Brain network local interconnectivity loss in aging APOE-4 allele carriers - PubMed (original) (raw)

Brain network local interconnectivity loss in aging APOE-4 allele carriers

Jesse A Brown et al. Proc Natl Acad Sci U S A. 2011.

Abstract

Old age and possession of the APOE-4 allele are the two main risk factors for developing later onset Alzheimer's Disease (AD). Carriers of the APOE-4 allele have known differences in intrinsic functional brain network activity across the life span. These individuals also demonstrate specific regional differences in gray and white matter gross structure. However, the relationship of these variations to whole brain structural network connectivity remains unclear. We performed diffusion tensor imaging (DTI), T1 structural imaging, and cognitive testing on aging APOE-4 noncarriers (n = 30; mean age = 63.8±8.3) and APOE-4 carriers (n = 25; mean age = 60.8 ±9.7). Fiber tractography was used to derive whole brain structural graphs, and graph theory was applied to assess structural network properties. Network communication efficiency was determined for each network by quantifying local interconnectivity, global integration, and the balance between these, the small worldness. Relative to noncarriers, APOE-4 carriers demonstrated an accelerated age-related loss of mean local interconnectivity (r = -0.64, P ≤ 0.01) and regional local interconnectivity decreases in the precuneus (r = -0.64), medial orbitofrontal cortex (r = -0.5), and lateral parietal cortex (r = -0.54). APOE-4 carriers also showed significant age-related loss in mean cortical thickness (r = -0.52, P < 0.05). Cognitively, APOE-4 carriers had significant negative correlations of age and performance on two episodic memory tasks (P < 0.05). This genotype-specific pattern of structural connectivity change with age thus appears related to changes in gross cortical structure and cognition, potentially affecting the rate and/or spatial distribution of AD-related pathology.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest statement: The authors declare a conflict of interest. G.W.S. reports having served as a consultant and/or having received lecture fees from Dakim, Eisai, Forest, Medivation, Novartis, and Pfizer. G.W.S. also reports having received stock options from Dakim.

Figures

Fig. 1.

Fig. 1.

(A and B) Mean clustering coefficient (MCC) and mean cortical thickness (MCT) residuals based on partial correlations with age plotted for _APOE_-4 noncarriers (_APOE_-4 NC, open circles, dashed line) and _APOE_-4 carriers (solid circles, solid line). Partial correlations controlled for sex, scanner, and, in the MCC case only, total network cost. Both MCC and MCT had a significant interaction between APOE and genotype (P < 0.05).

Fig. 2.

Fig. 2.

(A) DTI average weighted network with node radius corresponding to value of negative correlation of age with clustering coefficient for _APOE_-4 carriers. The width of each edge in the graph corresponds to the average fiber density between those regions. Nodes colored in yellow have significant negative _APOE_-4 × age interactions for clustering coefficient (P < 0.05, FDR corrected), nodes colored in red indicate the same measure at an exploratory threshold (P < 0.005, uncorrected). (B) The same nodes from A displayed on an anatomical brain model. Node abbreviations: AC, anterior cingulate; FORB, frontal orbital cortex; ITGa, inferior temporal gyrus (anterior); ITGp, inferior temporal gyrus; PCNT, precentral gyrus; PCUN, precuneus (posterior); SMGp, supramarginal gyrus (posterior); and SUBC, subcallosal cortex (part of the ventromedial prefrontal cortex).

Similar articles

Cited by

References

    1. Naj AC, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet. 2011;43:436–441. - PMC - PubMed
    1. Corder EH, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261:921–923. - PubMed
    1. Mahley RW. Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science. 1988;240:622–630. - PubMed
    1. Bookheimer S, Burggren A. APOE-4 genotype and neurophysiological vulnerability to Alzheimer's and cognitive aging. Annu Rev Clin Psychol. 2009;5:343–362. - PMC - PubMed
    1. Caselli RJ, et al. Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele. Neurology. 2004;62:1990–1995. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources