2.2. Neuropsychological assessment

The WRAP cognitive test battery assesses many domains and has been previously described (Darst, et al., 2015, Sager, et al., 2005). For these analyses, we used one composite variable estimating cognitive functioning at age 54 (the mean age at baseline) and six factor scores representing longitudinal functioning across memory and executive function domains.

A composite index, named progression score (PS), was computed using a set of eight cognitive measures, including Trails A and B (Reitan and Wolfson, 1985), Digit Span Forward and Digit Span Backward (Wechsler, 1997), Rey Auditory Verbal Learning Test (AVLT) summed score across five learning trials (Lezak, et al., 2004), AVLT delayed recall (Lezak, et al., 2004), Boston Naming Test (Kaplan, et al., 1983), and the Mini-Mental State Examination (Folstein, et al., 1975). Visits with fewer than four of these measurements were excluded. We applied the PS model (Bilgel, et al., 2015, Jedynak, et al., 2012) to align individuals along a linear cognitive trajectory based on their longitudinal cognitive measure profiles, adjusting for inter-individual differences in rates of change, with a higher PS indicating greater overall cognitive decline across the eight measures. We accounted for correlations among cognitive measures and constrained the progression scores to increase linearly with age within each individual. To remove confounding effects of age at entry into WRAP, the progression score was estimated at age 54, the mean age at baseline.

A factor analysis of the neuropsychological test scores was performed as described previously (Dowling, et al., 2010, Jonaitis, et al., 2015, Koscik, et al., 2014). The resulting factor scores were standardized into z scores (~N [0, 1]), using means and standard deviations obtained from the whole sample at baseline (visit 1) or visit 2 for a subset of tests that were first administered at this visit. There were four cognitive factor z scores for memory (Immediate Memory, Verbal Learning & Memory, Story Recall, and Visual Learning & Memory) and two for executive function (Working Memory and Speed & Flexibility). Tests comprising each of these factors have been previously described (Darst, et al., 2015). Due to the small number of individuals carrying the functional variants, these six factor scores were also averaged to create a summary cognitive measure of the factor scores for each individual. Consequently, we did not adjust for multiple comparisons when examining the mean z score and used the individual cognitive factor scores to inform which domains were driving the association with the mean z score.