Psychotic Alzheimer?s disease (AD+P) is a distinct AD variant with a more rapid cognitive deterioration and a hastened mortality for which safe and effective treatment is lacking. CSF biomarker and neuropathological studies suggest that AD+P results from an acceleration of tau phosphorylation. The development of novel compounds to treat AD+P would be facilitated by the development of a preclinical behavioral model, made possible by neuropathological correlation studies that uniquely identify tau phosphorylation in psychosis risk. The NIMH Research Domain Criteria (RDoC) initiative provides a framework for the transdiagnostic conceptualization of psychosis risk driven by dopamine, and has been incorporated in the design of a novel candidate behavioral model of AD+P that is characterized by increased dopaminergic tone and hyperphophorylated tau- the DM mouse. In the proposed application the DM and other tau models will be utilized in order to investigate dopamine in a pharmacological induction paradigm of AD+P, and in order to study the relationship between tau phosphorylation and psychosis-relevant behaviors. The completion of the proposed set of experiments may point the way to further research in the development of a preclinical avenue for drug development in the treatment of AD+P.
Alzheimer?s disease is often complicated by psychosis, a syndrome of delusions (fixed false beliefs) and hallucinations (seeing or hearing things in the absence of stimulus). Currently, there are no preclinical models available with which to test desperately needed therapies before going into human trials. The current application proposes to develop an experimental animal model of psychotic Alzheimer?s disease that could be utilized in the development of new drug therapies.
