Clearance systems in the brain-implications for Alzheimer disease

Accumulation of toxic protein aggregates-amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.