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bioRxiv · 10.1101/2021.05.12.443879

Evidence against altered excitatory/inhibitory balance in the posteromedial cortex of young adult APOE E4 carriers: a resting state 1H-MRS study

Costigan, A. G.·Umla-Runge, K.·Evans, C. J.·Raybould, R.·Graham, K. S.·Lawrence, A. D.
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Abstract

A strategy to gain insight into early changes that may predispose people to Alzheimers disease is to study the brains of younger cognitively healthy people that are at increased genetic risk of AD. The Apolipoprotein (APOE) E4 allele is the strongest genetic risk factor for AD, and several neuroimaging studies comparing APOE E4 carriers with non-carriers at age ~20-30 have detected hyperactivity (or reduced deactivation) in posteromedial cortex (PMC), a key hub of the default network (DN) which has a high susceptibility to early amyloid deposition in AD. Transgenic mouse models suggest such early network activity alterations may result from altered excitatory/inhibitory (E/I) balance, but this is yet to be examined in humans. Here we test the hypothesis that PMC fMRI hyperactivity could be underpinned by altered levels of excitatory (glutamate) and/or inhibitory (GABA) neurotransmitters in this brain region. Forty-seven participants (20 APOE E4 carriers and 27 non-carriers) aged 18-25 underwent resting-state proton magnetic resonance spectroscopy (1H-MRS), a non-invasive neuroimaging technique to measure glutamate and GABA in vivo. Metabolites were measured in a PMC voxel of interest and in a comparison voxel in the occipital cortex (OCC). There was no difference in either glutamate or GABA between the E4 carriers and non-carriers in either MRS voxel, nor in the ratio of glutamate to GABA, a measure of E/I balance. Default Bayesian t-tests revealed evidence in support of this null finding. Results suggest that PMC hyperactivity in APOE E4 carriers is unlikely to be associated with, or indeed may precede, alterations in local resting-state PMC neurotransmitters, thus informing the spatio-temporal order and the cause/effect dynamic of neuroimaging differences in APOE E4 carriers. HighlightsO_LIHyperactivity in posteromedial (PM) network in people at AD genetic risk (APOE E4) C_LIO_LISuch PM network hyperactivity may initiate pathogenic cascade that triggers AD C_LIO_LIAPOE mouse models suggest hyperactivity driven by excitatory/inhibitory imbalance C_LIO_LIUsing 1H-MRS at 3T we studied PMC E/I balance in young adult APOE E4 carriers C_LIO_LIFound evidence against altered E/I balance in young adult APOE E4 carriers C_LI

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Costigan, A. G., Umla-Runge, K., Evans, C. J., Raybould, R., Graham, K. S., Lawrence, A. D.. 2021-05-14. Evidence against altered excitatory/inhibitory balance in the posteromedial cortex of young adult APOE E4 carriers: a resting state 1H-MRS study. https://doi.org/10.1101/2021.05.12.443879

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