Effect of simvastatin on CSF Alzheimer disease biomarkers in cognitively normal adults.

Abstract

To examine potential disease-modifying effects of statin drugs, we conducted a 12-month randomized, placebo-controlled clinical trial of simvastatin in cognitively normal adults using change in CSF Alzheimer disease biomarkers as primary outcome measure. Participants were 45-64 years old and statin-naive with normal cognition and normal or mildly elevated cholesterol. Forty-six participants completed the 1-year study per protocol (25 in the simvastatin and 21 in the placebo group). Simvastatin was titrated to 40 mg/d. CSF Aβ₄₂, total tau, and p-tau₁₈₁ were measured at baseline and after 12 months of treatment using the INNO-BIA AlzBio3 assay. We used analysis of covariance to assess differences in biomarker change from baseline between treatment groups, adjusting for age, sex, and <i>APOE</i> ε4 status. Changes from baseline did not differ significantly between treatment groups for any CSF biomarker, with <i>p</i> values of 0.53, 0.36, and 0.25 for CSF Aβ₄₂, total tau, and p-tau₁₈₁, respectively. There was no significant modifying effect of sex, <i>APOE</i> ε4, or baseline high-density lipoprotein or triglycerides on treatment group for any of the biomarkers (all <i>p</i> > 0.18). However, a significant interaction between treatment group and baseline low-density lipoprotein (LDL) was observed for p-tau₁₈₁ (<i>p</i> = 0.003), where greater decreases from baseline in CSF p-tau₁₈₁ concentrations were associated with higher baseline LDL level for the simvastatin group. Simvastatin-related reductions in CSF p-tau₁₈₁ concentrations may be modulated by LDL cholesterol. The potential disease-modifying effects of simvastatin on CSF phospho-tau should be further investigated in persons with hypercholesterolemia.