The Brain is more than the Sum of its Molecular Parts
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Over the past year, the pharmaceutical company Eli Lilly has generated significant buzz surrounding solanezumab, a monoclonal antibody directed against amyloid B, the peptides implicated in the development of Alzheimer’s disease. Researchers hypothesized that solanezumab might effectively clear amyloid-β, thereby improving memory and other cognitive skills. Unfortunately, this hypothesis has not been substantiated. The announcement of the failure of EXPEDITION 3, a phase 3 trial conducted by Eli Lilly, raises interesting questions about the intense focus on molecules such as amyloid-β and tau to cure Alzheimer’s disease.

Research failure provides an opportunity to review some of the basic questions and assumptions underlying a specific focus of empirical investigation.  One question we might ask is whether clearance of amyloid-β or any other agent will actually improve cognition.  In the case of Alzheimer’s disease, the prodromal phase is long, and introducing an agent that clears toxic molecules long after the degenerative process has begun, may have little impact on cognitive functioning. At this point, substantial, nonreversible damage has been done.  Perhaps, clearance agents might be better understood as possibly lessening the progression of cognitive impairment but not improving cognitive functioning.

Second, Alzheimer’s is clearly a disease that can present in many different ways, and may be better described in terms of subtypes, if not separate diseases.  This being the case, how likely is it that one molecule (such as amyloid-β) will explain the entire variance of the disease? 

The focus on a specific molecule appears to be too reductionist, and inconsistent with how the brain works at a systems level.  Certainly, molecular and cellular processes are very important, but the exclusive focus on them ignores the fact that the brain is far more complex than its molecular structure.  For example, there is growing evidence that changes in electrical activity may be associated with Alzheimer’s disease.

We may find more success in combating Alzheimer’s and related dementias by broadening our research approach.  More research targeting molecules is needed but should not be conducted at the expense of studies that may improve our understanding of the broader brain systems associated with neurodegenerative diseases.

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