Effects of Probucol on plasma amyloid-β transport in patients with hyperlipidemia: a 12-week randomized, double-blind, placebo-controlled trial

Background: Although dyslipidemia has been acknowledged as a risk factor for Alzheimer’s disease (AD), the effects of lipid-lowering drugs on AD have not been determined. The primary pathophysiological hallmark of AD is the deposition of amyloid-β (Aβ) plaques in the brain. Plasma Aβ levels are influenced by the transport of Aβ from the central nervous system to the peripheral blood. This study investigates the effects of Probucol, a lipid-lowering and antioxidant drug, on plasma Aβ transport. Methods: A total of 120 hyperlipidemic patients with normal cognition were randomly assigned (1:1 ratio) to receive either Probucol (1000 mg daily for 12 weeks) or a placebo. Plasma Aβ, soluble receptor of advanced glycation end products (sRAGE), and fasting lipid profiles were measured at baseline and every 6 weeks. Results: A total of 108 participants completed the study, with 55 in the Probucol group. The cohort consisted of 58 (53.7%) women, with a mean age of 58.4 ± 8.0 (range, 45–80) years. After 12 weeks of treatment, the changes in plasma Aβ₄₂ and sRAGE levels significantly differed between the Probucol and placebo groups (ΔAβ₄₂: β = 6.827, P = 0.030; ΔsRAGE: β = 98.668, P = 0.004). Furthermore, ΔsRAGE was positively correlated with the change in Aβ₄₂ (β = 0.018, P = 0.048). When adjusted for ΔsRAGE, the effect of Probucol on plasma Aβ₄₂ levels was attenuated (β = 5.065, P = 0.116). In the Probucol group only, ΔsRAGE was significantly correlated with oxidized low-density lipoproteins (β = 4.27, P = 0.011), total cholesterol (β = 67.50, P = 0.046), and low-density lipoproteins (β = − 91.01, P = 0.011). Conclusions: Daily oral administration of Probucol (1000 mg) for 12 weeks significantly increased plasma Aβ₄₂ levels, likely through modulation of sRAGE. This effect may be attributed to the antioxidant and lipid-lowering properties of Probucol. These findings suggest that Probucol could potentially serve as a protective agent against the pathological processes of AD. Trial registration: This study was registered on the Chinese Clinical Trial Registry platform in June 2019 (Trial registration number: ChiCTR-1900023542).