Linking statins and lipids in Parkinson's disease

Lipids are essential for neuronal physiology as a major component of cell membranes. They are involved in permeability regulation, and signaling processes, with the brain remaining the most lipid-rich organ in the body. Statins, a class of lipid-lowering agents that inhibit 3-hydroxy-3-methyl-glutarylcoenzyme A reductase, are widely used in cardiovascular disease, but have increasingly garnered interest for treating neurodegenerative diseases such as Parkinson’s disease (PD) because of its purported neuroprotective effects, the mechanisms of which remain poorly understood. Experimental studies have demonstrated reduced nigral expression of proinflammatory molecules and reduced activation of glial cells in an 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model, and lovastatin-treated a-synuclein transgenic mice showed significant reduction of neuronal asynuclein aggregates. Much of the epidemiological literature has similarly favored a protective effect of statins on PD risk. Large prospective population studies with long follow-up periods such as the Health Professional Follow-up Study and the Nurses’ Health Study reported lower PD risk among statin users (adjusted pooled RR, 0.74) relative to nonusers, whereas a Taiwanese study reported lower incidence of PD in statin users than in nonusers in a dose-dependent manner (HR, 0.65 in females, 0.6 in males). Continuation of lipophilic statins was shown to be associated with decreased risk of PD (HR, 0.42), especially in women and the elderly. An earlier meta-analysis reported a 23% risk reduction in statin users compared with nonusers (RR, 0.77), whereas a more recent meta-analysis reported a similar degree of PD risk reduction (adjusted RR, 0.74) for users of statins. Importantly, these metaanalyses noted significant study heterogeneity and publication bias, with the protective effect of statins not sustained in the long term. The results of these studies may be confounded by statin indication, and there is prevailing uncertainty if the apparent “protective” effect of statins is conferred by the drug itself or by changes in cholesterol levels. Baseline low-density lipoprotein (LDL) levels do not appear to significantly affect PD risk. Higher lipid levels have been associated with moderately decreased PD risk in both case-control and prospective studies, as well as with a lower incidence of PD. Significant inverse associations of hypertension, hypercholesterolemia, and diabetes mellitus with PD risk was reported in Japan, whereas the prospective Honolulu-Asia Aging Study cohort reported an increased incidence of PD with decreasing LDL levels in a dose-dependent manner. In this study, Liu and colleagues similarly found that a diagnosis of hyperlipidemia was associated with lower PD prevalence. Conversely, high total cholesterol at baseline was associated with increased PD risk in both sexes combined after adjustment for confounders. Prospective data from the Atherosclerosis in Community (ARIC) cohort showed that after accounting for totaland LDL-cholesterol levels, statins were associated with higher PD risk (OR, 2.39). Higher total cholesterol was associated with lower PD risk after adjusting for statin usage and confounders. A systematic review investigating adjustment for cholesterol levels when evaluating statin effects found that among 6 studies that did not adjust for cholesterol, a protective effect of statins was observed (RR, 0.75); however, no protective effect was observed among 4 studies that adjusted for either cholesterol or hyperlipidemia (RR, 0.91; 95% CI, 0.681.22), suggesting that the apparent protective effect of statins on PD risk may at least be confounded by statin indication and immortal time bias. This retrospective case-control analysis by Liu and colleagues in this issue of the journal, used a large -----------------------------------------------------------*Correspondence to: Eng-King Tan, MD, Department of Neurology, Singapore General Hospital, Block 1 Level 3, Outram Road, Singapore 169108; tan.eng.king@singhealth.com. sg