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.

Introduction

Neuropathological hallmarks of Alzheimer's disease, beta amyloid plaques and neurofibrillary tangles, can be found in the brain decades before the onset of clinical symptoms (Braak and Braak, 1995). In vivo detection of pathological changes that are closely associated with future cognitive deterioration could be critical for targeting novel therapies to those persons most likely to benefit from intervention. The spatial distribution of intraneuronal tangle pathology, rather than the pattern of extracellular amyloid deposition, is associated with neuronal loss and cognitive dysfunction (Gomez-Isla et al., 1997, Petersen et al., 2006). In fact, these neurofibrillary tangles first occur in the transentorhinal region before spreading to the hippocampus and other neighboring cortices (Braak and Braak, 1995). Multiple imaging metrics now exist for the identification of these neuropathological markers both before the onset, and during the progression of Alzheimer's disease. Modern methods include positron emission tomography (PET), using radioactive ligands that bind to plaques and tangles in the brain (Protas et al., 2010), magnetic resonance imaging (MRI) of brain structure (Donix et al., 2010a), function (Xu et al., 2009), or connectivity (Brown et al., 2011) which allow for the in vivo characterization of persons at risk for Alzheimer's disease. With its high resolution, MRI technology can provide the most direct in vivo visualization of neuronal structure in the various disease stages as reflected by the spatial patterns of gray matter atrophy (Thompson et al., 2003).

Neuropathological stages of the disease, first defined using histopathological methods and now visualized in the living brain using MRI, became essential for our understanding of Alzheimer's disease. Hemispheric differences in either direct or indirect measures of pathology are less well recognized. There is also no specific recommendation for how to address a possible hemispheric pathology distribution asymmetry in the original staging procedures (Braak and Braak, 1991). Without a clearer understanding of brain asymmetry differences in both pre-clinical and clinical Alzheimer's disease, it may be difficult, if not impossible, for clinicians to interpret such regional observations in individual subjects as disease-related or as a variant in brain development and aging.

Structural brain asymmetry and functional hemispheric specialization are fundamental features across species (Toga and Thompson, 2003). In the human brain, the perisylvian region shows the most prominent hemispheric asymmetry reflecting language specialization and handedness, which are interrelated in complex ways (Geschwind and Levitsky, 1968, Galaburda et al., 1978). Environmental and genetic factors contribute to the functional lateralization as well as to structural hemispheric asymmetry, ranging from gender and hormonal influences to experience-induced effects (Galaburda and Geschwind, 1981, Diamond, 1991, Diaz et al., 1994, Shaywitz et al., 1995). Pathological processes can also modulate hemispheric asymmetry and vice versa. Examples are planum temporale asymmetry reductions in dyslexia patients or gender-associated structural hemispheric asymmetry that possibly influences learning disorder incidence rate differences among men and women (Larsen et al., 1990, Toga and Thompson, 2003).

The hippocampus is a brain area for which hemispheric asymmetry has been reported in healthy individuals. In a meta-analysis, Pedraza et al. (2004) revealed larger right hippocampal volumes when compared with the left side in a sample of 82 studies. In a recent investigation, Lucarelli et al. (2013) also showed larger right hippocampal volumes in healthy adults. The authors detected a hemispheric asymmetry increase with age as well as gender effects with men showing greater asymmetry in hippocampus volumes (Lucarelli et al., 2013). Woolard and Heckers (2012) highlight that the functional relevance of this well-established right>left hippocampal volume asymmetry in healthy people is not well understood. However, regional asymmetry differences within the hippocampus as well as their differential predictive value for cognitive abilities, suggest a functional implication of this asymmetry (Woolard and Heckers, 2012).

Data also indicate that the left hemisphere could be more susceptible to neurodegeneration in Alzheimer's disease than the right hemisphere (Loewenstein et al., 1989, Janke et al., 2001). Although the spatial pattern of neuropathological changes in Alzheimer's disease development is relatively similar in both hemispheres, left hemispheric changes are more severe and may precede changes in the right hemisphere by up to 2 years (Thompson et al., 2003). This asymmetry in pathology distribution has been shown in vivo in patients with Alzheimer's disease, using metabolic measures, such as 18-F-fluorodeoxyglucose (FDG)-PET (Loewenstein et al., 1989) or advanced MRI based brain mapping techniques (Thompson et al., 2003). Histopathological data also show hemispheric asymmetry in neurofibrillary tangle but not amyloid plaque pathology distribution among postmortem samples from patients with Alzheimer's disease (Moossy et al., 1988). The neurofibrillary tangle asymmetry occurred in the hippocampus and entorhinal cortex but not in other brain regions investigated (Moossy et al., 1988). More recent histopathological data highlight that hemispheric asymmetry in Alzheimer's disease pathology distribution could even reflect different disease stages in the same brain (Stefanits et al., 2012). However, there is some variability in the existing literature. Postmortem histopathological findings did not suggest hemispheric differences (Arnold et al., 1991), and recent structural MRI data highlight asymmetric but not necessarily left-lateralized gray matter atrophy in Alzheimer's disease patients (Derflinger et al., 2011). It seems possible that patient groups differ in the pattern of contributing factors, such as disease severity or the presence of genetic variables, which could potentially influence hemispheric asymmetry.

Interestingly, the e4 allele of the apolipoprotein E gene (APOE-4), a major genetic risk factor for late-onset sporadic Alzheimer's disease (Corder et al., 1993) could be one of these variables. APOE-4 contributes to changes in brain structure and function already in children (Shaw et al., 2007) and young adults (Reiman et al., 2004). Data suggest that these changes do not reflect pathology but demonstrate the involvement of APOE proteins in brain development that influences physiological and pathological processes later in life. Such changes may render subjects at higher risk for Alzheimer's disease (Shaw et al., 2007), but the APOE-4 allele is also associated with improved cognitive abilities in childhood (Mondadori et al., 2007) and protective effects during embryogenesis (Zetterberg et al., 2002). These antagonistically pleiotropic APOE-4 characteristics at different stages of the life span are increasingly recognized in Alzheimer's disease research because of the shift towards younger study subjects driven by today's early detection focus.

In contrast, the possible influence of the APOE-4 allele on hemispheric differences in brain structure and function is less well investigated, although APOE effects are known to be regionally specific (Burggren et al., 2008, Donix et al., 2010a, Liu et al., 2010a). The evidence from childhood studies supports the existence of APOE-associated effects on asymmetric brain development. Using a voxel-based morphometric approach, Shaw et al. (2007) showed thinner entorhinal cortex in children and adolescents carrying the APOE-4 allele in the left hemisphere, whereas right entorhinal cortex thickness did not vary due to the risk allele. Children carrying the APOE-2 allele, which may have neuroprotective effects in late life (Talbot et al., 1994), showed reduced visuospatial skills and a higher prevalence of left-handedness than non-carriers of the allele (Bloss et al., 2010), again suggesting clinically relevant APOE effects on hemispheric asymmetry. In patients with Alzheimer's disease, Pievani et al. (2011) found smaller hippocampal volume in the left hemisphere but not in the right hemisphere among APOE-4 allele carriers when compared with non-carriers and healthy controls. Using FDG-PET, Alzheimer's disease patients carrying the risk allele compared with non-carriers showed differences in glucose metabolism in the left inferior temporal region only in a mild stage of the disease, suggesting APOE-4 involvement in the development rather than in the progression of the disease (Lee et al., 2003). It is in line with this hypothesis that other imaging studies did not find an association between the APOE-4 allele and hemispheric asymmetry in Alzheimer's disease (Hirono et al., 1998, Barnes et al., 2005), possibly indicating APOE-4 effects becoming less obvious with greater disease associated neural changes.

In this study we wanted to investigate whether carrying the APOE-4 allele would influence regional hemispheric asymmetry in patients with early Alzheimer's disease as well as in healthy middle-aged and older people. Using high resolution structural MRI and a cortical unfolding technique (Zeineh et al., 2001) we focused on the entorhinal cortex and the hippocampus. These regions are preferentially susceptible to Alzheimer's disease pathology (Braak and Braak, 1991), and they exhibit APOE-associated structural changes detectable with MRI in healthy people across the life span (Shaw et al., 2007, Burggren et al., 2008, Donix et al., 2010b). We hypothesized that healthy APOE-4 carriers compared with non-carriers show a greater left-right hemispheric asymmetry in entorhinal and hippocampal cortical thickness, whereas the risk allele's influence would be less substantial in patients with Alzheimer's disease.