Immunotherapy has shown promise in improving cognitive impairments in Alzheimer’s disease (AD) patients. However, further research is needed to explore target optimization and enhance the effective delivery of antibodies into the brain parenchyma. In this study, we aimed to explore methods for enhancing the efficiency of antibody entry into the brain parenchyma via cisterna magna injection to reduce plaque formation and decrease the levels of Aβ42 within hippocampal neurons. We employed intraperitoneal injection of 1M hypertonic saline to augment the delivery of antibodies in the cerebrospinal fluid (CSF) and to investigate the effects of Aβ antibody 6E10 in AD mouse models, such as APPNLGF, APPNLF knockin, 5xFAD, and wild type mice. We utilized both fluorescently labeled and unlabeled 6E10 antibodies for injections into the cisterna magna and unilateral hippocampal injections in mice. Our preliminary findings revealed that intraperitoneal injection of hypertonic saline augmented antibodies in the brain after cisterna magna injection and reduced plaques in the cortex and hippocampus of 4-month-old APPNLGF and 5xFAD mice. For intrahippocampal antibody injection, hypertonic saline augmented the delivery of antibodies into the cortex and hippocampus. Additionally, preliminary data indicate that a substantial amount of antibody penetrated into hippocampal neurons of APPNLGF mice, resulting in decreased levels of Aβ42 within the neurons. Extending the circulation time of antibodies in the CSF allows more antibodies to both enter neurons and clear plaques in the brain.