Commentary on “Cytoskeletal modulators and pleiotropic strategies for Alzheimer drug discovery.” Atorvastatin's effect in Alzheimer's dementia (LEADe) study

2 The efficacy of statins for treating dyslipidemia and preenting complications of coronary artery disease such as myoardial infarctions is well established [1–5], and has lead to apid adoption worldwide. Statins act by inhibiting 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase, and are rst-line agents for reducing serum total cholesterol and lowensity lipoprotein cholesterol (LDL-C). AD and cardiovascular disease (CVD) share several comon risk factors, and observational studies have suggested that he risk of AD is reduced in patients who receive statin therapy n mid-life. Lowering cholesterol with statins has been shown o reduce -amyloid production and could provide a mechaism for modifying the progression of AD. Alzheimer’s disase (AD) is characterized pathologically by the deposition of xtracellular -amyloid and the accumulation of neurofibrilary tangles. Strategies to delay the onset of progression of AD ave largely targeted the plaques formed by the deposition of -amyloid.. Cholesterol may play an important role in the evelopment and progression of AD. One proposed benefit of tatins is the prevention of Alzheimer’s disease (AD), potenially related to cholesterol reducing [6] and/or anti-inflammaory properties [7]. In animal models, elevated cholesterol evels have been shown to increase processing of amyloid recursor protein (APP) and associated -amyloid production. Randomized, double-blind, placebo-controlled, clinical rials (RCT) sufficiently large to provide definitive evidence or the benefits of statin therapy in AD have not yet been onducted, although a recent pilot RCT suggested that atorastatin improved AD symptoms [8]. Most observational tudies have also reported that statin exposure protects gainst AD [9–13], but two recent studies found no signifcant association between statin use and subsequent onset of ementia or AD [14,15]. The latter two studies controlled