Psychometric features of the ADAS-Cog: Identifying a potential cognition endpoint for prodromal Alzheimer's disease

Abstract

The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 11) is a well-recognized, regulatory approved endpoint in Alzheimer's disease (AD) featuring seven paper-pencil tasks and four investigator-rated items. Although it has been widely used in clinical trials of mild to moderate AD the instrument does not appear to be sensitive to disease progression in the milder stages and many items show ceiling effects. This becomes problematic as drug development is increasingly moving towards clinical trials in prodromal AD. Endpoints that lack sensitivity require lengthier trials with larger sample sizes. This study aims to explore psychometric features of ADAS-Cog (13 item ADNI version) in MCI and mild AD patients using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI-1) and from there tailor a new “prodromal ADAS-Cog” (ProADAS-Cog) composite score that may be more sensitive to disease progression in prodromal AD. A statistical analysis was conducted to evaluate the distribution of ADAS-Cog sub-items at baseline and to explore the sensitivity of various composite scores to disease progression. Prodromal AD was defined as ADNI MCI plus elevated CSF Tau and/or low Abeta according to ADNI cutoffs. Seven out of the original 11 ADAS-Cog sub-items were at ceiling for at least 50% of the mild AD subjects (MMSE 21–26). In the MCI cohort, 8 of the 11 sub-items were at ceiling for at least 50% of the subjects. The subsequent analysis led to an adjusted ProADAS-Cog, a measure of memory, orientation, language and attention. Applying this battery to the ADNI data suggested that sample sizes for disease modifying clinical trials could potentially be reduced by ∼40% in a 24 months study in a prodromal AD population. The ADNI data set suggests the ADAS-Cog battery lacks sensitivity to decline in mild and prodromal AD, hence requiring lengthy trials in order to show separation from placebo in a disease modifying trial. This work resulted in a shorter more sensitive “ProADAS-Cog” battery, but further research is needed in order to validate this battery in different mild/prodromal AD cohorts.