Negative results from the Alzheimer’s Prevention Initiative’s (API) Colombian study

So far, several trials of anti-amyloid monoclonal antibodies have failed to provide unequivocal evidence of reversing or even slowing cognitive decline in subjects with mild cognitive impairment (MCI) or mild Alzheimer’s dementia, despite marked success at removing amyloid plaques. Interest among Alzheimer’s investigators has been shifting to preventative trials in subjects who have biomarker evidence of Alzheimer’s pathology in the brain but do not yet have any cognitive impairment. The first of these preventative trials began in 2014 testing the anti-amyloid monoclonal antibody solanezumab in subjects with positive amyloid brain PET scans but no sign of cognitive impairment.  The trial is scheduled to end in December of this year, and results should follow soon after. Other preventative trials are getting underway with potentially more potent anti-amyloid drugs. 

Two weeks ago, preliminary results of an important preventative trial were released in a press release from the Banner Alzheimer’s Institute. The Alzheimer’s Prevention Initiative Autosomal Dominant Alzheimer’s Disease Trial (API ADAD Trial) in collaboration with the University of Antioquia in Medellin studied a large, Colombian kindred carrying the presenilin-1 mutation. Presenilin-1 mutations are rare, accounting for only 1% of Alzheimer’s cases, but having just one copy of this mutated gene virtually assures that the carrier will get Alzheimer’s disease, and cognitive impairment begins much earlier than in late-onset Alzheimer’s, on average at age 44. The trial studied the effect over 5-8 years of crenezumab, an anti-amyloid monoclonal antibody that targets the soluble, oligomeric form of beta-amyloid, on cognitive changes in initially unimpaired members of this kindred. The research subjects did not know the results of their genetic testing. One group of carriers of the presenilin-1 mutation was randomly assigned to receive crenezumab.  Another group of carriers received placebo.  A third group consisting of non-carriers also received placebo. Unfortunately, the subjects receiving crenezumab had no apparent benefit.  There was no significant delay in the onset of cognitive impairment.

These are only preliminary results, but they are not encouraging. A detailed report on the study is expected at the Alzheimer’s Association International Conference in San Diego next month (July 31 to August 4). Why was crenezumab chosen for this trial? At the time the study was being planned, there had been a shift in thinking about beta-amyloid.  Animal and in vitro studies showed that the soluble, oligomeric form of beta-amyloid was much more neurotoxic than the non-soluble form found in plaques. It certainly was a reasonable decision at the time to choose crenezumab, seemingly the best drug to remove soluble amyloid. However subsequent trials of crenezumab in subjects with late-onset Alzheimer’s disease showed no benefit, and more recent trials have focused on drugs targeting amyloid plaques, but none of these have been encouraging except for borderline slowing of cognitive decline in one of two identical trails of aducanumab.

More and more I am thinking that what we call Alzheimer’s disease has many different causes. Clearly the autosomal-dominant mutations like presenilin-1 cause disease that superficially looks like late-onset Alzheimer’s, but it is not the same disease, at least at the genetic level and probably also at the biochemical and neuropathological levels. This doesn’t mean that we should give up the quest for effective, disease-modifying medications for Alzheimer’s.  It does mean that we will need to work even harder to untangle the causes of an Alzheimer’s phenotype and then match our medications appropriately to the specific cause.