Ascertainment bias in the clinical diagnosis of Alzheimer disease

Background: The clinical diagnosis of Alzheimer disease (AD) is often based, at least in part, on poor cognitive test performance compared with normative values. Objective: To examine the presence and extent of an ascertainment bias (omission of affected individuals) produced by such criteria when applied as early as possible in the course of the disease. Design: Longitudinal study (1979-2008). Setting: Washington University Alzheimer Disease Research Center, St Louis, Missouri. Participants: Of 78 individuals aged 65 to 101 years enrolled as healthy controls, 55 later developed autopsy-confirmed AD; 23 remained cognitively healthy and did not have neuropathologic AD. Main Outcome Measures: Criteria for the diagnosis of AD based on various cutoff points (1.5, 1.0, and 0.5 SDs below the mean for robust test norms) for 2 standard psychometric measures from each of 3 cognitive domains (episodic memory, visuospatial ability, and working memory) were applied to data from the first assessment associated with an independent clinical diagnosis of cognitive impairment for those who developed symptomatic AD and from the last assessment for those who did not. Results: Areas under the curve from receiver operating characteristic analyses ranged from 0.71 to 0.49; sensitivities and specificities were unsatisfactory even after adjusting for age and education, using combinations of tests, or examining longitudinal decline before clinical diagnosis. Conclusion: Reliance on divergence from group normative values to determine initial cognitive decline caused by AD results in failure to include people in the initial symptomatic stage of the illness.