The hidden variables problem in Alzheimer's disease clinical trial design

As the leading cause of dementia worldwide, Alzheimer's disease has garnered intense academic and clinical interest. Yet, trials in search of a disease‐modifying therapy have failed overwhelmingly. We suggest that, in part, this may be attributable to the influence of disruptive variables inherent to the framework of a clinical trial. Specifically, we observe that everyday factors such as diet, education, mental exertion, leisure participation, multilingualism, sleep, trauma, and physical activity, as well as clinical/study parameters including environment, family coaching, concurrent medications, and illnesses may serve as potent confounders, disruptors, or sources of bias to an otherwise significant drug‐disease interaction. This perspective briefly summarizes the potential influence of these hidden variables on the outcomes of clinical trials and suggests strategies to abate their impact.