Sleep disorders have previously been connected with the neurodegenerative pathology of Alzheimer’s disease (AD) due to the aggregation of β-amyloid(Aβ)peptides and tau proteinsinduced by sleep deprivation (SD). However, the underlying mechanisms remain unclear. Therefore, this study was performed to clarify how Aβ-related metabolism is regulated after SD. Three-month-old Sprague-Dawley rats (250–300 g) were randomly divided into 5 groups: two SD groups(i.e.,SD-2d and SD-4d), two platform control groups(i.e.,PC-2d and PC-4d) and a home cage control group (CC). For the two SD groups, themodified multiple platform method (MMPM) was used to induce SD.Our experiments confirmed that SD impaired cognitive function and increased the levels of Aβ peptides, a hallmark of AD. Additionally, we found that SD significantly increasedthe levels of the β-site amyloid precursor protein (APP)-cleaving enzyme 1(BACE1, β-secretase), but had little impacton the levels of Aβ-degradationenzymes.This resultmay be the main cause of the over-expression of Aβ1-42 and Aβ1-40. Our results suggested that SD accelerates the progression of AD bymodulating Aβ-related metabolism. This findinghasimportant implications for the diagnosis and prevention of AD.