Cognitive Practice Effects Delay Diagnosis; Implications for Clinical Trials.

Objective: Practice effects on cognitive tests obscure decline, thereby delaying detection of mild cognitive impairment (MCI). This reduces opportunities for slowing Alzheimer9s disease progression and can hinder clinical trials. Using a novel method, we assessed the ability of practice-effect-adjusted diagnoses to detect MCI earlier, and tested the validity of these diagnoses based on AD biomarkers. Methods: Of 889 Alzheimer9s Disease Neuroimaging Initiative participants who were cognitively normal (CN) at baseline, 722 returned at 1-year-follow-up (mean age=74.9; SD=6.8). Practice effects were calculated by comparing returnee scores at follow-up to demographically-matched individuals who had only taken the tests once, with an additional adjustment for attrition effects. Practice effects for each test were subtracted from follow-up scores. The lower scores put additional individuals below the impairment threshold for MCI. CSF amyloid-beta, phosphorylated tau, and total tau were measured at baseline and used for criterion validation. Results: Practice-effect-adjusted scores increased MCI incidence by 26% (p<.001). Adjustment increased proportions of amyloid-positive MCI cases (+20%) and reduced proportions of amyloid-positive CNs (-6%) (ps<.007). With the increased MCI base rate, adjustment for practice effects would reduce the sample size needed for detecting significant drug treatment effects by an average of 21%, which we demonstrate would result in multi-million-dollar savings in a clinical trial. Interpretation: Adjusting for practice effects on cognitive testing leads to earlier detection of MCI. When MCI is an outcome, this reduces recruitment needed for clinical trials, study duration, staff and participant burden, and can dramatically lower costs. Importantly, biomarker evidence also indicates improved diagnostic accuracy.