The “amyloid hypothesis” of Alzheimer’s disease postulates that Alzheimer’s is caused by the accumulation of a protein named beta-amyloid that produces the “gunky” deposits called plaques in the brain.  Despite the evidence that this is not the root cause (may be an effect of the brain changes in Alzheimer’s rather than a cause), the theory has become scientific orthodoxy, dogma and accepted on faith rather than evidence.  It has dominated research aimed at slowing or reversing Alzheimer’s disease leaving little funding for other approaches.

 But there is a kink in the armor.  There is accumulating evidence that treating amyloids is not the solution.  For example, six new drugs that decrease beta-amyloid reached phase II and III clinical trials in 2012.  Three of the studies were discontinued because concerns about safety or lack of efficacy.    Furthermore, we know that the brains of those who will develop Alzheimer’s disease is different from the brains of those who don’t.  However, it is also clear that having amyloid deposits does not guarantee that one will develop symptoms.  Even autopsy studies, heretofore the “definitive” proof, demonstrate that we can die with the pathology of Alzheimer’s disease but without clinically relevant symptoms.

To date the clinical trials of amyloid drugs have been conducted on those who already clearly have Alzheimer’s disease.  The assumption is that intervention is too late; the pathology has advanced too far to reverse or slow.  The next strategy in pursuit of the amyloid hypothesis is to intervene earlier, before the brain is so severely damaged.

Hence the ambitious attempt to recruit seniors who are willing to have their brains scanned for amyloids well before any memory symptoms and are willing to enter a clinical trial of an anti-amyloid drug, the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (“Study tests healthy seniors for silent signs of Alzheimer’s disease,” June 10, 2014, Naples Daily News).  The question is “can intervening early make a difference for those who do [develop Alzheimer’s disease]?  We won’t know the results for several years but this is the clearest test of the amyloid hypothesis to date. 

In the meantime, Alzheimer’s is a complex disease that has no simple neurobiology.  There is current research that focuses on biological processes other than amyloids.  For example, we need to pursue more rigorously the other major pathology, Tau proteins that form tangles in the brain of those with Alzheimer’s disease.  We need to pursue research into the hypothesis that Alzheimer’s disease is related to “Type III diabetes.”  We need to pursue the “mitochondria hypothesis” (Laura Spinney, “Genetic risk for Alzheimer’s Ignored for decades,” 2014, Scientific American). We need to broaden our gaze if we are to find better treatments than we have now.