INTRODUCTION: This study examined the effects of long-term cervical lymphadenectomy (cLE) on cognitive and Alzheimer's disease (AD)-like tauopathy changes. METHODS: Male C57BL/6 mice were used to assess cLE impacts on sleep, brain pathways, and pathologies. RNA sequencing and proteomics analyzed gene/protein changes, with results verified by western blotting and immunofluorescence. RESULTS: CLE led to sleep and psychiatric disorders, linked to mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) pathway activation. Activation of ERK may interfere with autophagy and is associated with phosphorylated tau accumulation. Peripheral blood analysis shows decreased brain waste in the peripheral blood post-cLE, implicating impaired lymphatic drainage and brain waste build-up. DISCUSSION: These findings suggest a potential connection between cLE and AD-like tauopathy, potentially influencing surgical decisions.