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

Lipids Health Dis. 2024 Dec 19;23(1):410. doi: 10.1186/s12944-024-02398-1.

Abstract

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).

Keywords: Alzheimer’s disease; Hyperlipidemia; Plasma amyloid beta; Probucol; Soluble receptor of advanced glycation end products (sRAGE).

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / blood
  • Alzheimer Disease / drug therapy
  • Amyloid beta-Peptides* / blood
  • Amyloid beta-Peptides* / metabolism
  • Antioxidants / pharmacology
  • Antioxidants / therapeutic use
  • Double-Blind Method
  • Female
  • Humans
  • Hyperlipidemias* / blood
  • Hyperlipidemias* / drug therapy
  • Male
  • Middle Aged
  • Probucol* / pharmacology
  • Probucol* / therapeutic use
  • Receptor for Advanced Glycation End Products / blood
  • Receptor for Advanced Glycation End Products / metabolism

Substances

  • Probucol
  • Amyloid beta-Peptides
  • Receptor for Advanced Glycation End Products
  • Antioxidants