Association Between Hippocampus, Thalamus, and Caudate in Mild Cognitive Impairment APOEε4 Carriers: A Structural Covariance MRI Study

Objective: Although, the apolipoprotein E (APOE) genotype is widely recognized as one of the most important risk factors for Alzheimer's disease (AD) development, the neural mechanisms by which the epsilon 4 allele promotes the AD occurring remain under debate. The aim of this study was to evaluate neurobiological effects of the APOE-genotype on the pattern of the structural covariance in mild cognitive impairment (MCI) subjects. Methods: We enrolled 95 MCI subjects and 49 healthy controls. According to APOE-genotype, MCI subjects were divided into three groups: APOE epsilon 4 non-carriers (MCI epsilon 4-/-, n = 55), APOE epsilon 4 heterozygous carriers (MCI epsilon 4+/-, n = 31), and APOE epsilon 4 homozygous carriers (MCI epsilon 4+/+, n = 9) while all controls were APOE epsilon 4 non-carriers. In order to explore their brain structural pattern, T1-weighted anatomical brain 1.5-T MRI scans were collected. A whole-brain voxel-based morphometry analysis was performed, and all significant regions (p < 0.05 family-wise error, whole brain) were selected as a region of interest for the structural covariance analysis. Moreover, in order to evaluate the progression of the disease, a clinical follow-up was performed for 2 years. Results: The F-test showed in voxel-based morphometry analysis a strong overall difference among the groups in the middle frontal and temporal gyri and in the bilateral hippocampi, thalami, and parahippocampal gyri, with a grading in the atrophy in these latter three structures according to the following order: MCI epsilon 4+/+ > MCI epsilon 4+/- > MCI epsilon 4-/- > controls. Structural covariance analysis revealed a strong structural association between the left thalamus and the left caudate and between the right hippocampus and the left caudate (p < 0.05 family-wise error, whole brain) in the MCI epsilon 4 carrier groups (MCI epsilon 4+/+ > MCI epsilon 4+/-), whereas no significant associations were observed in MCI epsilon 4-/- subjects. Of note, the 38% of MCIs enrolled in this study developed AD within 2 years of follow-up. Conclusion: This study improves the knowledge on neurobiological effect of APOE epsilon 4 in early pathophysiological phenomena underlying the MCI-to-AD evolution, as our results demonstrate changes in the structural association between hippocampal formation and thalamo-striatal connections occurring in MCI epsilon 4 carriers. Our results strongly support the role of subcortical structures in MCI epsilon 4 carriers and open a clinical window on the role of these structures as early disease markers.