Dosage and Efficacy of Probucol-induced apoE to Negate Cognitive Deterioration
Condition: Dementia of the Alzheimer Type; Age-related Cognitive Decline; Mild Cognitive Impairment Due to Alzheimer Disease
MeSH terms: Alzheimer Disease; Cognitive Dysfunction
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      DEPEND is an open-label but dosage-masked trial of the retired cholesterol-lowering drug
      probucol as an agent to increase availability of apolipoprotein E (apoE) in the cerebrospinal
      fluid (CSF) of cognitively intact older persons at risk of Alzheimer's dementia. Absorption
      of oral probucol is variable. In a sample of 23 cognitively intact persons over age 55,
      DEPEND will therefore develop an algorithm to prescribe individualized dosing to achieve
      plasma concentration that will likely increase availability of CSF apoE. These persons will
      then use their individualized dosage for 12 months to assess longer-term effects of the drug
      on CSF apoE concentration, while monitoring closely for evidence of adverse consequences of
      use.
    

Detailed description: 
      Probucol is a cholesterol-lowering drug that has been removed from the market in Canada and
      the US, but remains in clinical use in Asia. In rodents, probucol increases synthesis and
      availability of apolipoprotein E (apoE) in the cerebrospinal fluid (CSF). ApoE is the protein
      product of the polymorphic gene APOE, allelic variation in which remains the strongest known
      risk factor (other than age itself) for Alzheimer's dementia. Oral Probucol is absorbed
      variably. Administration of a single, fixed dose therefore results in a wide range of plasma
      concentrations when the drug is given to various individuals in a fixed dosage. Limited human
      data suggest that higher plasma and CSF concentrations of probucol result in stronger
      increases in CSF apoE concentration. The dual aims of DEPEND are therefore 1) to develop an
      individualized dosing regimen that will result in plasma concentrations that are likely to
      increase CSF apoE concentration by 50%; and 2) to treat 20 persons at elevated risk of
      Alzheimer's dementia, each at his/her ideal individual dosage, for 12 months, observing the
      resulting change in CSF concentrations of apoE. Simultaneously, subjects will be observed
      carefully for evidence of any treatment effects on cognition or other probable markers of
      progression in pre-clinical Alzheimer's disease, as well as safety risks that might deter
      further human experimentation with the drug.
    

Intervention name(s): Probucol
Intervention type(s): Drug
Intervention description(s): Probucol was used with good effect for more than a decade in Canada and the US to reduce plasma cholesterol. Although withdrawn from the Canadian and US markets by its manufacturer for commercial reasons, it is still widely used for this purpose in Japan and Korea. Over the past decade, long-term follow-up studies in Asian populations at high risk of cardiovascular events have shown that the drug reduces the incidence of these events in a manner not unlike "statin" drugs used widely in Canada and the US.
Other intervention name(s): Lorelco (trade name in Japan)
Intervention MeSH terms: Probucol
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: apolipoprotein E; Alzheimer; pre-clinical; pre-symptomatic; dose-finding; prevention