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. 2024:43:103635.
doi: 10.1016/j.nicl.2024.103635. Epub 2024 Jun 24.

Functional network centrality indicates interactions between APOE4 and age across the clinical spectrum of Alzheimer's Disease

Aïda B Fall  1 , Maria Giulia Preti  2 , Mohamed Eshmawey  3 , Sonja M Kagerer  4 , Dimitri Van De Ville  2 , Paul G Unschuld  5 ; Alzheimer’s Disease Neuroimaging Initiative
Affiliations

Functional network centrality indicates interactions between APOE4 and age across the clinical spectrum of Alzheimer's Disease

Aïda B Fall et al. Neuroimage Clin. 2024.

Abstract

Advanced age is the most important risk factor for Alzheimer's disease (AD), and carrier-status of the Apolipoprotein E4 (APOE4) allele is the strongest known genetic risk factor. Many studies have consistently shown a link between APOE4 and synaptic dysfunction, possibly reflecting pathologically accelerated biological aging in persons at risk for AD. To test the hypothesis that distinct functional connectivity patterns characterize APOE4 carriers across the clinical spectrum of AD, we investigated 128 resting state functional Magnetic Resonance Imaging (fMRI) datasets from the Alzheimer's Disease Neuroimaging Initiative database (ADNI), representing all disease stages from cognitive normal to clinical dementia. Brain region centralities within functional networks, computed as eigenvector centrality, were tested for multivariate associations with chronological age, APOE4 carrier status and clinical stage (as well as their interactions) by partial least square analysis (PLSC). By PLSC analysis two distinct brain activity patterns could be identified, which reflected interactive effects of age, APOE4 and clinical disease stage. A first component including sensorimotor regions and parietal regions correlated with age and AD clinical stage (p < 0.001). A second component focused on medial-frontal regions and was specifically related to the interaction between age and APOE4 (p = 0.032). Our findings are consistent with earlier reports on altered network connectivity in APOE4 carriers. Results of our study highlight promise of graph-theory based network centrality to identify brain connectivity linked to genetic risk, clinical stage and age. Our data suggest the existence of brain network activity patterns that characterize APOE4 carriers across clinical stages of AD.

Keywords: Alzheimer’s disease; Apolipoprotein E4; Brain age; Eigenvector centrality; Functional connectivity; Genetics.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Brain plot representing the first PLS brain salience pattern of correlation driven by age, the presence of APOE4 and cognitive symptoms. We can observe a decreased centrality in the somatomotor and ventral attention networks (blue) and an increased centrality in the left inferior parietal area (orange) correlated with age, the presence of APOE4 and cognitive symptoms. The values are bootstrap ratios thresholded at the absolute value of 2, corresponding to a 95% confidence interval. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 2
Fig. 2
Bar plot representing the behavioral saliences of the first PLS component, indicating significant contribution of age, the presence of APOE4 and cognitive symptoms, as well as the interaction between age and symptoms, to the brain-behavior correlation. The bars correspond to the confidence interval 95%.
Fig. 3
Fig. 3
Brain plot representing the second PLS brain salience pattern of correlation driven by APOE4 and its interaction with age. We can observe an increased centrality in the frontal lobes (light orange) and a decreased centrality in the left posterior opercular as well as the right insular and frontal opercular (light blue) that is correlated with age and the presence of APOE4. The values are z-scored and thresholded at a bootstrap ratio of 2. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 4
Fig. 4
Bar plot representing the PLS behavioral salience, capturing multivariate correlation between APOE4, age-APOE4 interaction and the eigenvector centrality in the brain salience pattern shown in Fig. 3. The bars correspond to the confidence interval 95 %.
Fig. 5
Fig. 5
Aging score for the first PLS component projected on chronological age and colored by APOE4 carrier status and cognitive symptoms index. We observed an effect of both the presence of cognitive symptoms and APOE4, more pronounced for the presence of cognitive symptoms. B) Aging score for the second PLS component projected on chronological age and colored by APOE4 carrier status and by cognitive symptoms index. We observed an effect of both the presence of cognitive symptoms and APOE4, but much more pronounced for the presence of APOE4, in fact there is a clear opposition between having or not the genetic risk factor for Alzheimer’s disease.
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