Susceptibility of the conventional criteria for mild cognitive impairment to false-positive diagnostic errors

Abstract

Background: We assessed whether mild cognitive impairment (MCI) subtypes could be empirically derived within the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort and examined associated biomarkers and clinical outcomes.

Methods: Cluster analysis was performed on neuropsychological data from 825 MCI ADNI participants.

Results: Four subtypes emerged: (1) dysnomic (n = 153), (2) dysexecutive (n = 102), (3) amnestic (n = 288), and (4) cluster-derived normal (n = 282) who performed within normal limits on cognitive testing. The cluster-derived normal group had significantly fewer APOE ε4 carriers and fewer who progressed to dementia compared with the other subtypes; they also evidenced cerebrospinal fluid Alzheimer's disease biomarker profiles that did not differ from the normative reference group.

Conclusions: Identification of empirically derived MCI subtypes demonstrates heterogeneity in MCI cognitive profiles that is not captured by conventional criteria. The large cluster-derived normal group suggests that conventional diagnostic criteria are susceptible to false-positive errors, with the result that prior MCI studies may be diluting important biomarker relationships.

Keywords: Alzheimer's disease; Cluster analysis; Dementia; MCI; Mild cognitive impairment; Misclassification; Misdiagnosis; Neuropsychology.

Conflict of interest statement

Conflict of Interest Disclosures: Dr. Bondi serves as Associate Editor for the Journal of the International Neuropsychological Society. Dr. Galasko serves as Editor for Alzheimer’s Research and Therapy, and as a paid consultant on Data Safety Monitoring Boards for Pfizer, Inc., Elan, Inc., and Balance Pharmaceuticals, Inc. Dr. Salmon serves as a consultant for CHDI Foundation, Novartis, and Bristol-Meyers Squibb. The other authors report no disclosures.

Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1

Neuropsychological performance for the cluster groups. Error bars denote standard deviations. The horizontal dotted line indicates the typical cutoff for impairment (−1.5 SDs).

Fig. 2

CSF (A) hyperphosphorylated tau (p-tau181p) concentrations (B) beta-amyloid (Aβ1-42) concentrations and (C) ratio of p-tau181p/Aβ1-42 for the cluster groups and normal control group. Error bars denote standard deviations.

Fig. 3

Hazard function showing risk of progression to dementia across time for the cluster groups.