Biological heterogeneity in ADNI amnestic mild cognitive impairment

Abstract

Background: Previous work examining normal controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI) identified substantial biological heterogeneity. We hypothesized that ADNI mild cognitive impairment (MCI) subjects would also exhibit heterogeneity with possible clinical implications.

Methods: ADNI subjects diagnosed with amnestic MCI (n=138) were clustered based on baseline magnetic resonance imaging, cerebrospinal fluid, and serum biomarkers. The clusters were compared with respect to longitudinal atrophy, cognitive trajectory, and time to conversion.

Results: Four clusters emerged with distinct biomarker patterns: The first cluster was biologically similar to normal controls and rarely converted to Alzheimer's disease (AD) during follow-up. The second cluster had characteristics of early Alzheimer's pathology. The third cluster showed the most severe atrophy but barely abnormal tau levels and a substantial proportion converted to clinical AD. The fourth cluster appeared to be pre-AD and nearly all converted to AD.

Conclusions: Subjects with MCI who were clinically similar showed substantial heterogeneity in biomarkers.

Keywords: ADNI; Alzheimer's disease; Amnestic MCI; Clustering; Heterogeneity.

Figure 1

Distributions by cluster for a subset of clustering biomarkers. The solid gray line represents the mean from the ADNI normal controls and the dashed line represents the AD mean.

Figure 2

The Z-scores shown were created by subtracting the ADNI normal mean and dividing by the ADNI normal standard deviation for each biomarker shown, so that zero represents actual normality, not normality within the MCI subgroup. Signs have been reversed so that large, positive values always indicate more severe damage. Hipp = hippocampal volume, Vent = ventricle volume.

Figure 3

Estimated atrophy in all four MCI clusters over a 3 year period. Estimates come from linear mixed effects regression models with random effects for slope and intercept and control for age and the interaction of age with time. There were significant differences between MCI 1 and MCI 3 and 4 for all measures. MCI 1 differed from MCI 2 in ventricles and entorhinal cortex at baseline and brain and hippocampus atrophy over time. Secondary analysis excluding MCI 1 and using MCI 3 as the referent found no significant differences in intercept between MCI 3 and MCI 4 for any of the MRI measures. MCI 4 experienced significantly more rapid deterioration in the entorhinal cortex than MCI 3. MCI 2 and MCI 3 differed significantly in both slope and intercept for all MRI measures.

Figure 4

‘Survival’ estimates from interval censored accelerated failure time models, where survival indicates maintaining a diagnosis of MCI rather than converting to AD. Model results indicate that MCI 2, 3, and 4 all differ significantly from MCI 1 but do not differ significantly among each other in time to conversion.