Lipid raft localization has recently been linked to another protein of the cholinergic system, namely acetylcholinesterase (AChE), although the functional implications of this are as yet unclear (Xie et al., 2010b; Hicks et al., 2011) . AChE inhibition by compounds such as rivastigmine or galantamine represents the major therapeutic option for treating the cognitive impairment seen in the early stages of AD yet the relationship between AChE and AD represents something of a paradox. AChE exists in a number of different molecular forms (G 1 , G 2 , G 4 ) of which the tetrameric G 4 form is predominant in brain. In AD, brain G 4 AChE levels are seen to fall as the disease progresses, while G 1 and G 2 levels rise somewhat, as compared to normal brains (Atack et al., 1983; Garcia-Ayllon et al., 2010) . AChE is found associated with amyloid plaques, leading to the suggestion that AChE may promote Aβ aggregation (Moran et al., 1993; Inestrosa et al., 1996) . In some brain regions with AD pathology, virtually all of the AChE is localized in these complexes (Mesulam et al., 1987) . A direct interaction between Aβ and AChE has been proposed, with binding occurring at the peripheral anionic site (PAS) of the enzyme. Those AChE inhibitors which occupy the PAS (e.g., propidium) show the most significant reductions in fibril formation (Bartolini et al., 2003) since the catalytic site is not required for interaction with Aβ (Inestrosa et al., 1996) . Furthermore, monoclonal antibodies directed against the PAS inhibit fibril formation (Reyes et al., 1997) , which has led to the development of PAS blockers, such as the DUO compounds, that also occupy the active site. They show inhibitory activity on AChE as well as inhibition of Aβ 40 fibril formation (Alptuzun et al., 2010) and have been suggested as potential novel AD therapeutics targeting two facets of the disease. The related enzyme butyrylcholinesterase (BuChE), as well as a synthetic peptide derived from the BuChE C terminus (BSP41), have also been shown to reduce amyloid fibril formation (Diamant et al., 2006) . The corresponding AChE synthetic peptide, however, did not significantly affect Aβ fibril formation.