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Background: The g-secretase complex generates the C-terminus of As from APP and thus determines the potential for oligomerization, formation and propensity for deposition. Inhibition of g-secretase activity blocks As production and is being tested as disease modifying treatment for AD. However, g-secretase inhibitors (GSIs) also block the cleavage of other g-secretase substrates such as Notch, which can lead to gastrointestinal and immune related toxicity. g-secretase modulators (GSMs), on the other hand, reduce specifically the formation of As42, without affecting the signaling functions of other g-secretase substrates. This selective reduction of As42 levels after GSM treatment is accompanied by an increase in the production of the shorter and less toxic As species. Methods: We investigate the effect of GSMs and GSIs on As levels in cerebrospinal fluid (CSF) from beagle dogs and utilize specific and sensitive immunoassays for the quantification of As species of different lengths. Results: We show that GSM treatment leads to decreased levels of As42 and increased levels of shorter As peptides in dog CSF. Our data support that quantification of shorter As peptides can be used as a pharmacodynamic marker of GSM treatment. As expected, the results show that GSIs are able to decrease the levels of all As peptides in dog CSF. Conclusions:We have produced highly sensitive and specific assays that can detect As species in dog CSF. Our data show that GSMs are able to selectively reduce the levels of the As42 toxic species and increase the levels of shorter As species, thus representing a promising approach for a disease-modifying treatment of AD.