Alzheimer's disease is characterized by the accumulation of amyloid deposits in 
the brain and the progressive loss of cognitive functions. Although the precise 
role of amyloid-β in disease progression remains somewhat controversial, many 
efforts to halt or reverse disease progression have focussed on reducing its 
synthesis or enhancing its removal. It is believed that brain and peripheral 
soluble amyloid-β are in equilibrium and it has previously been hypothesized 
that a reduction in peripheral amyloid-β can lower brain amyloid-β, thereby 
reducing formation of plaques predominantly composed of insoluble amyloid-β; the 
so-called peripheral sink hypothesis. Here we describe the use of an amyloid-β 
degrading enzyme, the endogenous metallopeptidase neprilysin, which is fused to 
albumin to extend plasma half-life and has been engineered to confer increased 
amyloid-β degradation activity. We used this molecule to investigate the effect 
of degradation of peripheral amyloid-β on amyloid-β levels in the brain and 
cerebrospinal fluid after repeated intravenous dosing for up to 4 months in 
Tg2576 transgenic mice, and 1 month in rats and monkeys. This molecule proved 
highly effective at degradation of amyloid-β in the periphery but did not alter 
brain or cerebrospinal fluid amyloid-β levels, suggesting that the peripheral 
sink hypothesis is not valid and is the first time that this has been 
demonstrated in non-human primates.