Amyloid‐β precursor protein synthesis inhibitors for Alzheimer's disease treatment

and Aria Neurosciences investigators have confirmed with 2-([pyridine-2-ylmethyl]-amino)-phenol (2-PMAP) that inhibition of amyloid-β precursor protein (APP) synthesis offers an alternative to and possibly a significant advance over existing approaches to Alzheimer's disease (AD).[1]As the repeated clinical trial failures in AD warn, along with all other AD investigators they now face daunting tasks ahead.Methods and knowledge of AD pathological mechanisms may not be available to successfully time 2-PMAP interventions early enough in the course of AD to prevent possible amyloid β-induced irreversible pathologies such as phosphorylated-tau protein.It may not be possible to meet US Food and Drug Administration clinical efficacy requirements during preclinical stages decades earlier when clinical pathology cannot be reversed but only prevented possibly years later.[2,3] Methods used in AD drug development currently may be a barrier of equal importance to the identification of candidate drugs.Methodological problems are seen in the report from Asuni et al,[1] who attempted to compare 2-PMAP to phenserine, another APP synthesis inhibitor.They are to be commended for seeking comparisons to an existing drug in the same class, rather than a less informative comparison to placebo.Unfortunately, their choice of methodologies invalidates the comparisons they offer.We bring these technicalities to readers' attention to illustrate how methodological perils can mislead investigators, confuse readers, and confound AD drug developments.