Chronic sleep disruption (CSD), from insufficient or fragmented sleep, commonly occurs and is an important risk factor for Alzheimer's disease (AD). Underlying mechanisms, however, are not understood. CSD in mice results in degeneration of locus coeruleus neurons (LCn) and CA1 hippocampal neurons and increases hippocampal amyloid-β42 (Aβ42), entorhinal cortex (EC) tau phosphorylation (p-tau) and glial reactivity. LCn injury is increasingly implicated in AD pathogenesis. CSD increases NE turnover in LCn, and LCn norepinephrine (NE) metabolism activates asparagine endopeptidase (AEP), an enzyme known to cleave amyloid precursor protein (APP) and tau into neurotoxic fragments. We hypothesized that CSD would activate LCn AEP in an NE-dependent manner to induce LCn and hippocampal injury. Here, we studied LCn, hippocampal and EC responses to CSD in mice deficient in NE (dopamine β-hydroxylase (Dbh)-/-) and control male and female mice, using a model of chronic fragmentation of sleep (CFS). Sleep was equally fragmented in Dbh-/- and control male and female mice, yet only Dbh-/- mice conferred resistance to CFS loss of LCn, LCn p-tau, and LCn AEP upregulation and activation as evidenced by an increase in AEP-cleaved APP and tau fragments. Absence of NE also prevented a CFS increase in hippocampal AEP-APP and Aβ42 but did not prevent CFS-increased AEP-tau and p-tau in the EC. Collectively, this work demonstrates AEP activation by CFS, establishes key roles for NE in both CFS degeneration of LCn neurons and CFS promotion of forebrain Aβ accumulation and, thereby, identifies a key molecular link between CSD and specific AD neural injuries.Significance Statement Sleep disruption commonly occurs and increases the risk of AD, yet molecular mechanisms are not understood. LCn provide NE to most of the brain, where NE has largely neuroprotective roles. However, the metabolism of NE in LCn can promote the formation of pathogenic amyloid and tau fragments implicated in AD neural injury. Here, we found that sleep disruption increases the formation of toxic amyloid and tau fragments in LCn and that NE drives the formation of these fragments, LCn loss and hippocampal amyloid-β accumulation. This work identifies a molecular window into sleep loss neural injury pertinent to late-onset or spontaneous AD.