Schematic presentation of the potential mechanisms (1 − 2 − 3) of statins on neurocognition: (1) the potential role of total cholesterol reduction and/or alterations in isoprenoid levels; (2) the influence of age, education level, increased body mass index, waist hip ratio, insulin resistance, and other possible risk factors; (3) the meaning of the modulation of NMDA receptor and/or activation of Aβ cascade and/or β-amyloid and tau phosphorylation. Detailed information on the suggested mechanisms can be found in the section: Potential pathomechanisms involved in neurocognition.
Statins may increase endothelial nitric oxide syntheses and decrease endothelin-1, thereby increasing cerebral blood flow (Cucchiara and Kasner, 2001 and Sahebkar et al., 2015). The antioxidant, anti-inflammatory, and platelet effects of statins may also play a role in neuroprotection (Serban et al., 2015). On the other hand, controversial recent research has suggested that the cholesterol-independent activities of statins possibly involve alterations in isoprenoid levels (Ling & Tejada-Simon, 2016). A reduction of isoprenoids in the central nervous system might result in effective biochemical and behavioural improvements in certain neurological disorders (Ling & Tejada-Simon, 2016) (Fig. 1). Actually, besides regulating the synthesis of cholesterol, statins also inhibit the production of mevalonate and downstream isoprenoids (farnesyl pyrophosphate and geranylgeranyl pyrophosphate), which appears to contribute to the effects of statins on, among others, neurological disorders (Ghosh et al., 2009, Ling and Tejada-Simon, 2016 and Osterweil et al., 2013). There is also evidence that statin therapy induces a significant reduction of isoprenoids (such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate) in the brain with only a slight effect on cholesterol level (Wood, Mupsilonller, & Eckert, 2014). While still controversial, recent research has suggested that statins have cholesterol-independent activities in the central nervous system, and therefore might be involved in brain function. One prominent effect is the inhibition on the prenylation of small G proteins (Ling & Tejada-Simon, 2016). However, in the brain, whether inhibition of isoprenylation will occur without compromising safe cholesterol levels is still uncertain and poorly studied. Several available studies, however, support the idea that, while changes in plasma cholesterol can be significant, only minimal changes in brain cholesterol occur after treatment with statins, pointing to their effects in the brain as independent of local cholesterol metabolism (Butterfield et al., 2011 and Eckert et al., 2009). It remains controversial and poorly determined which effect, cholesterol-dependent or cholesterol-independent is more closely related to the reported effects of statins on neurological diseases. Biochemically, a key question is at which level is the mevalonate/cholesterol synthesis pathway affected, and whether this plays a role in any symptoms observed (Ling & Tejada-Simon, 2016).