Ascertainment Bias in the Clinical Diagnosis of Alzheimer Disease

Abstract

To implement effective treatment, when available, it is important to identify individuals as early as possible in the neuropathologic course of Alzheimer disease (AD). Clinical diagnosis often relies on comparison of performance on cognitive tests with group norms. In their seminal article, Blessed et al¹ reported that some cases had substantial neuropathologic abnormalities at autopsy but performed well on measures of cognition, an observation confirmed by other researchers.^2-5 Blessed et al^1(p807) suggested that “a certain amount of the change estimated by plaque counts may be accommodated within the reserve capacity of the cerebrum without causing manifest intellectual impairment.” Thus, individuals with greater biological cerebral reserve could experience extensive neuropathologic abnormalities but not reach the threshold for expression of symptoms necessary for clinical diagnosis because of that reserve capacity.⁶ This hypothesis, later expanded to include cognitive reserve (eg, experience and strategies),⁷ has been popular in research on AD.