Increased posterior default mode network activity and structural connectivity in young adult APOE-ε4 carriers: a multimodal imaging investigation

Abstract

Young adult APOE-ε4 carriers show increased activity in posterior regions of the default mode network (pDMN), but how this is related to structural connectivity is unknown. Thirty young adults (one half of whom were APOE-ε4 carriers; mean age 20 years) were scanned using both diffusion and functional magnetic resonance imaging. The parahippocampal cingulum bundle (PHCB)-which links the pDMN and the medial temporal lobe-was manually delineated in individual participants using deterministic tractography. Measures of tract microstructure (mean diffusivity and fractional anisotropy) were then extracted from these tract delineations. APOE-ε4 carriers had lower mean diffusivity and higher fractional anisotropy relative to noncarriers in PHCB, but not in a control tract (the inferior longitudinal fasciculus). Furthermore, PHCB microstructure was selectively associated with pDMN (and medial temporal lobe) activity during a scene discrimination task known to be sensitive to Alzheimer's disease. These findings are consistent with a lifespan view of Alzheimer's disease risk, where early-life, connectivity-related changes in specific, vulnerable "hubs" (e.g., pDMN) lead to increased neural activity. Critically, such changes may reflect reduced network efficiency/flexibility in APOE-ε4 carriers, which in itself may portend a faster decline in connectivity over the lifespan and ultimately trigger early amyloid-β deposition in later life.

Keywords: Alzheimer's disease; Default mode network; Diffusion MRI; Medial temporal lobe; Scene processing.

Fig. 1

Comparing PHCB tissue microstructure between APOE-ε4 carriers and noncarriers. (A) Left: Deterministic tractography was conducted in each participant, and free water–corrected indices of bilateral PHCB microstructure (MD, FA) were extracted. Right: To examine associations with functional activity, these metrics were correlated with BOLD activity from an independently defined pDMN functional ROI during a perceptual discrimination task (Shine et al., 2015). Example scene trials for the perceptual “odd-one-out” discrimination task are shown. (B) Plots comparing mean bilateral PHCB MD and FA for APOE-ε4 carriers and noncarriers. Individual data points are displayed jittered on each bar. (C) Scatter plots showing the association between scene (vs. “size” baseline) activity in the pDMN and MD (left) and FA (right) in the PHCB. A total of 25 data points are shown on each scatter plot (13 carriers, blue markers; 12 noncarriers, orange markers; see Section 3.4). Abbreviations: BOLD, blood-oxygen level dependent; FA, fractional anisotropy; MD, mean diffusivity; PHCB, parahippocampal cingulum bundle; pDMN, posterior default mode network; ROI, region of interest. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Comparing parahippocampal cingulum bundle (PHCB) microstructure in APOE-ε4 carriers and noncarriers using TBSS. (A) A significant cluster (shown in green) was found showing greater FA in APOE-ε4 carriers versus noncarriers in the posterior PHCB (p < 0.05, TFCE-corrected). (B) A subthreshold cluster (shown in red-yellow) reflecting lower MD in APOE-ε4 carriers versus noncarriers was identified in the posterior PHCB (p < 0.005, uncorrected). For visualization purposes, clusters have been “thickened” using “TBSS fill” in FSL. There were no voxelwise differences for MD that survived stringent correction. Abbreviations: FA, fractional anisotropy; MD, mean diffusivity; PHCB, parahippocampal cingulum bundle; TBSS, tract-based spatial statistics. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Correlations between scene activity in the medial temporal lobe and parahippocampal cingulum bundle (PHCB) microstructure. Scatter plots showing the association between PHCB mean diffusivity and scene (vs. “size” baseline) activity in the (A) posterior parahippocampal gyrus (PHG, green markers) and (B) hippocampus (blue markers). A total of 25 data points are shown on each scatter plot (13 carriers, dark markers; 12 noncarriers, light markers; see Section 3.5).