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.
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Inclusion Criteria: * Family history of one or more parents or multiple siblings who developed Alzheimer-like dementia, as established by review of history and/or medical records, and by responses to a brief questionnaire describing characteristics of the relatives' condition * Aged 60+. May be aged 55-59 only if at least one parent or sibling experienced onset of Alzheimer's dementia at an age no more than 15 years beyond the prospective participant's current age * At least six years of formal education * Sufficient fluency in spoken and written English and/or French to participate in study visits and in psychometric testing * A collateral respondent available to provide information on the cognitive and health status of the participant, and to assist with monitoring of study interventions, if needed * Willingness to undergo four lumbar punctures for collection of CSF * Affirmation of prior informed consent to undergo genetic testing for APOE and other known or suspected AD risk factors * Ability and intention to participate in study visits per protocol, in the opinion of a study physician * Willingness to limit use of over-the-counter or prescription medicines (e.g., tricyclic antidepressants, anti-histamines) known to prolong QTc interval, or to potentiate the tendency of probucol to prolong this interval, in the opinion of a study physician * If on a statin or other lipid lowering drug that, in the opinion of a study physician, can safely be co-administered with probucol, willingness to remain on a stable dose of this medication during the entire trial period. * Provision of informed consent for this trial. Exclusion Criteria: * Known or identified cognitive disorder diagnosed previously by a physician, psychologist, nurse-clinician, or other health care provider, or by StoP-AD staff * Past or present use of a commercially available acetyl-cholinesterase inhibitor including tacrine, donepezil, rivastigmine, or galantamine * Past or present use of memantine or other approved cognitive enhancement prescription agent * History of heart disease, myocardial infarction or documented acute coronary syndrome, or arrhythmia (including atrial fibrillation) * Corrected QT interval using Bazett's formula (QTcB) interval \> 450 msec for males or 470 msec for females as detected by EKG and confirmed by consultant cardiologist * Clinically significant hypertension, anemia, liver disease, or kidney disease, in opinion of a study physician (participants with treated hypertension who are normotensive as a result of intervention may be enrolled.) * Concurrent use of over-the-counter or prescription medicines (e.g., tricyclic antidepressants, anti-histamines) known to prolong QTc interval, or to potentiate the tendency of probucol to prolong this interval, in the opinion of a study physician * Any inflammatory or chronic pain condition that necessitates regular use of opiates (e.g., oxycodone, hydrocodone, tramadol, meperidine, hydromorphone), or NSAIDs (more than 4 doses / week) * Current plasma creatinine \> 132 mmol/l (1.5 mg/dl) * Current alcohol, barbiturate or benzodiazepine abuse or dependence (in opinion of study physician) * Any other medical condition that, in the opinion of a study physician, makes it inadvisable for the participant to be assigned to regular dosage of probucol * Enrolment in any trial or experimental protocol that, in the opinion of a study physician, is likely to interfere with PREVENT-AD or any of its derivative protocols including this one * Any other condition that, in the opinion of a study physician, makes it medically inappropriate for the participant to enroll in the program