Alzheimer's disease (AD) amyloid beta-peptide (Aß) is generated via proteolytic processing of the ß-amyloid precursor protein (APP) by ß- and gamma-secretase. gamma-Secretase can be blocked by selective inhibitors but can also be modulated by a subset of non-steroidal anti-inflammatory drugs (NSAIDs) including sulindac sulfide. These drugs selectively reduce the generation of the aggregation-prone 42 amino acid Aß42 and concomitantly increase the levels of the rather benign Aß38. Here we show that Aß42 and Aß38 generation occurs independently from each other. The amount of Aß42 produced by cells expressing ten different familial AD (FAD)-associated mutations in presenilin (PS) 1, the catalytic subunit of gamma-secretase, appeared to correlate with the respective age of onset in patients. However, Aß38 levels did not show a negative correlation with the age of onset. Modulation of gamma-secretase activity by sulindac sulfide reduced Aß42 in the case of wt PS1 and two FAD-associated PS1 mutations (M146L and A285V). The remaining eight PS1 FAD mutants showed either no reduction of Aß42 or only rather subtle effects. Strikingly, even the mutations, which showed no effect on Aß42 levels allowed a robust increase of Aß38 upon treatment with sulindac sulfide. Similar observations were made for fenofibrate, a compound known to increase Aß42 and to decrease Aß38. For mutants that predominantly produce Aß42, the ability of fenofibrate to further increase Aß42 levels became diminished, whereas Aß38 levels were altered to varying extents for all mutants analyzed. Thus, we conclude that Aß38 and Aß42 production do not depend on each other. Using an independent NSAID derivative, we obtained similar results for PS1 as well as for PS2. These in vitro results were confirmed by in vivo experiments in transgenic mice expressing the PS2 N141I FAD mutant. Our findings therefore have strong implications on the selection of transgenic mouse models used for screening of the Aß42 lowering capacity of gamma-secretase modulators. Furthermore, human patients with certain PS mutations may not respond to gamma-secretase modulators.