Prophylactic treatment with verubecestat, a BACE inhibitor, slowed the deposition of amyloid plaques when treatment was initiated prior to significant pathology in a mouse model of Alzheimer’s disease.
Researchers from Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease (MODEL-AD), a consortium of experts at Indiana University (IU) School of Medicine, The Jackson Laboratory, Sage Bionetworks, The University of Pittsburgh School of Medicine and University of California, Irvine, recently published their study in: Alzheimer’s and dementia: translational research and clinical intervention.
Adrian Oblak, PhD, assistant professor of radiology and imaging sciences at the IU School of Medicine and lead author of the publication, said the study examined the efficacy of the drug verubecestat — a beta-secretase (BACE) inhibitor — administered in the early stages of Alzheimer’s disease, using the MODEL-AD Preclinical Testing Core Drug Screening Pipeline.
“While BACE inhibitors lowered amyloid beta plaque in patients with late-stage Alzheimer’s disease during clinical trials, many of those trials stopped due to side effects or lack of clinical efficacy,” Oblak said. “The drug had also been understudied in its effectiveness prior to the onset of Alzheimer’s disease, making it an ideal compound for MODEL-AD to study.”
Alzheimer’s disease (AD) is the most common form of dementia. Beta-secretase (BACE) inhibitors have been proposed as potential therapeutic interventions; however, starting treatment once the disease has progressed significantly has failed to effectively stop or treat the disease.
The researchers performed in vivo PET/MRI imaging to measure amyloid deposition and glucose uptake in the brains of the animal models, measured plasma and brain amyloid beta, and assessed the clinical and behavioral characteristics.
Stacey Rizzo, PhD, associate professor of neurobiology and geriatric medicine at the University of Pittsburgh’s Aging Institute and senior author of the paper, said this study confirms the consortium’s importance in advancing research on Alzheimer’s disease.
“The MODEL-AD consortium brings together experts from Alzheimer’s disease biology, mouse modeling, genetics, behavioral research, neuropharmacology and medical imaging to develop the research infrastructure that will benefit the entire Alzheimer’s research community,” said Rizzo. “There is currently no cure for Alzheimer’s disease and so there is an absolute need to find a treatment and develop prevention strategies.”
The National Institute on Aging, part of the National Institutes of Health, funded the MODEL-AD consortium to establish a robust infrastructure for the larger research community to improve preclinical to clinical translational studies and accelerate the pace of bringing effective and accelerate safe treatments for patients at risk for Alzheimer’s disease, Rizzo said.
“Under our rigorous unbiased screening strategy, we were able to prevent significant amyloid beta deposition, which was expected; however, the same dose range that was effective in preventing amyloid beta plaque formation resulted in similar side effects reported in the clinic and in the absence of cognitive improvement,” Oblak said of the study. “Therefore, we would not have prioritized this compound for progress.” in clinical trials if we had vetted the compound using this rigorous unbiased approach.”
The results of this study, Oblak said, like all animal models, protocols, and validation data studied by MODEL-AD, will be made readily available to all investigators for preclinical drug development, thanks to support from the NIA. Researchers can visit stopadportal.synapse.org to consider connections through this pipeline.
