Biological sex exerts distinct influences on brain levels of the β-amyloid (Aβ) peptide in both clinical depression and Alzheimer disease (AD), yet studies in animal models focus primarily on males. We examined behavioral 'despair'/depression (using the tail-suspension test) and memory (using the novel object recognition task) in J20 (hAPP) mice. Three month-old male (but not female) J20 mice exhibited less despair-like behavior, but more evidence of cognitive deficits. In young J20 mice, only soluble Aβ peptides -primarily Aβ(1-40)- were detected. There was no evidence of an effect on despair-like behavior in the six month-old J20 mice, although cognitive deficits were now evident in both sexes, and coincided with a greater proportion of the neurotoxic Aβ(1-42) species (in soluble as well as insoluble fractions). This age-dependent shift in Aβ peptide profile coincided with reduced expression of glycosylated species of ADAM-10 (α-secretase) and BACE1 (β-secretase), and an increased co-immunoprecipitation of presenilin-1 with nicastrin (components of the γ-secretase complex). Sex-dependent changes in depression-related monoaminergic, e.g. serotonin and dopamine (but not noradrenaline), systems were evident already in young J20 mice. It is critical to acknowledge that sex-dependent APP-related phenotypes might differentially influence modifiable depression-related monoaminergic signalling at some of the earliest pathological stages of clinical AD.