The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long “preclinical” phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from “normal” cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.

At present, there are many studies that collect information on aspects of neurologic and behavioral function (cognition, sensation, movement, emotion), but with little uniformity among the measures used to capture these constructs. Further, available measures are generally expensive, normed on homogenous nondiverse populations, not easily administered, do not cover the lifespan (or have easily linked pediatric and adult counterparts for the purposes of longitudinal comparison), and not based on the current thinking in the neuroscience community. There is also a paucity of measurement tools to gauge normal children in the motor and sensation domain areas, and many of these measures rely heavily on proxy reporting. Investigators have expressed the need for brief assessment tools that could address these issues and be used as a form of "common currency" across diverse study designs and populations. This ability to assess functionality along a common metric and "crosswalk" across measures is essential to the process of being able to pool data, which is often necessary when a large and diverse sample is needed. When individual studies employ unique assessment batteries, comparisons between studies and combining data from multiple studies can be problematic. The contract for the NIH Toolbox for the Assessment of Neurological and Behavioral Function (www.nihtoolbox.org) was initiated by the NIH Blueprint for Neuroscience Research (www.neuroscienceblueprint.nih.gov) to develop a set of state-of-the-art measurement tools to enhance collection of data in large cohort studies and to advance the biomedical research enterprise.The NIH Toolbox was not conceptualized as a substitute for the in-depth assessment of a behavioral domain or subdomain, and does not specifically target disease outcomes in its current format. As such, it is not intended for use as a diagnostic tool. Nonetheless, it is the hope that the normative data for NIH Toolbox performance in neurologic, psychiatric, and other disorders will be generated in the future through other research mechanisms. Developed via a systematic, iterative process that involved content experts and stakeholders, the NIH Toolbox was envisioned to incorporate the following characteristics:• Multidimensionality within each domain area • Versatility in terms of the types of studies where it can be employed, the portability of the measures across study designs, and the ability to crosswalk to existing and previous studies through the use of embedded benchmark items • Brevity to ensure low respondent burden and to address needs of researchers conducting large cohort studies • Methodologically sound • State-of-the-art in terms of psychometric approaches and technologies • Diversity in terms of having known measurement properties across racial and ethnic groups and numerous age ranges, as well as availability of English and Spanish versions • Dynamic to demonstrate sensitivity to change over time, and to allow for the adaptation of the measures over time in response to advances in science...