APOE-ε4-related differences in left thalamic microstructure in cognitively healthy adults

Abstract

APOE-ε4 is a main genetic risk factor for developing late onset Alzheimer's disease (LOAD) and is thought to interact adversely with other risk factors on the brain. However, evidence regarding the impact of APOE-ε4 on grey matter structure in asymptomatic individuals remains mixed. Much attention has been devoted to characterising APOE-ε4-related changes in the hippocampus, but LOAD pathology is known to spread through the whole of the Papez circuit including the limbic thalamus. Here, we tested the impact of APOE-ε4 and two other risk factors, a family history of dementia and obesity, on grey matter macro- and microstructure across the whole brain in 165 asymptomatic individuals (38-71 years). Microstructural properties of apparent neurite density and dispersion, free water, myelin and cell metabolism were assessed with Neurite Orientation Density and Dispersion (NODDI) and quantitative magnetization transfer (qMT) imaging. APOE-ε4 carriers relative to non-carriers had a lower macromolecular proton fraction (MPF) in the left thalamus. No risk effects were present for cortical thickness, subcortical volume, or NODDI indices. Reduced thalamic MPF may reflect inflammation-related tissue swelling and/or myelin loss in APOE-ε4. Future prospective studies should investigate the sensitivity and specificity of qMT-based MPF as a non-invasive biomarker for LOAD risk.

Figure 1

Violin plots with overlaid box plots of the difference in the macromolecular proton fraction (MPF) in the left thalamus between APOE-ε4 carriers (n = 57) and non-carriers (n = 97) (p_BHadj = 0.026). Boxplots display the median and the interquartile range and violin plots the kernel probability density, i.e. the width of the yellow area represents the proportion of the data located there.

Figure 2

displays the effects of sex on cortical thickness (CT), subcortical volume (corrected for intracranial volume), isotropic signal fraction (ISOSF) and macromolecular proton fraction (MPF) across 34 cortical regions per hemisphere parcellated with the Desikan–Killiany atlas and seven subcortical regions per hemisphere (hippocampus, amygdala, thalamus, caudate, putamen, globus pallidus, nucleus accumbens). Region of interest segmentations were performed with FreeSurfer (version 5.3). Regions are colour-coded according to effect sizes indicated by Cohen’s d. Warm colours indicate positive and blue colours negative correlations. L = Left, R = Right.

Figure 3

displays the effects of age on cortical thickness (CT), subcortical volume (corrected for intracranial volume), isotropic signal fraction (ISOSF) and orientation dispersion index (ODI) across 34 cortical regions per hemisphere parcellated with the Desikan–Killiany atlas and seven subcortical regions per hemisphere (hippocampus, amygdala, thalamus, caudate, putamen, globus pallidus, nucleus accumbens). Region of interest segmentations were performed with FreeSurfer (version 5.3). Regions are colour-coded according to the size of the age effect indicated by Pearson correlation coefficient r. Warm colours indicate positive and blue colours negative correlations.