Association of Alzheimer’s disease GWAS loci with default mode network

fan su¹

¹southeast university, nanjing, China, People's Republic of

Synopsis

To investigate the altered pattern of DMN in amnestic mild cognitive impairment (aMCI) subjects and the genetic factors that lead to the DMN dysfunctions, 87 individuals with aMCI and 131 matched healthy controls were recruited and an average 3-year follow-up study was performed. We studied the differences of DMN between aMCI subjects and healthy controls at baseline and how the DMN changed over time. Regression analyses were performed to explore whether the GRS influence the DMN dysfunctions. We observed that DMN disengage in the early stage of AD and the combined effect of AD-related loci influence the DMN pattern.

Introduction

Decreased resting state functional connectivity within the default mode network (DMN) has been frequently reported in patients with Alzheimer’s disease (AD), while recent studies have proven the DMN to be more heterogeneous than previously assumed. Several fractionations of DMN have been demonstrated and follow-up studies have suggested the functional connectivity within DMN fractionations changed differentially in AD patients and healthy controls. However, the altered pattern of DMN in amnestic mild cognitive impairment (aMCI) subjects is not well understood. Further, the genetic factors that lead to the DMN dysfunctions are ill-defined.

Methods

87 individuals with aMCI and 131 matched healthy controls were recruited. They underwent resting state functional magnetic resonance imaging (fMRI) and they had the genetic risk scores (GRS) based on the 11 genome-wide association studies-promising loci. An average 3-year follow-up study was performed. We studied the differences of DMN between aMCI subjects and healthy controls at baseline and how the DMN changed over time. Regression analyses were performed to explore whether the GRS influence the DMN dysfunctions.

Results

At baseline, decreased functional connectivity in aMCI subjects versus controls was observed in right precuneus, left hippocampus, left parahippocampa, right frontal lobe and right cerebellum and increased functional connectivity were observed in left medial frontal gyrus and left supper parietal lobe. In the longitudinal study, the aMCI subjects showed differential functional connectivity changes compared to the healthy controls. Further, the regression analysis suggested that aMCI subjects with higher GRS showed increased functional connectivity change in left supper parietal lobe (β=0.667, P<0.001). Additionally, the increase of functional connectivity in left supper parietal lobe were positively related to the impairments of episodic memory (Logical memory test-20min delayed recall scores, r = 0.433, P = 0.007) the aMCI group.

Conclusions

The DMN disengage in the early stage of AD and the combined effect of AD-related loci influence the DMN pattern.

Acknowledgements

No acknowledgement found.

References

No reference found.

Figures

Figure 1. Validation of the seed-based functional connectivity analysis in aMCI subjects and healthy controls. The PCC cortical hub [coordinate in the MNI space: −2, −45, 34] was selected to generate a 6-mm radius spherical seed region. Thresholds were set at a corrected P<0.05, determined by Monte Carlo simulation.

Figure 2. Functional connectivity difference maps of aMCI subjects versus healthy controls at baseline in DMN. In aMCI subjects, functional connectivity in left medial frontal gyrus and left supper parietal lobe is increased and functional connectivity in bilateral precuneus, left hippocampus, left parahippocampa, right frontal lobe and right cerebellum is decreased (only visible for a few voxels here). Thresholds were set at a corrected P<0.05, determined by Monte Carlo simulation.

Figure 3. Differential longitudinal functional connectivity changes of regions in which aMCI subjects showed significantly different functional connectivity compared with healthy controls at baseline. Data represent the mean±SE.

Figure 4. (A) aMCI subjects with higher GRS showed increased functional connectivity change in left supper parietal lobe (β=0.667, P<0.001).(B) The increase of functional connectivity in left supper parietal lobe were positively related to the impairments of episodic memory (Logical memory test-20min delayed recall scores, r = 0.433, P = 0.007).

Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)

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