Aggregation of amyloid-beta (Aβ) is among the earliest pathological changes in Alzheimer's disease (AD, Kamenetz et al., 2003). In some individuals, however, memory and other cognitive functions remain intact, despite the presence of abundant Aβ pathology (Stern, 2012). This suggests that neurons and networks can recruit mechanisms that protect against Aβ pathology, a concept known as cognitive resilience (CR). Notably, this occurs in a sex-dependent manner, with greater CR in females (Buckley et al., 2019, Ossenkoppele et al., 2020).The underlying mechanisms of resilience to AD pathology remain largely unknown. While cognitive performance declines with disease progression in APP/PS1 mice, which carry mutations causing AD pathology, early ‘cognitive stimulation’ through early handling (EH) can protect them from APP-related cognitive deficits (Lesuis et al., 2017).The current study aims to determine the respective contributions of genetics, sex and (early) environmental factors to CR in male and female APP/PS1 and wild-type mice at 6 months of age. For this, groups were allocated on postnatal day (PND) 2, and EH was performed during PND2-9. To assess cognitive and locomotor performance, a battery of behavioral tests (open field, object recognition test, Barnes maze) was administered at 6 months of age. Behavioral data are being analyzed and biochemical, molecular, and genetic analysis of both sexes will follow. This may reveal insights into key factors influencing cognitive resilience in the context of Alzheimer's disease, providing potential avenues for sex-specific therapeutic interventions and strategies.