A composite endpoint using version 3 of the Alzheimers’ Disease Research Centers’ neuropsychological test battery

Abstract

AbstractBackgroundVersion 3 of the Uniform Data Set (UDS) has been collected by the National Alzheimer’s Coordinating Center (NACC) since 2015, which contains neuropsychological test scores on multiple domains. However, its potential utility as prevention trial outcomes needs to be examined, in comparison with other previously validated outcomes.MethodThe analytical sample was extracted from the December 2022 data freeze from NACC, which includes baseline and follow‐up visits from participants who were cognitively normal during initial visits. Standardized z‐scores for each cognitive domain (attention/working memory, episodic memory, semantic memory/language, executive function, visuospatial function) were calculated. Linear mixed effects models with random intercepts and slopes were used for studying longitudinal changes comparing participants who progressed to MCI or AD (decline subgroup) and those who remained cognitively normal for up to 4 years of follow‐up (stable subgroup), controlling for baseline age, sex, race, education and APOE‐e4 carrier status. We then constructed an approximate effect size weighted average of domain‐specific scores as a global composite measure, obtain effect size estimates using the mini‐mental state examination (MMSE), the Montreal Cognitive Assessment (MoCA) and the composite measure as outcomes, and perform sample size calculations using the following assumptions: a significance level of 5%, 80% power, an equal proportion randomized in a hypothesized intervention and a placebo control arms, in which the intervention group has a 10% to 30% reduction of progression to MCI during the study period, each participant has a baseline visit and up to four annual follow‐up visits, a dropout rate of 10% per year.ResultThe estimated difference of the annualized rate of change in z‐scores between the decline and stable subgroups ranged from 0.028 (attention) to 0.105 (executive function) standardized units for the domain‐specific scores, and 0.068 standard deviation units for the composite score. The composite score requires a smaller sample size for detecting the same level of reduction in progression compared to MoCA and MMSE.ConclusionUsing a global composite score of UDS version 3 neuropsychological tests as a prevention trial outcome would result in about 30‐50% reduction of sample size needed compared to MMSE and MoCA.