Increased hippocampal default mode synchronization during rest in middle-aged and elderly APOE ε4 carriers: relationships with memory performance

Abstract

The apolipoprotein (APOE) ε4 allele is a strong genetic risk factor for Alzheimer's disease (AD). Intrinsic fluctuations of brain activity measured by fMRI during rest may be sensitive to AD-related neuropathology. In particular, functional connectivity of the default-mode network (DMN) has gained recent attention as a possible biomarker of disease processes and associated memory decline in AD. Here, we tested the hypothesis of APOE-related alterations in DMN functional connectivity in 95 healthy individuals between 50 and 80 years of age, including 33 carriers of the ε4 allele. Based on previous studies, we hypothesized increased hippocampal DMN synchronization in APOE ε4 carriers. This was supported using independent component analysis in combination with a dual-regression approach for analysis of resting state data. Whole-brain analysis suggested effects also in other areas, including the posterior cingulate cortex, parietal cortex, and parahippocampal regions. DMN synchronization showed a negative correlation with performance on a test of memory functioning, suggesting a neurocognitive significance of the brain activity patterns during rest. Our findings indicate that increased genetic vulnerability for AD is reflected in increased hippocampal DMN synchronization during rest several years before clinical manifestation. We propose that the results reflect ε4-related failure in hippocampal decoupling, which might elevate the total hippocampal metabolic burden and increase the risk of cognitive decline and AD. The results provide an important confirmation of specific genotype effects on intrinsic fluctuations and support the use of functional connectivity indices as imaging-derived endophenotypes in the emerging field of imaging genetics.

Figure 1.

A, In red-yellow to the left is the DMN comprising three components from the gICA. In red-yellow to the right is the posterior DMN component in which we found increased functional synchronicity in APOE ε4 carriers. This component spans ACC, PCC, precuneal, and thalamic regions. The two DMN components that showed no significant effect of APOE are shown in blue and pink. B, The component spanning the primary visual cortex used as control. C, Significant (p < 0.05, corrected) effects of APOE on the posterior DMN from the analysis restricted to hippocampal and amygdala areas. D, Significant (p < 0.05, corrected) effects of APOE on the posterior DMN from the full-brain analysis. Numbers correspond to the z value of each slice in 1 mm MNI-152 space. The effects extend into thalamic regions, posterior parts of hippocampus, lateral parts of the frontal lobe, the PCC, parietal cortex, and parahippocampal regions. All images are shown in radiological orientation, where the x value increases in left direction, y value increases in anterior direction, and z value increases in superior direction. All images were transformed from 4 to 1 mm space for visualization purposes.

Figure 2.

Total discriminability raw score plots as a function of hippocampal DMN synchronization. Red, Carriers; blue, noncarriers. The fit line illustrates the significant negative linear association (r = −0.32, p < 0.01, partialing out age and sex). When we removed the outlier (synchronization > 20), the relationship was weaker but still significant (r = −0.27, p < 0.01).