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. 2020 Feb 7;12(1):e12002.
doi: 10.1002/dad2.12002. eCollection 2020.

APOE4 moderates effects of cortical iron on synchronized default mode network activity in cognitively healthy old-aged adults

Sonja M Kagerer  1   2 , Jiri M G van Bergen  1 , Xu Li  3   4 , Frances C Quevenco  1 , Anton F Gietl  1   2 , Sandro Studer  1 , Valerie Treyer  1   5 , Rafael Meyer  1   2 , Philipp A Kaufmann  5 , Roger M Nitsch  1   6   7 , Peter C M van Zijl  3   4 , Christoph Hock  1   6   7 , Paul G Unschuld  1   2   6
Affiliations

APOE4 moderates effects of cortical iron on synchronized default mode network activity in cognitively healthy old-aged adults

Sonja M Kagerer et al. Alzheimers Dement (Amst). .

Abstract

Introduction: Apolipoprotein E ε4 (APOE4)-related genetic risk for sporadic Alzheimer's disease is associated with an early impairment of cognitive brain networks. The current study determines relationships between APOE4 carrier status, cortical iron, and cortical network-functionality.

Methods: Sixty-nine cognitively healthy old-aged individuals (mean age [SD] 66.1 [± 7.2] years; Mini-Mental State Exam [MMSE] 29.3 ± 1.1) were genotyped for APOE4 carrier-status and received 3 Tesla magnetic resonance imaging (MRI) for blood oxygen level-dependent functional magnetic resonance imaging (MRI) at rest, three-dimensional (3D)-gradient echo (six echoes) for cortical gray-matter, non-heme iron by quantitative susceptibility mapping, and 18F-flutemetamol positron emission tomography for amyloid-β.

Results: A spatial pattern consistent with the default mode network (DMN) could be identified by independent component analysis. DMN activity was enhanced in APOE4 carriers and related to cortical iron burden. APOE4 and cortical iron synergistically interacted with DMN activity. Secondary analysis revealed a positive, APOE4 associated, relationship between cortical iron and DMN connectivity.

Discussion: Our findings suggest that APOE4 moderates effects of iron on brain functionality prior to manifestation of cognitive impairment.

Keywords: APOE4; DMN; ICA; MRI; PET; QSM; fMRI; flutemetamol; gradient echo; iron; preclinical Alzheimer's disease.

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Figures

Figure 1
Figure 1
Identification of resting‐state networks by independent component analysis (ICA) of blood oxygen level–dependent (BOLD) time course synchronicity at rest. Using ICA, 20 independent components could be identified, representing distinct BOLD time course synchronicity patterns at rest. Heat maps represent factor loading by voxel for each spatial component, estimated by group ICA (color bar: lowest, blue = −3; maximum, red = +7, horizontal lines in the green area = 0)
Figure 2
Figure 2
Spatial definition of the default mode network (DMN) based on blood oxygen level–dependent (BOLD) time course synchronicity within independent component 3. Indicated are axial slices indicating brain regions included by component 3. Significance levels of voxel‐level BOLD synchronicity are color coded (T‐map, highest values are yellow)
Figure 3
Figure 3
Effect of APOE4 carrier status on default mode network (DMN) activity. DMN activity, as indicated by synchronicity of blood oxygen level–dependent (BOLD) time courses, is associated with APOE4 carrier status (F‐map, highest values are yellow)
Figure 4
Figure 4
Effect of cortical iron burden on default mode network (DMN) activity. DMN activity is increased in study participants with high cortical iron (estimated by QSM) (F‐map, highest values are yellow)
Figure 5
Figure 5
(A) Synergistic interactions between APOE4 carrier status and cortical iron on default mode network (DMN) activity. Colors indicate local effect sizes, as generated by second level, one‐way analysis of covariance (ANCOVA) interaction analysis (T‐map, highest values are yellow). (B) DMN activity in APOE4 carriers relates to cortical iron burden. DMN activity is increased in APOE4 carriers with high cortical iron, as indicated by regression (F‐map, highest values are yellow)
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