The brain is a remarkably fragile organ with limited self-renewal capacity after insults. Consequently, it has developed a complex system of barriers to limit the access of unwanted matter, thus protecting itself from detrimental peripheral factors. As the brain is a highly metabolic organ, it also has developed a series of nonconventional clearance routes to drain tissue waste products. Correct functioning of these brain barriers and clearance routes is critical to appropriate entrance and exit of desired matter during homeostasis. However, dysfunction in these pathways has been observed in numerous neurological conditions, including Alzheimer’s disease. Despite these initial observations, the consequences of individual barrier/clearance route dysfunction on one another is unclear, but will be critical for a holistic understanding of these devastating conditions. We propose that these barriers and clearance routes form an interconnected system, and that dysfunction of one will precipitate deterioration in additional routes, ultimately worsening disease progression. Thus, restoration of a single disrupted pathway may be sufficient to rescue detrimental aspects of numerous routes, offering an attractive therapeutic intervention to prevent widespread impairments. We propose to explore a largely understudied barrier between the brain and surrounding membranes termed the meninges, which may offer a novel therapeutic delivery route to the brain. Additionally, we will examine the functional consequences of brain barrier impairments on clearance pathways, and vice versa, in the healthy and AD brain.