AMD is a heterogeneous disease with

AMD is a heterogeneous disease, with several different phenotypes, including types and size of drusen (Miller, 2013). Prior epidemiological studies examining the role of statins in AMD (Hall et al., 2001; Gehlbach et al., 2009, 2015; Guymer et al., 2013; VanderBeek et al., 2013; Cougnard-Gregoire et al., 2014; Klein et al., 2014a, 2007; Tan et al., 2007) did not stratify or distinguish patients based on AMD subtype. It is unlikely that statins would have across-the-board effectiveness in a heterogeneous disease, and for this reason we focused on patients with large soft drusen and drusenoid PEDs, which are known risk factors for progression to advanced disease. AMD is also multifactorial, with >100 reported at-risk EAI045 that can be grouped into pathways (Miller, 2013) with a subset of AMD-related genes that can be aligned on an atherosclerosis-like progression (Fritsche et al., 2015; Pikuleva and Curcio, 2014; Chen et al., 2010; Cheng et al., 2015; Neale et al., 2010; Reynolds et al., 2010; Fritsche et al., 2013). Although prior studies showed negative overall association between AMD and statin use, they did suggest a potential protective role in a subset of patients with soft drusen or in patient with the at risk CFH genotype CC (Y402H) risk gene (Guymer et al., 2013; Klein et al., 2007; Tan et al., 2007). These findings, taken together with our study, suggest that statins may have a particular role in certain (intermediate-high risk, large drusenoid deposits), but not all, AMD patients. Cardiovascular studies suggest that the effect of statins on regression of atheromatous pathology may not be related to actual serum LDL or HDL levels achieved, as shown by the PROVE-IT trial (Khush and Waters, 2004) or by a more recent head-to-head comparison of atorvastatin 80mg vs. rosuvastatin 40mg (Nicholls et al., 2011). Likewise, we did not observe any differences in cholesterol level reduction between responders and non-responders in our pilot study, suggesting that factors other than lipid lowering response may be important for the observed phenomena. That does not mean that lipid lowering is not needed; lipid lowering may be a permissive state for drusen regression to happen via other mechanisms. Aging macrophages have reduced levels of the cholesterol transporter ABCA1, impaired cholesterol efflux, and a pro-angiogenic polarization (Sene et al., 2013). Increased cholesterol intake recapitulates these “aging” changes in macrophages and leads to advanced neovascular AMD pathology in mice (Sene et al., 2013). Mechanistically, lipid lowering by statins may reverse this “aging” of macrophages and thereby improve AMD pathology. In addition, mice fed a high-fat diet exhibit RPE and BM changes similar to human aging and AMD, such as lipid droplets in the BM; administration of simvastatin led to significant reversal of these changes (Barathi et al., 2014). This suggests that lipid lowering may be a necessary factor in reversing AMD pathology (Barathi et al., 2014). Statins are thought to have antioxidant properties (Profumo et al., 2014). The RPE, bathed by the high oxygen tension environment of the choriocapillaris (Friedman et al., 1964; Linsenmeier and Braun, 1992), is susceptible to chronic oxidative stress, which may play a role in AMD pathogenesis (Hollyfield, 2010; Klein et al., 2014b; Suzuki et al., 2007, 2012; Winkler et al., 1999). Statins have been shown to reduce oxidative stress-induced injury to the RPE and increase viability (Kim et al., 2012; Qian et al., 2011). Statins modulate ApoB100 secretion in cultured human RPE cells via modulation of RPE cholesterol levels (Wu et al., 2010), although not all statins are equivalent, with lipophilic ones (like atorvastatin) being more effective than hydrophilic ones (such as pravastatin). This differential effect of statin class on RPE function is yet another potential confounding variable that can affect results of epidemiological studies that do not distinguish between classes of statins.