An attractive therapeutic strategy to treat Alzheimer’s Disease is to halt the accumulation of amyloid plaques by decreasing the production of Aβ1-42. A class of compounds called g-secretase modulators (GSMs) shift the g-secretase cleavage site of amyloid precursor protein resulting in a selective decreased production of amyloid beta (Aβ) peptide 1-42 and a concomitant increased production of the shorter Aβ peptides, Aβ1-37, Aβ1-38 and Aβ1-39. However, the biological significance of these peptides is still unclear. Our initial studies with transgenic mouse models suggest that one such short peptide, Aβ1-40, is a robust inhibitor of Aβ1-42 deposition in vivo. The last two hydrophobic residues at the C-terminal of Aβ1-42 are proposed to be critical for its enhanced rate of nucleation. Therefore we hypothesize that shorter Aβ peptides are anti-amyloidogenic and modify the toxicity of Aβ42 in vivo. In this study we examined the role of shorter Aβ peptides, Aβ1-36, Aβ1-37, Aβ1-38, Aβ1-39, Aβ1-40, Aβ1-42 and Aβ1-43, by generating transgenic Drosophila melanogaster. The Aβ peptides were expressed independently or co-expressed with Aβ1-42 specifically in the eye to assess phenotype and the neurons to measure behavioral function. Furthermore, we examined the effect of Aβ38, expressed using our BRI2 fusion strategy, in an APP mouse model. Overexpression of the shorter Aβ peptides, Aβ1-36, Aβ1-37, Aβ1-38 and Aβ1-39, was not toxic in the eye. Overexpression of Aβ1-42 resulted in a degenerative eye phenotype while expression of Aβ1-40 or Aβ1-43 had a slight effect on eye phenotype. Importantly, in flies co-expressing Aβ1-42 and the shorter Aβ peptides, Aβ1-36, Aβ1-37, Aβ1-38 and Aβ1-39, the degenerative phenotype and behavioral function was improved. These studies validate g-secretase modulation as a clinical strategy by characterizing the attenuating effect of shorter Aβ peptides.