During their lifetime, people are commonly exposed to several vascular risk factors that may affect brain ageing and cognitive function. In the last few years, increasing evidence suggests that pathological plasma lipid profiles contribute to the pathogenesis of late-onset Alzheimer's disease. Importantly, hypercholesterolemia, especially elevated low-density lipoprotein cholesterol values, that is, increased apolipoprotein B-100 (ApoB-100) levels, represents an independent risk factor. In this study, the effects of ApoB-100 overexpression, either alone or in combination with cerebral expression of human amyloid precursor protein (hAPP), on cognitive functions and brain pathology were assessed. Our results show that ApoB-100 overexpression induces memory decline and increases cerebral lipid peroxidation and amyloid beta levels compared to those in wild-type animals. Although double-transgenic ApoBxAPP animals did not develop more distinct behavioral deficits than single-transgenic hAPP littermates, hApoB-100 expression caused additional pathophysiological features, such as high LDL and low HDL-cholesterol levels, increased lipid peroxidation, and pronounced ApoB-100 accumulation in cerebral vessels. Thus, our results indicate that ApoBxAPP mice might better reflect the situation of elderly humans than hAPPsl overexpression alone.