The pathogenesis of Parkinson disease (PD) involves aggregation and accumulation of a-syn protein. There has been growing literature that suggests cholesterol-lowering drugs, like statins, may be neuroprotective for PD, though, to date, the relationship is unclear. Mechanisms hypothesized include reducing cholesterol levels and a-syn oxidation, or modulating the immune system. Furthermore, the identification of compounds that inhibit a-syn aggregation is a potential therapeutic approach for PD.

We observed partial inhibition of a-syn fibril growth by the fungal-derived statins, which structurally share a naphthalene. Of these, lovastatin (IC₅₀ = 19 ± 5 uM) provided the greatest inhibition, with simvastatin (IC₅₀ = 36 ± 5 uM) and mevastatin (IC₅₀ = 32 ± 2 uM) conferring similar lower levels of inhibition. In contrast, the synthetic statins that we tested (atorvastatin, cerivastatin, fluvastatin, pravastatin, pitavastatin, and rosuvastatin) and ezetimibe did not inhibit a-syn fibril growth. In a population-based sample of 48,295 incident PD patients age 66-90 from 2009 Medicare data, lovastatin use at baseline was associated with a modest but significant reduction in mortality over 5-6 years of follow-up (adjusted hazard ratio 0.92, 95% confidence interval 0.86-0.99, p=0.03). We confirmed this potential effect was beyond any generic effect among non-cases (interaction p-value<0.001).