UC San Diego

Cognitive practice effects (PEs) are often ignored and likely delay detection of mild cognitive impairment (MCI). The replacement-participants method of PE adjustment subtracts the scores of demographically-matched, test naïve, replacement participants from returnees’ follow-up scores. The aims of this project were to determine whether this PE adjustment: 1) results in earlier MCI detection; 2) improves diagnostic stability, accuracy, and validity based on concordance with Alzheimer’s disease biomarkers; and 3) reduces costs of clinical trials.

The method was adapted for studies that did not recruit replacement participants by identifying “pseudo-replacements”, a subset of baseline participants that are demographically-matched to returnees at follow-up. Alzheimer’s Disease Neuroimaging Initiative data were extracted. Study 1 (baseline cognitively unimpaired [CU], N=722) and study 2 (baseline MCI, N=329) calculated PEs at 1-year follow-up. Study 3 added data from a 2-year follow-up (N=809). Biomarkers include CSF tau and beta-amyloid. Cost estimates were based on recent grant budgets and effects of PE adjustment on required sample size in a large clinical trial. Primary analyses included McNemar χ 2 tests, logistic regressions, and generalized estimating equations.Study 1: PE-adjusted follow-up scores led to significantly greater incident MCI as compared to PE-unadjusted scores (124 vs. 104; +19%). Significantly more MCI participants were biomarker positive when PE-adjusted scores were utilized (173 vs. 152; +14%). Cost estimates showed that replacements could save a large Alzheimer’s disease clinical trial over $5,000,000. Study 2: PE adjustment significantly reduced reversion to CU as compared to PE-unadjusted scores (57 vs. 80; -29%). Study 3: Significant PEs were found at both follow-ups for baseline MCI and CU samples. When adjusting for PEs, participants remained stable over time or declined, as expected in this older sample. Several PEs increased at the second follow-up (range: +9% to +133%). Adjusting for PEs with the replacement method leads to earlier and more accurate MCI diagnoses, reduces reversion rates, and is cost effective for large-scale studies. Unlike other methods, it also unmasks PEs even when scores worsen over time. The results indicate that PEs warrant greater attention and also suggest the potential value of developing PE norms.