Scientific breakthroughs in neuroscience explain the need for sleep and the development of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases in terms of fluid dynamics: the waste created during the day is cleared away as we sleep or it accumulates. However, a decade of research after the original theory was posed has revealed that the underlying physical mechanisms are still not understood and that the advanced mathematical tools are needed. In this project we propose a research program addressing 1) new fluid dynamics mechanisms, 2) novel numerical analysis for advanced multi-physics brain simulations, and 3) a framework for patient-specific simulations. We will exploit reduced order and machine learning methods in addition to finite element solutions. With successful delivery, the "aCleanBrain" will establish the main drivers of brain fluid dynamics, provide a foundation for accurate, efficient and robust algorithms for multi-physics problems and develop a software framework for advanced biomechanical brain simulations.