Treating Alzheimer Disease: Is Diet and Exercise more Effective than Small Molecule Therapy?

As Alzheimer’s disease (AD) therapeutic research continues to pursue small molecule targeting, disease modifying therapy remains elusive [1]. Indeed, despite a wide array of pharmacologic agents at our disposal and the design and completion of dozens of clinical trials targeting Amyloid-beta (Aβ), no approach has shown any progress whatsoever in ameliorating the disease process, and affected patients continue to suffer and expire on the same cognitive trajectory as they have since the dawn of the species. One major defect in the so-called amyloid cascade hypothesis is that the hypothesis itself, as well as essentially all experimental modeling, is derived entirely from Mendelian conditions, i.e. familial autosomal dominant disease [2]. Such conditions are not only exceedingly rare (total number of amyloid β protein precursor mutation kindreds in the world number less than 100, for example), but encompass lifelong defects in cellular physiology. The repeated failures in sporadic AD therapy may simply be due to the inapplicability of this small molecule construct to something as complex as age-related sporadic neurodegeneration. Indeed, an in depth analysis of clinicopathological correlations in sporadic disease reveals that the pathology of AD (and a spectrum of chronic diseases), is indicative of a response to the aging environment, possibly even a productive response, in which case targeting such a response would be ineffective at best, and deleterious at worst. This is to say nothing of the empirical problem with targeting a single small molecule within the scope of the neuronal proteome, comprised of many thousands of protein transcripts at any give time.