Shared effects of the clusterin gene on the default mode network among individuals at risk for Alzheimer's disease

Abstract

Aims: To explore the common effects of the clusterin (CLU) rs11136000 variant on the default mode network (DMN) in amnestic mild cognitive impairment (aMCI) subjects and remitted geriatric depression (RGD) subjects.

Methods: Fifty-one aMCI subjects, 38 RGD subjects, and 64 cognitively normal elderly subjects underwent resting-state fMRI scans and neuropsychological tests at both baseline and a 35-month follow-up. Posterior cingulate cortex seed-based functional connectivity (FC) analysis was used to obtain the DMN patterns.

Results: A CLU gene×disease×time interaction for aMCI subjects was mainly detected in the core cortical midline structures of the DMN, and the interaction for RGD subjects was mainly detected in the limbic system. However, they overlapped in two frontal regions, where consistent effects of the CLU gene on FC alterations were found between aMCI and RGD groups. Furthermore, the alterations of FC with frontal, parietal, and limbic regions compensated for episodic memory impairments in CLU-CT/TT carriers, while no such compensation was found in CLU-CC carriers.

Conclusion: The CLU gene could consistently affect the DMN FC with frontal regions among individuals at risk for Alzheimer's disease, and the CLU-T allele was associated with more compensatory neural processes in DMN changes.

Keywords: Alzheimer's disease; clusterin; default mode network; geriatric depression; mild cognitive impairment.

Figure 1

CLU gene×disease×time interaction on the DMN. (A) The CLU gene×disease×time interaction in aMCI subjects and control subjects. (B) The CLU gene×disease×time interaction in RGD subjects and control subjects. (C) The overlaps between the interactive regions in aMCI subjects and in RGD subjects. The thresholds were set at a corrected P<.05 determined by Monte Carlo simulation for multiple comparisons. L, left; R, right

Figure 2

Post hoc tests and correlative analyses performed in overlapping regions. (A) In the left middle frontal gyrus, CLU‐CC carriers in both the aMCI group and the RGD group displayed longitudinally increased FC. (B) In the left medial orbital frontal gyrus, CLU‐CT/TT carriers in both the aMCI group and the RGD group displayed longitudinal decrease trends of FC. (C) For control CLU‐CT/TT subgroup, greater increase of FC with the left middle frontal gyrus was associated with less decline in episodic memory scores (r=.420, P=.046, two‐tailed). (D) For the aMCI CLU‐CT/TT subgroup, greater decrease of FC with the left medial orbital frontal gyrus was associated with less decline in episodic memory scores (r=−.650, P=.030, two‐tailed). * P<.05. DMN, default mode network; FC, functional connectivity