Aberrant functional connectivity in Papez circuit correlates with memory performance in cognitively intact middle-aged APOE4 carriers

Abstract

The main objective of this study is to detect the early changes in resting-state Papez circuit functional connectivity using the hippocampus as the seed, and to determine the associations between altered functional connectivity (FC) and the episodic memory performance in cognitively intact middle-aged apolipoprotein E4 (APOE4) carriers who are at risk of Alzheimer's disease (AD). Forty-six cognitively intact, middle-aged participants, including 20 APOE4 carriers and 26 age-, sex-, and education-matched noncarriers were studied. The resting-state FC of the hippocampus (HFC) was compared between APOE4 carriers and noncarriers. APOE4 carriers showed significantly decreased FC in brain areas that involve learning and memory functions, including the frontal, cingulate, thalamus and basal ganglia regions. Multiple linear regression analysis showed significant correlations between HFC and the episodic memory performance. Conjunction analysis between neural correlates of memory and altered HFC showed the overlapping regions, especially the subcortical regions such as thalamus, caudate nucleus, and cingulate cortices involved in the Papez circuit. Thus, changes in connectivity in the Papez circuit may be used as an early risk detection for AD.

Keywords: APOE4; Alzheimer's disease; Apolipoprotein E ε4; Caudate nucleus; Hippocampus; Memory network; Papez circuit; Resting-state functional connectivity; Thalamus.

Copyright © 2014. Published by Elsevier Ltd.

Figures

Figure 1

A representative view of the hippocampus as the seed region from a subject. The seed was manually traced (red voxels) in the T1-weighted high-resolution anatomical image.

Figure 2

Patterns of the hippocampus functional connectivity (HFC) for APOE4 noncarriers (left) and carriers (right). Warm colors and cool colors indicate positive and negative functional connectivity, respectively. DLPFC: dorsal lateral prefrontal cortex, IPC: inferior parietal cortex, MTG: middle temporal gyrus, ACC: anterior cingulate cortex, PCC: posterior cingulate cortex, MeFG: medial frontal gyrus, PCL: paracentral lobule.

Figure 3

Patterns of decreased HFC in APOE4 carriers compared with noncarriers. Cool colors indicate decreased HFC in APOE4 carriers. DLPFC: dorsal lateral prefrontal cortex; MeFG: medial frontal gyrus; SFG: superior frontal gyrus, IFG: inferior frontal gyrus, ACC: anterior cingulate gyrus, PCC: posterior cingulate gyrus.

Figure 4

The neural correlates of RAVLT delayed recall scores. Brain regions with positive correlation are indicated by red arrows. Those with negative correlation are indicated by blue arrows. DLPFC: dorsal lateral prefrontal cortex, MeFG: medial frontal gyrus, ACC: anterior cingulate gyrus, SFG: superior frontal gyrus, MTG: middle temporal gyrus.

Figure 5

(A) Conjunction between the brain regions with HFC changes and the neural correlates of episodic memory function. (B) Numerical presentation of the overlapping brain regions (colored red) between the neural correlates of memory function and the decreased HFC. The m-value in the y-axis indicates the Fisher-transformed HFC and error bars indicate the standard deviations. (C) Representative correlations between HFC and the RAVLT-DR scores from the overlapping brain regions. APOE4-: APOE4 noncarriers, APOE4+: APOE4 carriers, DLPFC: dorsal lateral prefrontal cortex, ACC: anterior cingulate gyrus. RAVLT-DR: Rey auditory verbal learning test for delayed recall.