In order to explore novel therapies in AD, we must consider the “AD malignant cycle” (Figure 1). In this scheme, cessation of Aβ overproduction is not sufficient to treat patients with sporadic AD, and important components of the cycle, brain ischemia, and CAA should also be noted. Insufficient Aβ clearance seems to be more crucial than Aβ overproduction in sporadic AD patients (Mawuenyega et al., 2010). Even in familial AD cases, the onset of dementia is often delayed until the fifth or sixth decade, suggesting that the aging-associated failure in clearance also plays a part in the pathogenesis of inherited types of the disease (Weller et al., 2008). Therefore, recent work has focused on the failure of Aβ elimination as the most important therapeutic targets and adopted a “neurovascular” approach as a strategy to tackle AD (Vardy et al., 2005; Deane et al., 2008; Carare et al., 2013).
