Dataset Information

Apolipoprotein E4 effects on topological brain network organization in mild cognitive impairment.

ABSTRACT: The Apolipoprotein E isoform E4 (ApoE4) is consistently associated with an elevated risk of developing late-onset Alzheimer's Disease (AD); however, less is known about the potential genetic modulation of the brain networks organization during prodromal stages like Mild Cognitive Impairment (MCI). To investigate this issue during this critical stage, we used a dataset with a cross-sectional sample of 253 MCI patients divided into ApoE4-positive (?Carriers') and ApoE4-negative ('non-Carriers'). We estimated the cortical thickness (CT) from high-resolution T1-weighted structural magnetic images to calculate the correlation among anatomical regions across subjects and build the CT covariance networks (CT-Nets). The topological properties of CT-Nets were described through the graph theory approach. Specifically, our results showed a significant decrease in characteristic path length, clustering-index, local efficiency, global connectivity, modularity, and increased global efficiency for Carriers compared to non-Carriers. Overall, we found that ApoE4 in MCI shaped the topological organization of CT-Nets. Our results suggest that in the MCI stage, the ApoE4 disrupting the CT correlation between regions may be due to adaptive mechanisms to sustain the information transmission across distant brain regions to maintain the cognitive and behavioral abilities before the occurrence of the most severe symptoms.

SUBMITTER: Sanabria-Diaz G

PROVIDER: S-EPMC7804004 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Apolipoprotein E4 effects on topological brain network organization in mild cognitive impairment.

Sanabria-Diaz Gretel G Melie-Garcia Lester L Draganski Bogdan B Demonet Jean-Francois JF Kherif Ferath F

Scientific reports 20210112 1

The Apolipoprotein E isoform E4 (ApoE4) is consistently associated with an elevated risk of developing late-onset Alzheimer's Disease (AD); however, less is known about the potential genetic modulation of the brain networks organization during prodromal stages like Mild Cognitive Impairment (MCI). To investigate this issue during this critical stage, we used a dataset with a cross-sectional sample of 253 MCI patients divided into ApoE4-positive (‛Carriers') and ApoE4-negative ('non-Carriers'). W ...[more]

PMID: 33436948

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Project description:BACKGROUND:Apolipoprotein E (APOE) ?4 allele is a major genetic risk factor for Alzheimer disease and mild cognitive impairment (MCI). Computer-based training programs can improve cognitive performance in elderly populations. However, the effects of computer-based interventions on MCI APOE ?4 carriers have never been studied before. OBJECTIVE:The effects of different web-based interventions and the APOE isoform-specific differences in training outcomes are investigated. METHODS:Using a quasi-experimental study design, 202 participants with MCI aged 60 years and older took part in three different intervention programs (physical and cognitive [Long-Lasting Memories, or LLM], cognitive [Active Control, or AC], or physical intervention [Physical Training Control, or PTC]) via an innovative information and communication technologies exergaming platform. Participants in each interventional group were subdivided into APOE ?4 carriers and non-APOE ?4 carriers. All participants underwent an extensive neuropsychological evaluation before and after the training, blood tests, and brain imaging. RESULTS:All interventions resulted in multiple statistically significant cognitive benefits after the intervention. Verbal learning (California Verbal Learning Test: immediate recall test score-LLM: P=.04; AC: P<.001), working memory (digit span forward and backward test scores-AC: P=.03; PTC: P=.02 and P=.006, respectively), and long-term memory (California Verbal Learning Test: delayed recall test score-LLM: P=.02; AC: P=.002; and PTC: P=.02) were improved. There was no statistically significant difference among the intervention effects. APOE ?4 presence moderates intervention effects as the LLM intervention improved only their task-switching processing speed (Trail Making Test, Part B: P=.03) and the PTC intervention improved only the working memory (digit span backward: P=.03). No significant performance alteration was noted for the APOE ?4+ cognitive AC training group. CONCLUSIONS:None of the applied interventions could be identified as the optimal one; it is suggested, however, that combined cognitive and physical training and physical training via exergaming may be more effective for the high-risk MCI ?POE ?4+ subgroup.

Project description:In addition to being the greatest genetic risk factor for Alzheimer's disease, expression of the ?4 allele of apolipoprotein E can lead to cognitive decline during ageing that is independent of Alzheimer's amyloid-? and tau pathology. In human post-mortem tissue and mouse models humanized for apolipoprotein E, we examined the impact of apolipoprotein E4 expression on brain exosomes, vesicles that are produced within and secreted from late-endocytic multivesicular bodies. Compared to humans or mice homozygous for the risk-neutral ?3 allele we show that the ?4 allele, whether homozygous or heterozygous with an ?3 allele, drives lower exosome levels in the brain extracellular space. In mice, we show that the apolipoprotein E4-driven change in brain exosome levels is age-dependent: while not present at age 6 months, it is detectable at 12 months of age. Expression levels of the exosome pathway regulators tumor susceptibility gene 101 (TSG101) and Ras-related protein Rab35 (RAB35) were found to be reduced in the brain at the protein and mRNA levels, arguing that apolipoprotein E4 genotype leads to a downregulation of exosome biosynthesis and release. Compromised exosome production is likely to have adverse effects, including diminishing a cell's ability to eliminate materials from the endosomal-lysosomal system. This reduction in brain exosome levels in 12-month-old apolipoprotein E4 mice occurs earlier than our previously reported brain endosomal pathway changes, arguing that an apolipoprotein E4-driven failure in exosome production plays a primary role in endosomal and lysosomal deficits that occur in apolipoprotein E4 mouse and human brains. Disruption of these interdependent endosomal-exosomal-lysosomal systems in apolipoprotein E4-expressing individuals may contribute to amyloidogenic amyloid-? precursor protein processing, compromise trophic signalling and synaptic function, and interfere with a neuron's ability to degrade material, all of which are events that lead to neuronal vulnerability and higher risk of Alzheimer's disease development. Together, these data suggest that exosome pathway dysfunction is a previously unappreciated component of the brain pathologies that occur as a result of apolipoprotein E4 expression.

Dataset Information

Apolipoprotein E4 effects on topological brain network organization in mild cognitive impairment.

Publications

Apolipoprotein E4 effects on topological brain network organization in mild cognitive impairment.

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