Simvastatin maintains white matter integrity in healthy middle‐aged adults with increased risk for Alzheimer’s disease: A secondary analysis of a randomized controlled trial

Abstract

AbstractBackgroundThe brain is the most cholesterol‐rich organ and myelin contains 70% of total brain cholesterol. Statins are potent cholesterol‐lowing medications used by millions of adults for prevention of cerebrovascular disease, yet the effect of statins on cholesterol‐rich brain white matter (WM) is largely unknown. In this study, diffusion tensor imaging (DTI) data collected during an 18‐month randomized controlled trial in healthy middle‐aged adults with a parental family history of Alzheimer’s disease (ClinicalTrial.gov NCT00939822) was used to determine the effect of simvastatin (40mg/daily) on WM integrity.Method73 participants were randomly assigned to drug or placebo (placebo group: N=38, baseline age 55.7±8.0yrs, 76.3% female; simvastatin group: N=35, baseline age 56.7±6.3yrs, 68.6% female) and underwent MRI (T1‐weighted, T2FLAIR, and DTI at baseline, 6m, 12m, and 18m). DTI parameter maps were used for longitudinal WM microstructure and tract‐based spatial statistics analyses. Total gray matter (GM), WM, and WM hyperintensity (WMH) volumes were calculated from T1‐weighted and T2FLAIR imaging. ANCOVA models (covariates: age, sex, APOE4‐genotype) tested the effect of treatment group on percent change in neuroimaging measures at each study visit. Model‐based path analysis tested whether the effects of simvastatin on WM microstructure were mediated by change in serum total cholesterol (TC) levels.ResultThere were no differences in baseline neuroimaging measures between treatment groups. At 18 months, the simvastatin group showed significantly attenuated decline in fractional anisotropy (FA) and attenuated increase in radial diffusivity (RD) in total WM relative to the placebo group (Fig1). At 12 and 18 months, the simvastatin group showed preserved WM volume relative the placebo group, but no differences in GM or WMH volume (Fig2). Approximately 30% of the effect of simvastatin on change in WM microstructure was mediated by change in serum TC (Fig3).Conclusion18 months of simvastatin use in statin‐naïve middle‐aged adults resulted in preserved WM microstructure and volume compared to placebo, suggestive of a potential protective effect of simvastatin on WM. Changes in FA and RD (but not axial diffusivity) suggest simvastatin‐induced alterations in myelin content, and partial mediation by change in serum TC suggests pleotropic effects of simvastatin on WM.