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Targeting amyloid-β (Aβ) accumulation seems a promising strategy for the treatment of cerebral amyloid angiopathy (CAA) and neurodegenerative diseases. However, it is still challenging to develop a safe and efficient technology for brain-wide perivascular Aβ clearance. Using intrathecally injected adeno-associated virus 9 (AAV9) encoding soluble form of neprilysin (sNEP), we showed that AAV-sNEP reduced Aβ accumulation and improved cognitive deficits in Tg-SwDI transgenic mice. Meningeal cells, adventitial cells and smooth muscle cells in leptomeningeal arteries and penetrating arterioles were transfected by intrathecal injection of AAV9-sNEP, hence generating sufficient sNEP to exert beneficial effects by perivascular Aβ clearance, protecting against smooth muscle cell damage and pericyte loss, maintaining blood-brain barrier (BBB) integrity, and eventually improving cognitive decline in Tg-SwDI mice. This study provides pre-clinical evidence that intrathecal delivery of AAV-mediated sNEP may be a promising therapeutic strategy for the treatment of CAA. Funding Statement: This study was supported by the Science and Technology Development Fund, Macau SAR (020/2017/A1 and 039/2017/AFJ); multi-year research grant, University of Macau, (MYRG2016-00184-ICMS-QRCM and MYRG2018-00242-ICMS); Science and Technology Program of Guangzhou (No. 2014J4500031) and Guangzhou Clinical Research and Translational Center for Major Neurological Disease (No. 201604020010). Declaration of Interests: The authors declared no conflicts of interest. Ethics Approval Statement: All animal experiments were approved by the ethics committee at the University of Macau (Macau, China) and Sun Yat-Sen University, and performed in compliance with the institutional guidelines.