Prevention of Alzheimer’s disease by control of beta-amyloid production in the periphery

Abstract

Using a novel approach for identification of disease modifier genes, it was demonstrated that the level of expression of the Presenilin2 gene by the liver regulates the accumulation of pathogenic concentrations of Alzheimer’s disease (AD)-initiating beta-amyloid within the brain. The anti-leukemia therapeutic imatinib (trade name Gleevec), which does not cross the blood-brain barrier, reduced liver production of beta-amyloid and lowered its accumulation in the brain below pathogenic levels.  These observations suggest that Alzheimer’s disease is preventable. The imatinib-related compound, imatinib para-diaminomethylbenzene trihydrochloride, is more than three-fold more potent in inhibiting beta-amyloid production than imatinib and exhibits only 1/16^th of the activity of imatinib in the  inhibition of Abl kinase (the imatinib target in leukemia), resulting in a selectivity ratio of nearly 60 for the AD indication. These studies suggest that prophylactic reduction of beta-amyloid at the site of its production in the livers of aging humans has the potential to lower the incidence AD and point to the identity of a drug that can accomplish that goal.