Preclinical drug screening in new generation Alzheimer’s disease mouse models: The MODEL-AD Consortium Strategy

Historically, preclinical screening of test compounds for Alzheimer’s Disease (AD) employed behavioral endpoints in rodent models as the primary screen. Often the rodent models used did not necessarily have construct validity for AD, and experiments often evaluated the ability of a test compound to reverse an acute pharmacological deficit (e.g. scopolamine induced memory deficit) in wild-type or normal animals. Other screens evaluated the ability of the test compound to normalize a behavioral phenotype, and these studies rarely used biomarkers or other clinically translational endpoints. Young or naïve wild-type animals were often used in place of aging animals, and critically pharmacokinetic (PK) and pharmacodynamic data in the AD model at the biologically and pathologically relevant ages had not been evaluated. The Model Organism Development and Evaluation for Late-onset AD (MODEL-AD) program has been established with the goals of: 1) identifying novel genetic variants, genes and biomarkers from LOAD patient data; 2) generating and validating mouse models with construct and face validity for LOAD; and 3) developing a preclinical testing strategy to evaluate potential therapeutic agents for the treatment of AD in these new models. The Preclinical Testing Core (PTC) has established a streamlined preclinical strategy with go/no-go decision points that allow critical and unbiased assessments of potential therapeutic agents while matching each test compounds’ specific mechanism of action to the animal model best suited to interrogate its symptom and/or disease modifying activity. The PTC screening strategy includes an initial primary screen to determine appreciable mutli-dose PK and target tissue activity in the disease model at the pathologically relevant age followed by predictive PK/PD modeling. A secondary screen evaluating target engagement and disease modifying activity of the test compound utilizing non-invasive PET/MRI as a pharmacodynamic readout of cerebral changes in metabolism (18F-FDG), cerebral blood flow (64Cu-PTSM), beta amyloid deposition (18F-AV45), and tau deposition (18F-AV1451). Provided the compound meets the a priori criteria for success in the primary and secondary screens, the tertiary screen will evaluate symptom modifying effects of the test compound to normalize a disease-related phenotype in cognition tests, relative to the age- and sex-matched littermate WT controls. All raw data, standard operating procedures, methods and protocols will be made publicly accessible via the external facing Sage portal to the AD research community at large.