The detection of the early phenotypic modifications of Alzheimer's disease (AD) models is fundamental to understand the progression and identify pharmacologic targets of this pathology. However, a large variability within different models and between age-matched mice from the same model has been observed. This variability could be due to heterogeneity in the Aβ production. Present results showed the existence of a large variability in the Aβ deposition in both hippocampus and cortex in 6-month-old PS1xAPP mice. This variability was not due to the expression of hAPP751SL, however, linear relationship between hPS1M146L mRNA and Aβ production was identified. The Aβ content was related to the incorporation of the hPS1M146L into functional γ-secretase complexes, detected by the presence of the corresponding human or endogenous PS1-CTFs. Animals expressing low amount of hPS1M146L mRNA, displayed low hPS1-CTF incorporation and produced a low amount of Aβ peptides. Conversely, mice with relatively high hPS1 mRNA expression displayed high hPS1-CTF and high Aβ deposition. Furthermore, the Aβ total and Aβ1-42 content was increased dramatically by the expression of hPS1M146L (as compared with transgenic APPsl littermates). Therefore, variations in the expression of transgenic form of hPS1M146L in this model, or even between different models, influenced strongly the incorporation of the mutated PS1 into functional γ-secretase complexes, the production of Aβ peptides and, in consequence, the detrimental effects of Aβ peptides. These data might implicate an “apparent gain-of-function” of the γ-secretase complex by the expression of the mutated PS1M146L. © 2007 Wiley-Liss, Inc.