BACE inhibitors show promise as early treatment in new AD lab studies

3D illustration of human brain with Alzheimer's disease - dementia
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Prophylactic treatment with verubecestat, a BACE inhibitor, slowed amyloid plaque deposition when treatment was started before significant pathology in a mouse model of Alzheimer’s disease.

Researchers from In vivo Development and Evaluation for Late Alzheimer’s Disease (MODEL-AD), a consortium of experts at Indiana University (IU) School of Medicine, Jackson Laboratory, Sage Bionetworks, University of Pittsburgh School of Medicine, and University of California, Irvine, recently published their studies in Alzheimer’s disease and dementia: translational research and clinical intervention.

Adrian Oblak, Ph.D., assistant professor of radiological and imaging sciences at IU School of Medicine and first author of the publication, said the study investigated the efficacy of verubecestat — a beta-seriesase (BACE) inhibitor — given in the early stages of Alzheimer’s disease, using a pipeline. The baseline drug screening for preclinical testing MODEL-AD.

“Although BACE inhibitors reduced beta-amyloid deposits in patients with late-stage Alzheimer’s disease during clinical trials, many of these studies were discontinued due to adverse events or clinical ineffectiveness,” Oblak said. “The drug was also under investigation for its efficacy prior to the onset of Alzheimer’s disease, making it an ideal compound for the MODEL-AD model to study.”

Alzheimer’s disease (AD) is the most common form of dementia. Beta-series (BACE) inhibitors have been suggested as potential therapeutic interventions; However, starting treatment once the disease has progressed significantly has failed to stop the disease or treat it effectively.

The researchers performed in vivo positron emission tomography/magnetic resonance imaging to measure amyloid deposition and glucose uptake in the brain of animal models, measured plasma and brain amyloid beta and evaluated clinical and behavioral characteristics.

This study underscores the consortium’s importance in advancing Alzheimer’s research, said Stacey Rizzo, PhD, assistant professor of neurobiology and geriatrics at the University of Pittsburgh’s Institute on Aging and senior author of the paper.

“The MODEL-AD Consortium brings together experts from the fields of Alzheimer’s disease biology, mouse models, genetics, behavioral research, neuropharmacology, and medical imaging to develop research infrastructure that will benefit the entire Alzheimer’s research community,” said Rizzo. “There is currently no cure for Alzheimer’s disease, and therefore there is an urgent need to find a cure and to develop preventive strategies.”

The National Institute on Aging, part of the National Institutes of Health, has funded the MODEL-AD consortium to create a robust infrastructure for the larger research community to improve preclinical-to-clinical translation studies and accelerate the delivery of effective and safe treatments to patients at risk for Alzheimer’s disease, Rizzo said.

“Under our strict, unbiased screening strategy, we were able to significantly prevent amyloid-beta deposition, which was expected; however, the same dose range that was effective in preventing the formation of amyloid-beta plaques resulted in similar side effects reported in the clinic and in Absence of cognitive improvement,” Oblak said of the study. “Therefore, we would not have prioritized this compound for advancement in clinical trials had we screened the compound using this rigorous, unbiased approach.”

The results of this investigation, like all models, protocols and validation data for animals studied with MODEL-AD, are quickly available to all researchers for preclinical drug development, Oblak said, thanks to the support of the NIA. Researchers can visit To submit compounds for consideration through this pipeline.