Gamma-secretase, a membrane bound protease which cleaves the transmembrane protein amyloid- protein precursor (APP), is a therapeutic target for Alzheimer’s disease. Gamma-secretase inhibitors (GSIs) and modulators (GSMs) are being investigated as potential disease-modifying agents. Preclinical in vivo models to monitor the activity on gamma-secretase are described in different species such as mouse, rat, and guinea pigs. All these models have their value in testing compounds with amyloid lowering properties, however, compound characteristics and pharmacokinetic properties, as well as other species characteristics such as limited sampling volumes of cerebrospinal fluid (CSF), recommended the use of a larger, non-rodent animal species. For this purpose, a screening model in dogs was developed for testing GSIs and GSMs. This study showed that GSIs and GSMs had a dose- and time-dependent effect on Aβ37, Aβ38, Aβ40, and Aβ42 in CSF. Changes in liver function were evidenced by a transient increase in bilirubin with the GSMs and incidental increases in alanine aminotransferase for GSMs as well as GSIs. Microarray analysis of liver biopsies enabled to elucidate potential mechanisms behind the liver function changes. The relevance of the liver findings should be further evaluated in chronic pre-clinical safety studies and in humans. This study concludes that the dog is a very appropriate species to assess efficacy and safety of compounds which have an effect on APP processing such as GSMs, GSIs, and BACE-inhibitors.