outline robust causal inference principles to safeguard against common pitfalls. Candidate ADRD treatments emerging from this approach will hold promise as plausible disease‐modifying therapies for evaluation in randomized controlled trials.