Proof of Concept Trial of Probucol, an Inducer of apoE, for Prevention of Alzheimer’s Dementia
McGill University, Centre for Studies on Prevention of Alzheimer’s Disease, Douglas Hospital Research Centre
Scores of clinical trials have failed to find drugs for the treatment of Alzheimer’s disease (AD) dementia. Newer trials are seeking ways to postpone or prevent onset of AD symptoms. While others are testing drugs that attack Alzheimer amyloid for this purpose, we have proposed a series of studies to explore a different approach. A gene called APOE has several normal variants that predict a person’s development of ‘sporadic’ AD dementia at different ages. We shall examine the effects of a safe drug that mimics the effects of the least risky variant of APOE by increasing the availability of its gene product, apolipoprotein E (apoE). The drug is probucol, a generic prescription cholesterol-lowering agent that is still used in Asia but is no longer available in North America. We shall conduct a small ‘proof-of-concept’ clinical trial to test whether probucol does in fact increase availability of the two most common forms of apoE in human cerebrospinal fluid (CSF). We propose also to develop a new method to identify the ideal dose of probucol each individual needs to achieve this effect. Finally, we shall verify that the drug is safe when given to older people at risk of AD.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
Alzheimer’s disease (AD) dementia is mostly a disorder of late old age, but it affects some people who are decades younger than others. A drug that can postpone the onset of dementia should extend healthy life by several years, or even avert dementia altogether. The APOE gene is a powerful determinant of the age at which people develop AD dementia. Drugs that mimic the effects of low-risk variants of APOE should therefore defer or deter dementia onset, eliminating much of the population burden of AD. One such effect is increased availability of the APOE gene product, apolipoprotein E (apoE). We intend to verify that the retired cholesterol-lowering drug probucol mimics low-risk APOE variants by increasing availability of apoE.
We expect to demonstrate that probucol increases availability of apoE in the cerebrospinal fluid of treated individuals. We wish also to learn whether the drug acts comparably on different genetically determined variants of apoE. Furthermore, we intend to develop a method of finding the ideal dose of probucol needed by each person to achieve this effect. Finally, we hope to demonstrate that probucol used in this way is safe and well tolerated, and is therefore an appropriate drug for testing as a candidate preventive treatment against AD dementia onset.
We carried out the first half of the dose-finding phase in a Proof of Concept (POC) protocol designed to test whether the retired cholesterol drug probucol induces an increase in cerebrospinal fluid apolipoprotein E (apoE). In 24 healthy volunteers at risk for Alzheimer’s dementia we measured apoE before and after a 3-month test dosing interval. The results showed little effect of the drug on apoE levels, suggesting that a longer exposure to probucol might be needed to achieve the predicted effect. A statistical trend hinted that the drug’s effects might be stronger in people who carry the APOE e4 risk allele. With careful monitoring, the expected prolongation of the QT interval on the electrocardiogram was safely controlled, and no serious adverse clinical events were observed. However, a review at this point concluded that continuation of the protocol was not justified, and the program was stopped.