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Disrupted topology of the resting state structural connectome in middle-aged APOE ?4 carriers.

ABSTRACT: The apolipoprotein E (APOE) ?4 allele is the best characterized genetic risk factor for Alzheimer's disease to date. Older APOE ?4 carriers (aged 60 + years) are known to have disrupted structural and functional connectivity, but less is known about APOE-associated network integrity in middle age. The goal of this study was to characterize APOE-related differences in network topology in middle age, as disentangling the early effects of healthy versus pathological aging may aid early detection of Alzheimer's disease and inform treatments. We performed resting state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) in healthy, cognitively normal, middle-aged adults (age 40-60; N?=?76, 38 APOE ?4 carriers). Graph theoretical analysis was used to calculate local and global efficiency of 1) a whole brain rs-fMRI network; 2) a whole brain DTI network; and 3) the resting state structural connectome (rsSC), an integrated functional-structural network derived using functional-by-structural hierarchical (FSH) mapping. Our results indicated no APOE ?4-associated differences in network topology of the rs-fMRI or DTI networks alone. However, ?4 carriers had significantly lower global and local efficiency of the integrated rsSC compared to non-carriers. Furthermore, ?4 carriers were less resilient to targeted node failure of the rsSC, which mimics the neuropathological process of Alzheimer's disease. Collectively, these findings suggest that integrating multiple neuroimaging modalities and employing graph theoretical analysis may reveal network-level vulnerabilities that may serve as biomarkers of age-related cognitive decline in middle age, decades before the onset of overt cognitive impairment.

SUBMITTER: Korthauer LE

PROVIDER: S-EPMC6249680 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Disrupted topology of the resting state structural connectome in middle-aged APOE ε4 carriers.

Korthauer L E LE Zhan L L Ajilore O O Leow A A Driscoll I I

NeuroImage 20180524

The apolipoprotein E (APOE) ε4 allele is the best characterized genetic risk factor for Alzheimer's disease to date. Older APOE ε4 carriers (aged 60 + years) are known to have disrupted structural and functional connectivity, but less is known about APOE-associated network integrity in middle age. The goal of this study was to characterize APOE-related differences in network topology in middle age, as disentangling the early effects of healthy versus pathological aging may aid early detection of ...[more]

PMID: 29803958

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Project description:BackgroundSubjective cognitive decline (SCD) is characterized by self-reported cognitive deficits without measurable cognitive impairment. It has been suggested that individuals with SCD exhibited brain structural alterations in widespread cortical thinning or gray matter loss in the medial temporal and frontotemporal regions. Apolipoprotein E (APOE) ε4 allele is thought to be a genetic marker associated with risk of SCD. Neuropsychiatric symptoms may provide insight in detecting higher-risk elders for early Alzheimer's disease as well. Therefore, we aim to explore the characteristics of brain morphology in SCD and to determine whether it is influenced by APOE ε4 as well as neuropsychiatric symptoms in SCD.MethodsA total of 138 cognitively normal older individuals from the SILCODE cohort underwent a clinical interview, neuropsychological assessments, a blood test, and MRI. A two-sample t-test was used to examine the cortex volume and bilateral cortical surface area alterations between SCD (n = 65) and controls (n = 73). A general linear model analysis was used to test for both main and interaction effects of clinical phenotype (SCD vs. controls) and APOE on global and regional cortex volume and bilateral cortical surface area and thickness. A multiple linear regression analysis was conducted to determine the effects of the APOE genotype on the relationships between morphometric features and neuropsychiatric symptoms in SCD.ResultsCompared with controls, individuals with SCD showed decreased total cortical volumes and cortical surface area. SCD APOE ε4 carriers showed additive reduction in the right cortical surface area. The evaluation scores of anxiety symptoms were negatively associated with the right cortical surface area in SCD APOE 4 non-carriers.ConclusionsIndividuals with SCD had an altered cortical surface area, and APOE genotype and anxiety symptoms are modified factors on the cortical surface area decrease in SCD.Trial registrationClinicalTrials.gov (Identifier: NCT03370744 ). Registered 15 March 2017.

Project description:PurposeTo determine whether the APOE-ε4 allele modulates the relationship between regional β-amyloid (Aβ) accumulation and cognitive change in middle-aged cognitively unimpaired (CU) participants.MethodsThe 352 CU participants (mean aged 61.1 [4.7] years) included completed two cognitive assessments (average interval 3.34 years), underwent [18F]flutemetamol Aβ positron emission tomography (PET), T1w magnetic resonance imaging (MRI), as well as APOE genotyping. Global and regional Aβ PET positivity was assessed across five regions-of-interest by visual reading (VR) and regional Centiloids. Linear regression models were developed to examine the interaction between regional and global Aβ PET positivity and APOE-ε4 status on longitudinal cognitive change assessed with the Preclinical Alzheimer's Cognitive Composite (PACC), episodic memory, and executive function, after controlling for age, sex, education, cognitive baseline scores, and hippocampal volume.ResultsIn total, 57 participants (16.2%) were VR+ of whom 41 (71.9%) were APOE-ε4 carriers. No significant APOE-ε4*global Aβ PET interactions were associated with cognitive change for any cognitive test. However, APOE-ε4 carriers who were VR+ in temporal areas (n = 19 [9.81%], p = 0.04) and in the striatum (n = 8 [4.14%], p = 0.01) exhibited a higher decline in the PACC. The temporal areas findings were replicated when regional PET positivity was determined with Centiloid values. Regionally, VR+ in the striatum was associated with higher memory decline. As for executive function, interactions between APOE-ε4 and regional VR+ were found in temporal and parietal regions, and in the striatum.ConclusionCU APOE-ε4 carriers with a positive Aβ PET VR in regions known to accumulate amyloid at later stages of the Alzheimer's disease (AD) continuum exhibited a steeper cognitive decline. This work supports the contention that regional VR of Aβ PET might convey prognostic information about future cognitive decline in individuals at higher risk of developing AD.Clinicaltrialsgov Identifier: NCT02485730. Registered 20 June 2015 https://clinicaltrials.gov/ct2/show/NCT02485730 and ClinicalTrials.gov Identifier:NCT02685969. Registered 19 February 2016 https://clinicaltrials.gov/ct2/show/NCT02685969 .

Dataset Information

Disrupted topology of the resting state structural connectome in middle-aged APOE ?4 carriers.

Publications

Disrupted topology of the resting state structural connectome in middle-aged APOE ε4 carriers.

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