Sleep disturbance is among the most common clinical problem and possesses a significant concern for the geriatric population. Recently, increasing evidence has indicated that disturbed sleep may not only affect neuropsychological functions, but also contribute to the cognitive impairment and, therefore, significantly increase dementia risk. In the present study, we examined the potential impacts of chronic sleep deprivation (SD) on learning-memory and AD-related pathologies in A?PPswe/PS1?E9 transgenic (TG) mice and their wild-type (WT) littermates. Our results indicated that mice (both TG and WT) exposed to 2-month SD showed an altered amyloid-?protein precursor processing, an elevated level of phosphorylated tau protein, and impaired cognitive performance as compared to non-sleep deprivation (NSD) controls. Moreover, the SD-treated TG mice exhibited more amyloid-?1-42 production and developed more senile plaques in the cortex and hippocampus than NSD-treated TG mice. In addition, SD caused a striking neuronal mitochondrial damage, caspase cascade activation, and neuronal apoptosis in the hippocampus of both TG and WT mice. More importantly, all these behavioral, neuropathological, and biochemical changes induced by chronic SD were long lasting and were irreversible during a 3-month normal housing condition. Collectively, these results indicate that chronic SD impairs learning and memory, exacerbates AD pathologies, and aggravates the mitochondria-mediated neuronal apoptosis in a long-lasting manner. Our findings provide important experimental evidence to prove that chronic sleep disturbance is a risk factor for AD.