The assessment of cognition is a key feature of study participant selection, evaluation, and characterisation in Alzheimer’s disease (AD) clinical drug trials. Measurement science requires using reliable, valid, and sensitive instruments for these purposes and typical trial measures, such as the ADAS-cog and MMSE, show adequate levels of reliability. Due to the absence of adequate indices of working memory, attention, and executive function, they cannot be considered valid tests. Further, scoring conventions and range restrictions limit their sensitivity. Hence a number of innovative solutions have been proposed and tested, with varying degrees of success. In this chapter we review critically cognitive measures such as the Neuropsychological Test Battery, the Repeatable Battery for the Assessment of Neuropsychological Status, and digital cognitive tests, such as those drawn from the CogState, CANTAB, and CDR systems. These measures are all considered with specific regard to issue of validity, assay sensitivity, and clinical relevance. We propose a methodology for establishing proof of concept for new chemical entities to rescue or preserve cognition in individuals living with AD.