<b><i>Background:</i></b> A possible contributing factor to the development of cognitive deficits in Alzheimer's disease (AD) patients involves the exposure to early life stress. <b><i>Objective:</i></b> We explored the impact of stress on synaptic plasticity (long-term potentiation, LTP) of 6-month-old triple-transgenic mice (3×Tg-AD). <b><i>Methods:</i></b> 3×Tg-AD and control (NonTg) mice were exposed to three stressors at the age of 2 and 4 months. Excitatory postsynaptic potentials were recorded in the stratum radiatum of the CA1 region of hippocampal slices, in a two-pathway paradigm. <b><i>Results:</i></b> Slices taken from 3×Tg-AD mice exhibited significant deficits in LTP compared with NonTg slices. Early stress led to a further decrease in LTP in these mice, while it did not affect NonTg mice. LTP in 3×Tg-AD and stressed 3×Tg-AD mice was rescued by pre-exposure to 0.2 µ<smlcap>M</smlcap> ryanodine. In an attempt to find a molecular correlate for the effects of stress in the 3×Tg-AD mice, we found that stressed mice have an altered ratio of Aβ42/40 both in the cortex and hippocampus. <b><i>Conclusions:</i></b> Stress experiences in young adults may accelerate the cognitive loss in AD mice, adding another dimension to the plethora of factors that lead to AD.