Resting-state network disruption and APOE genotype in Alzheimer's disease: a lagged functional connectivity study

Abstract

Background: The apolipoprotein E epsilon 4 (APOE-4) is associated with a genetic vulnerability to Alzheimer's disease (AD) and with AD-related abnormalities in cortical rhythms. However, it is unclear whether APOE-4 is linked to a specific pattern of intrinsic functional disintegration of the brain after the development of the disease or during its different stages. This study aimed at identifying spatial patterns and effects of APOE genotype on resting-state oscillations and functional connectivity in patients with AD, using a physiological connectivity index called "lagged phase synchronization".

Methodology/principal findings: Resting EEG was recorded during awake, eyes-closed state in 125 patients with AD and 60 elderly controls. Source current density and functional connectivity were determined using eLORETA. Patients with AD exhibited reduced parieto-occipital alpha oscillations compared with controls, and those carrying the APOE-4 allele had reduced alpha activity in the left inferior parietal and temporo-occipital cortex relative to noncarriers. There was a decreased alpha2 connectivity pattern in AD, involving the left temporal and bilateral parietal cortex. Several brain regions exhibited increased lagged phase synchronization in low frequencies, specifically in the theta band, across and within hemispheres, where temporal lobe connections were particularly compromised. Areas with abnormal theta connectivity correlated with cognitive scores. In patients with early AD, we found an APOE-4-related decrease in interhemispheric alpha connectivity in frontal and parieto-temporal regions.

Conclusions/significance: In addition to regional cortical dysfunction, as indicated by abnormal alpha oscillations, there are patterns of functional network disruption affecting theta and alpha bands in AD that associate with the level of cognitive disturbance or with the APOE genotype. These functional patterns of nonlinear connectivity may potentially represent neurophysiological or phenotypic markers of AD, and aid in early detection of the disorder.

Figure 1. Averaged eLORETA solutions (current density at cortical voxels) of EEG sources for each frequency band in patients and controls.

AD, Alzheimer's disease; HC, healthy controls; L, left; R, right.

Figure 2. eLORETA statistical maps of alpha1 oscillations in patients with Alzheimer's disease vs. controls.

Colored areas represent the spatial extent of voxels with significant difference in source current density (p<0.05, corrected). The MRI slices are located at the MNI-space coordinates of the voxel with highest significance. The color scale represents log F-ratio values (threshold: log F = −0.99, p<0.05). L, left; R, right; A, anterior; P, posterior.

Figure 3. eLORETA statistical maps of alpha1 oscillations in patients with Alzheimer's disease carrying the APOE-4 allele vs. noncarriers.

Colored areas represent the spatial extent of voxels with significant difference in source current density (p<0.05, corrected). The MRI slices are located at the MNI-space coordinates of the voxel with highest significance. The color scale represents log F-ratio values (threshold: log-F = −1.03, p<0.05). L, left; R, right; A, anterior; P, posterior.

Figure 4. eLORETA wire diagram illustrating cortical areas with significantly decreased (blue wires; threshold: t = −3.49, p<0.05 corrected) and increased (red wires; threshold: t = 4.26, p<0.05 corrected) alpha2 and theta lagged phase synchronization, respectively, in patients with Alzheimer's disease vs. controls.

Results are displayed on a transparent fiducial cortical surface. The points to which the lines are connected represent the center of the ROIs.

Figure 5. eLORETA wire diagram (top) and boxplots (bottom) of cortical areas with significantly decreased alpha2 lagged phase synchronization (blue wires) in APOE-4 carriers vs. noncarriers among patients with Alzheimer's disease (threshold: t = −3.98; p<0.05, corrected).

The significant connectivity wires are displayed on a transparent fiducial cortical surface. The points to which the lines are connected represent the center of the ROIs. The boxes represent interquartile ranges of lagged phase synchronization between A) frontal areas and B) parieto-temporal areas. The lines across the boxes indicate medians, and the whiskers show the highest and lowest values, excluding outliers.

Figure 6. eLORETA wire diagram of significant correlations between theta lagged phase synchronization values and the Mini-Mental State Examination scores in patients with Alzheimer's disease and controls (threshold: r = −0.27; p<0.05, corrected).

The blue color of the wires indicate a negative correlation. Results are displayed on a transparent fiducial cortical surface. The points to which the lines are connected represent the center of the ROIs. The bottom panel shows scatterplots of the strongest correlations. The results displayed correspond to the connectivity between A) left temporal-right prefrontal cortex, and B) left anterior temporal-right central cortex.