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

Abstract

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.

Hydroxychloroquine lowers Alzheimer’s disease and related dementias risk and rescues molecular phenotypes related to Alzheimer’s disease

“…The full study protocol for patient-level analysis in Medicare claims was pre-registered on clinicaltrials.gov prior to data analysis (NCT04691505) and contains detailed information on implementation including all codes that were used to identify study variables to allow future replication. These analyses were performed within the ongoing DREAM study [3]. The following sections summarize key methodologic details.…”

“…We recently defined a hypothetical network of interacting and intersecting metabolic pathways in Alzheimer's disease, linked to dysregulation in brain glycolysis-the Alzheimer's Disease Aberrant Metabolism (ADAM) network [3]. We nominated genetic regulators of metabolic and signaling reactions in the ADAM network as plausible AD drug targets.…”

“…We nominated genetic regulators of metabolic and signaling reactions in the ADAM network as plausible AD drug targets. Cytokine signaling through the Januskinase-signal transducer and activator of transcription (JAK/ STAT) pathway was nominated as one such drug target for pharmacoepidemiologic analyses in the Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study [3]. Prior studies have suggested that dysregulation in this pathway may be associated with neurodegenerative diseases [4,5] and may therefore may be a plausible therapeutic target [6][7][8].…”

Mechanistic Insights for Drug Repurposing and the Design of Hybrid Drugs for Alzheimer’s Disease

“…Desai and co-workers have taken the initiative to integrate the metabolic and transcriptional abnormalities observed in AD with a large pharmacoepidemiologic analysis of large cohortbased studies under the Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study. 142 Advances in technology have facilitated the generation of "Big data" such as transcriptomic, metabolomic, and mass spectroscopy (MS) data, among others. Nevertheless, advanced technical solutions can foster the analysis and integration of biomedical data.…”

“…The lack of detailed in vitro , in vivo , and strong epidemiological evidence for some of the drugs remains a major stumbling block in DR. As a result, standard evaluation techniques such as the Delphi consensus approach have been adopted to address such challenges. , The Delphi-type process involves a systematic review by a panel of experts to shortlist drug candidates based on the strength of the available evidence. Desai and co-workers have taken the initiative to integrate the metabolic and transcriptional abnormalities observed in AD with a large pharmacoepidemiologic analysis of large cohort-based studies under the Drug Repurposing for Effective Alzheimer’s Medicines (DREAM) study . Advances in technology have facilitated the generation of “Big data” such as transcriptomic, metabolomic, and mass spectroscopy (MS) data, among others.…”