Boosting slow-wave activity (SWA) by modulating slow-waves through closed-loop auditory stimulation (CLAS) might provide a powerful nonpharmacological tool to investigate the link between sleep and neurodegeneration. Here, we establish mouse CLAS (mCLAS)-mediated SWA enhancement in a mouse model of Alzheimer’s disease (AD, Tg2576 transgenic mice), with the overall aim of exploring its effects onto AD-specific sleep deficits and early disease hallmarks. We found that tracking a 2Hz component of slow-waves combined with auditory triggers targeting a 30° up-phase produces a significant SWA increase in WT and AD mice ranging 15-30% from baseline, versus a MOCK group. Notably, pathological sleep traits where acutely rescued by mCLAS, which elicited a 14% decrease of pathologically heightened NREM sleep fragmentation in AD mice, accompanied by a steep decrease in microarousal events during both the light and dark periods. Moreover, prolonged mCLAS prompted an improvement in spatial working memory performance in AD mice, as assessed via the T-maze test. In terms of pathological hallmarks, we found a decrease of retinal Aβ accumulation in the stimulated animals, preliminary reflecting lowered pathological protein burden in the CNS. Overall, our results indicate that auditory phase-targeting elicits alleviation of neurodegeneration-associated sleep phenotypes by potentiating sleep consolidation, rescuing memory impairments and modulating protein accumulation. Future experiments assessing further long-term effects of CLAS on brain pathological markers may have a major impact on the therapy of neurodegenerative diseases, setting CLAS as a novel treatment candidate for neurodegeneration patients.