Author(s): Rudy J Castellani 1 , Xiongwei Zhu 2 , George Perry [[dagger]] 3
Pharmacological intervention in Alzheimer'âs disease (AD) has been the subject of intensive, time consuming and costly investigations in the past 25 years, particularly with the elucidation of the protein constituents of pathological lesions presumed to have pathogenic relevance and therefore be the prime target for reversal  . The enthusiasm centered on lesion-based constructs to treat the disease, however, this approach has been tempered in the last 10 years by repeated failures of immunotargeting, including untoward outcomes such as the precipitation of meningoecephalitis, and cognitive measures reported as worse than placebo  .
Specifically, we have seen proof of concept (i.e., reduction of amyloid-[beta]Î² by immunotherapeutic constructs, or amyloid-[beta]Î² 'clearing'â) and continued relentless progression of disease. The temptation to 'move the goal posts'â as it were, to a prodromal state is predictable. Yet, a renewed view of lesion-based approaches through the original and appropriate scientific prism, that is the acceptance of the null hypothesis until proven otherwise, is in order. Furthermore, a wholesale re-examination of the issue of modern therapy and exploration of alternative approaches is needed.
Several issues are therefore open to questioning and worth examining. First, the concept of familial versus sporadic disease has been addressed only obliquely in the literature. The prevailing underlying premise suggests that when a germline mutation produces a disease phenotype mimicking sporadic disease, the Mendelian condition is the 'familial form'â of the sporadic disease  . Indeed, this concept is so pervasive that patients with familial AD are excluded from clinical trials, despite the fact that the constructs, animal models and pathogenic cascades were elaborated from pathogenic mutations. Yet it is becoming ever more clear...