Subtypes of Alzheimer's Disease Display Distinct Network Abnormalities Extending Beyond Their Pattern of Brain Atrophy

Abstract

Different subtypes of Alzheimer's disease (AD) with characteristic distributions of neurofibrillary tangles and corresponding brain atrophy patterns have been identified using structural magnetic resonance imaging (MRI). However, the underlying biological mechanisms that determine this differential expression of neurofibrillary tangles are still unknown. Here, we applied graph theoretical analysis to structural MRI data to test the hypothesis that differential network disruption is at the basis of the emergence of these AD subtypes. We studied a total of 175 AD patients and 81 controls. Subtyping was done using the Scheltens' scale for medial temporal lobe atrophy, the Koedam's scale for posterior atrophy, and the Pasquier's global cortical atrophy scale for frontal atrophy. A total of 89 AD patients showed a brain atrophy pattern consistent with typical AD; 30 patients showed a limbic-predominant pattern; 29 patients showed a hippocampal-sparing pattern; and 27 showed minimal atrophy. We built brain structural networks from 68 cortical regions and 14 subcortical gray matter structures for each AD subtype and for the controls, and we compared between-group measures of integration, segregation, and modular organization. At the global level, modularity was increased and differential modular reorganization was detected in the four subtypes. We also found a decrease of transitivity in the typical and hippocampal-sparing subtypes, as well as an increase of average local efficiency in the minimal atrophy and hippocampal-sparing subtypes. We conclude that the AD subtypes have a distinct signature of network disruption associated with their atrophy patterns and further extending to other brain regions, presumably reflecting the differential spread of neurofibrillary tangles. We discuss the hypothetical emergence of these subtypes and possible clinical implications.

Keywords: Alzheimer's disease; graph theory; heterogeneity; neurofibrillary tangles; structural MRI; subtypes.

Figure 1

Visual examples of the brain atrophy patterns in the different AD subtypes. Atrophy patterns were determined based on the combination of MTA, PA, and GCA-F visual rating scales. In the three visual rating scales, a score of zero denotes no atrophy, whereas scores from one to three (PA and GCA-F) or four (MTA) indicate an increasing degree of atrophy. Typical AD was defined as abnormal MTA together with abnormal PA and/or abnormal GCA-F. Limbic-predominant was defined as abnormal MTA alone with normal PA and GCA-F. Hippocampal-sparing included abnormal PA and/or abnormal GCA-F, but normal MTA. Minimal atrophy AD was defined as normal scores in MTA, PA, and GCA-F. The figure shows examples for each AD subtype and the healthy controls. A, anterior part of the brain; AD, Alzheimer's disease; GCA-F, global cortical atrophy scale–frontal subscale; L, left; MTA, medial temporal atrophy scale; P, posterior part of the brain; PA, posterior atrophy scale; R, right.

Figure 2

Structural brain networks. A, anterior part of the brain; AD, Alzheimer's disease; L, left; P, posterior part of the brain; R, right. (A) Brain regions included as cortical nodes; (B) brain regions included as subcortical nodes; (C) weighted correlation matrices by study group; (D) brain graphs by study group.

Figure 3

Modules. Module I in yellow, module II in dark blue, module III in orange, module IV in light blue. A, anterior part of the brain; AD, Alzheimer's disease; L, left; P, posterior part of the brain; R, right. (A) Healthy controls; (B) Typical AD patients; (C) Limbic-predominant AD patients; (D) Hippocampal-sparing AD patients; (E) minimal atrophy AD patients.

Figure 4

Comparison of the AD subtypes with the healthy controls in global network measures. Network densities are displayed on the x-axis from min = 5% to max = 40%, in steps of 1%. Between-group differences in the global graph measures are displayed on the y-axis. AD, Alzheimer's disease.

Figure 5

Comparison of the AD subtypes with the healthy controls in nodal network measures. The right box shows examples of resting-state functional MRI brain networks for interpretation of the nodal results obtained in the current study. Our graph nodes were assigned to the default-mode, fronto-parietal, and visual networks according to a previous review (52). AD, Alzheimer's disease; A, anterior; l, lateral; L, left; m, medial; MRI, magnetic resonance imaging; P, posterior; R, right.