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

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

doi:10.1016/j.ynirp.2021.100059

A.G Costigan, K Umla-Runge + Show 4 more

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https://doi.org/10.1016/j.ynirp.2021.100059

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Abstract

A strategy to gain insight into early changes that may predispose people to Alzheimer's disease (AD) 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 years 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 years 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, or 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. Our findings suggest that PMC hyperactivity in APOE E4 carriers is unlikely to be associated with, or possibly may precede, alterations in local resting-state PMC neurotransmitters, thus informing our understanding of the spatio-temporal sequence of early network alterations underlying APOE E4 related AD risk.

Highlights

The Apolipoprotein (APOE) E4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease (AD), where possession of one E4 allele increases risk of AD by ~3–4 times, and two alleles by ~12–14 times compared to the AD-neutral E3/E3 genotype (Belloy et al, 2019; Farrer et al, 1997)
We predicted APOE E4 carriers would show lower posteromedial cortex (PMC) GABA+ and/or higher Glx and Glx/GABA+ ratio than noncarriers, resulting in altered E/I balance favouring excitation. This was based on converging lines of evidence: previous Functional magnetic resonance imaging (fMRI) studies of young adult APOE E4 carriers showing PMC hyperactivation/reduced deacti vation (Filippini et al, 2009; Persson et al, 2008; Shine et al, 2015; but see Mentink et al, 2021); fMRI-1H-MRS findings that levels of task-related PMC deactivation are related to local resting Glx and GABA+ concentrations and resultant E/I balance (Gu et al, 2019; Hu et al, 2013); and circuit-based models of AD, based on studies of transgenic AD mice, which suggest that early hyperactivity is linked to
This study provides evidence against differences in PMC Glx, GABA+ and E/I balance in young adult APOE E4 carriers versus non-carriers

Summary

Introduction

The Apolipoprotein (APOE) E4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease (AD), where possession of one E4 allele increases risk of AD by ~3–4 times, and two alleles by ~12–14 times compared to the AD-neutral E3/E3 genotype (Belloy et al, 2019; Farrer et al, 1997). There is a growing consensus that AD-related brain changes and pathology occur decades before the onset of symptoms (Jack et al, 2018; Jagust, 2018; Masters et al, 2015; Sperling et al, 2014). The posteromedial cortex (PMC) is a key region of interest for such studies in young people at increased AD genetic risk. The PMC is susceptible to early amyloid (Aβ) plaque deposition, one of the hallmark pathologic features of AD (Buckner et al, 2005; Maass et al, 2019; Palmqvist et al, 2017), with APOE E4 allele carriers having both a younger age of onset and faster rates of PMC amyloid deposition relative to non-carriers (Burnham et al, 2020; Mishra et al, 2018). The cause of early Aβ aggregation within PMC is currently unknown, but may reflect a lifespan regional vulnerability (Buckner et al, 2005; Sepulcre et al, 2018)

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