Dataset Information

Oscillatory hyperactivity and hyperconnectivity in young APOE-?4 carriers and hypoconnectivity in Alzheimer's disease.

ABSTRACT: We studied resting-state oscillatory connectivity using magnetoencephalography in healthy young humans (N = 183) genotyped for APOE-?4, the greatest genetic risk for Alzheimer's disease (AD). Connectivity across frequencies, but most prevalent in alpha/beta, was increased in APOE-?4 in a set of mostly right-hemisphere connections, including lateral parietal and precuneus regions of the Default Mode Network. Similar regions also demonstrated hyperactivity, but only in gamma (40-160 Hz). In a separate study of AD patients, hypoconnectivity was seen in an extended bilateral network that partially overlapped with the hyperconnected regions seen in young APOE-?4 carriers. Using machine-learning, AD patients could be distinguished from elderly controls with reasonable sensitivity and specificity, while young APOE-e4 carriers could also be distinguished from their controls with above chance performance. These results support theories of initial hyperconnectivity driving eventual profound disconnection in AD and suggest that this is present decades before the onset of AD symptomology.

SUBMITTER: Koelewijn L

PROVIDER: S-EPMC6491037 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Oscillatory hyperactivity and hyperconnectivity in young <i>APOE</i>-ɛ4 carriers and hypoconnectivity in Alzheimer's disease.

Koelewijn Loes L Lancaster Thomas M TM Linden David D Dima Diana C DC Routley Bethany C BC Magazzini Lorenzo L Barawi Kali K Brindley Lisa L Adams Rachael R Tansey Katherine E KE Bompas Aline A Tales Andrea A Bayer Antony A Singh Krish K

eLife 20190430

We studied resting-state oscillatory connectivity using magnetoencephalography in healthy young humans (N = 183) genotyped for APOE-ɛ4, the greatest genetic risk for Alzheimer's disease (AD). Connectivity across frequencies, but most prevalent in alpha/beta, was increased in APOE-ɛ4 in a set of mostly right-hemisphere connections, including lateral parietal and precuneus regions of the Default Mode Network. Similar regions also demonstrated hyperactivity, but only in gamma (40-160 Hz). In a sepa ...[more]

PMID: 31038453

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Project description:APOE ε4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and accounts for 50-65% of late-onset AD. Late-onset AD patients carrying or not carrying APOE ε4 manifest many clinico-pathological distinctions. Thus, we applied a weighted gene co-expression network analysis to identify specific co-expression modules in AD based on APOE ε4 stratification. Two specific modules were identified in AD APOE ε4 carriers and one module was identified in non-carriers. The hub genes of one module of AD APOE ε4 carriers were ISOC1, ENO3, GDF10, GNB3, XPO4, ACLY and MATN2. The other module of AD APOE ε4 carriers consisted of 10 hub genes including ANO3, ARPP21, HPCA, RASD2, PCP4 and ADORA2A. The module of AD APOE ε4 non-carriers consisted of 16 hub genes including DUSP5, TNFRSF18, ZNF331, DNAJB5 and RIN1. The module of AD APOE ε4 carriers including ISOC1 and ENO3 and the module of non-carriers contained the most highly connected hub gene clusters. mRNA expression of the genes in the cluster of the ISOC1 and ENO3 module of carriers was shown to be correlated in a time-dependent manner under APOE ε4 treatment but not under APOE ε3 treatment. In contrast, mRNA expression of the genes in the cluster of non-carriers' module was correlated under APOE ε3 treatment but not under APOE ε4 treatment. The modules of carriers demonstrated genetic bases and were mainly enriched in hereditary disorders and neurological diseases, energy metabolism-associated signaling and G protein-coupled receptor-associated pathways. The module including ISOC1 and ENO3 harbored two conserved promoter motifs in its hub gene cluster that could be regulated by common transcription factors and miRNAs. The module of non-carriers was mainly enriched in neurological, immunological and cardiovascular diseases and was correlated with Parkinson's disease. These data demonstrate that AD in APOE ε4 carriers involves more genetic factors and particular biological processes, whereas AD in APOE ε4 non-carriers shares more common pathways with other types of diseases. The study reveals differential genetic bases and pathogenic and pathological processes between carriers and non-carriers, providing new insight into the mechanisms of the differences between APOE ε4 carriers and non-carriers in AD.

Dataset Information

Oscillatory hyperactivity and hyperconnectivity in young APOE-?4 carriers and hypoconnectivity in Alzheimer's disease.

Publications

Oscillatory hyperactivity and hyperconnectivity in young <i>APOE</i>-ɛ4 carriers and hypoconnectivity in Alzheimer's disease.

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