Future prospects and challenges for Alzheimer's disease drug development in the era of the NIA-AA Research Framework

The development of novel therapeutics aimed at slowing and eventually preventing progression of Alzheimer’s disease (AD) remains an important international public health goal. Despite the ongoing recent failures of clinical trials to demonstrate efficacy in modifying the clinical course of AD, delaying the onset of disabling symptoms remains an important strategic objective [1–5]. There have been extensive discussions exploring the reasons for the poor performance in recent drug-development efforts for AD at venues such as the Alzheimer’s Association’s Research Roundtable, Alzheimer’s Association International Conference, Clinical Trials on Alzheimer’s Disease, and the European Union–United States Task Force. The conclusions offered can be summarized to include (1) wrong drug, (2) wrong dose, (3) wrong target, (4) wrong study design, (5) wrong outcome measures, (6) wrong analytical method, (7) wrong stage of disease (i.e., “too late” or “too early”), (8) problems with recruitment and retention, (9) unacceptable tolerability, (10) wrong conceptual model of the disease, (11) wrong patients, and/or (12) poor study conduct. These conclusions have led to a recalibration of the thinking in the field. Now the crucial questions being asked include (1) what have we learned from these trials; (2) what needs to be done differently to achieve the goal of developing effective and impactful disease-modifying therapies; and (3) do we need to change our hypotheses about pathogenesis? In this issue of Alzheimer’s & Dementia (A&D), a landmark paper is published, “NIA-AA Research Framework: Towards a Biological Definition of Alzheimer’s Disease,” that offers a promising new orientation for the development of effective new clinical interventions and methods to diagnose, assess, and monitor AD. In 2011, the Alzheimer’’s Association (AA) and the National Institute on Aging (NIA) authored a series of manuscripts that described the diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of AD. Since the publication of those papers in A&D, a new initiative organized by the AA and the NIA sought to unite the 2011 guidelines into a single update called the Research Framework. The name—Research Framework—communicates two important ideas: (1) the recommendations are for observational