APOE associated hemispheric asymmetry of entorhinal cortical thickness in aging and Alzheimer's disease

Abstract

Across species structural and functional hemispheric asymmetry is a fundamental feature of the brain. Environmental and genetic factors determine this asymmetry during brain development and modulate its interaction with brain disorders. The e4 allele of the apolipoprotein E gene (APOE-4) is a risk factor for Alzheimer's disease, associated with regionally specific effects on brain morphology and function during the life span. Furthermore, entorhinal and hippocampal hemispheric asymmetry could be modified by pathology during Alzheimer's disease development. Using high-resolution magnetic resonance imaging and a cortical unfolding technique we investigated whether carrying the APOE-4 allele influences hemispheric asymmetry in the entorhinal cortex and the hippocampus among patients with Alzheimer's disease as well as in middle-aged and older cognitively healthy individuals. APOE-4 carriers showed a thinner entorhinal cortex in the left hemisphere when compared with the right hemisphere across all participants. Non-carriers of the allele showed this asymmetry only in the patient group. Cortical thickness in the hippocampus did not vary between hemispheres among APOE-4 allele carriers and non-carriers. The APOE-4 allele modulates hemispheric asymmetry in entorhinal cortical thickness. Among Alzheimer's disease patients, this asymmetry might be less dependent on the APOE genotype and a more general marker of incipient disease pathology.

Keywords: APOE-4 allele; Cortical unfolding; Entorhinal cortex; Hippocampus; Magnetic resonance imaging.

Figure 1. Cortical unfolding

After manual segmentation of white matter and cerebrospinal fluid on high-resolution magnetic resonance images the resulting grey matter is computationally unfolded and flattened [C, right side shown]. Boundaries between subregions are delineated on all images acquired covering the hippocampal region from anterior [A] to posterior [B] parts. These demarcations are later projected onto the two-dimensional map. CADG=anterior cornu ammonis fields and dentate gyrus, CA23DG=cornu ammonis fields 2,3 and dentate gyrus, CA1=CA field 1, SUB=subiculum, ERC=entorhinal cortex, PRC=perirhinal cortex, PHC=parahippocampal cortex, FUS=fusiform cortex (boundary depicts medial fusiform vertex).

Figure 2. Hemispheric cortical thickness asymmetry in the hippocampus and entorhinal cortex

Apolipoprotein E e4 allele carriers show a left-right cortical thickness asymmetry in the entorhinal region (ERC) among all study participants, whereas non-carriers of the risk allele show this regional asymmetry only in the Alzheimer’s disease patient group. In the hippocampus (HC), hemispheric cortical thickness differences do not vary due to the presence of the APOE-4 allele. Raw means, error bars represent standard deviation. Significant differences are indicated (*, p<0.007, Bonferroni corrected)