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Substantial evidence implicates 𝛽-amyloid (A𝛽) peptides in the etiology of Alzheimer’s disease (AD). A𝛽 is produced by the proteolytic cleavage of the amyloid precursor protein by 𝛽- and 𝛾-secretase suggesting that 𝛾-secretase inhibition may provide therapeutic benefit for AD. Although many 𝛾-secretase inhibitors have been shown to be potent at lowering A𝛽, some have also been shown to have side effects following repeated administration. All of these side effects can be attributed to altered Notch signaling, another 𝛾-secretase substrate. Here we describe the in vivo characterization of the novel 𝛾-secretase inhibitor SCH 697466 in rodents. Although SCH 697466 was effective at lowering A𝛽, Notch-related side effects in the intestine and thymus were observed following subchronic administration at doses that provided sustained and complete lowering of A𝛽. However, additional studies revealed that both partial but sustained lowering of A𝛽 and complete but less sustained lowering of A𝛽 were successful approaches for managing Notch-related side effects. Further, changes in several Notch-related biomarkers paralleled the side effect observations. Taken together, these studies demonstrated that, by carefully varying the extent and duration of A𝛽 lowering by 𝛾-secretase inhibitors, it is possible to obtain robust and sustained lowering of A𝛽 without evidence of Notch-related side effects. [ABSTRACT FROM AUTHOR]