Longitudinal changes in medial temporal cortical thickness in normal subjects with the APOE-4 polymorphism
Research highlights
►The APOE-4 allele is associated with medial temporal cortical thinning in healthy people. ►APOE-4 allele carriers compared to non-carriers show greater cortical thinning in the subiculum and entorhinal region over a two2-year interval. ►High resolution MRI can reveal subregional medial temporal cortical thickness changes in healthy subjects.
Introduction
Alzheimer's disease (AD) has multiple and interacting etiologic factors. The ε4 allele of the apolipoprotein E gene (APOE-4) on chromosome 19 is the only well-established genetic risk factor for sporadic AD (Brouwers et al., 2008). Carrying the APOE-4 allele is associated with higher risk for developing AD and earlier age of onset (Corder et al., 1993). However, the APOE-4 allele does not cause the disease, and the relatively high prevalence in the general population suggests antagonistically pleiotropic effects, which can be found in many genetic variants (Wright et al., 2003).
Neuroimaging studies have revealed structural and functional brain differences among cognitively healthy APOE-4 carriers when compared to non-carriers. Using functional magnetic resonance imaging (fMRI), Bookheimer et al. (2000) found increased magnitude and extent of brain activation during tasks requiring memory in healthy APOE-4 carriers compared to non-carriers. Other fMRI data support these findings (Bondi et al., 2005). Positron emission tomography (PET) reveals reduced glucose metabolism associated with APOE-4 genetic risk in healthy people (Reiman et al., 2005). Cognitively normal APOE-4 carriers also show increased uptake of the amyloid binding ligand PIB (Reiman et al., 2009) and the amyloid and tau binding ligand FDDNP (Small et al., 2009) when compared to subjects not carrying the risk allele.
Advances in spatial resolution and image analysis techniques allow examining regional brain characteristics that might be associated with AD risk in the normal population. This work may contribute to identifying people at greater risk for future cognitive decline. It may also enhance understanding of the relationship between AD risk factors, regional brain structure, and cognitive performance. Hippocampal atrophy is known to be associated with memory impairment and AD (de Leon et al., 1996, Rusinek et al., 2003), but it remains controversial whether hippocampal atrophy is present in healthy people due to APOE-4 genetic risk (Cherbuin et al., 2008, Jack et al., 1998, Mueller et al., 2008). Recent data have shown that when compared to volumetry, medial temporal lobe (MTL) cortical thickness measures may provide better representation of associations between APOE genetic variants and MTL structure changes, given the laminar organization of the cerebral cortex, and the expected subtlety of changes within healthy subjects (Burggren et al., 2008). Cortical thickness measurements have been used to assess structural cortical changes with reasonable accuracy and reliability across many diseases, including memory disorders (Bakkour et al., 2009, Thompson et al., 2003). While several MRI studies have documented reduced volume (Apostolova et al., 2006, Devanand et al., 2007) and cortical thinning (Morra et al., 2009, Thompson et al., 2007) in mild cognitive impairment (MCI) and AD subjects, there has been very little work done examining longitudinal MRI changes in healthy volunteers with a genetic risk for AD.
One approach developed in our laboratory examines subregions of the MTL system using high-resolution MRI combined with cortical unfolding. First applied to the visual cortex (Engel et al., 1997), we adapted this procedure to the MTL (Ekstrom et al., 2009a, Zeineh et al., 2000, Zeineh et al., 2001). This approach uses high-resolution MRI images and increases the visibility of the convoluted MTL cortex while allowing us to measure cortical thickness directly and separately across subregions of the MTL. Using this approach, Burggren et al. (2008) identified reduced cortical thickness in the subiculum (SUB) and entorhinal cortex (ERC) among healthy elderly APOE-4 carriers.
Because APOE proteins are differentially involved in neuronal repair and plasticity processes (Teter et al., 2002), we predict greater decline in neural integrity during the aging process in APOE-4 carriers. In the present study, we used the cortical unfolding approach to identify cortical thinning in a 2-year follow-up among cognitively intact elderly subjects with and without the APOE-4 allele. We hypothesized that subjects with the APOE-4 genetic risk would show increased cortical thinning over time in SUB and ERC, regions susceptible to AD pathology.
Section snippets
Subjects
Thirty-two subjects (16 APOE-4 carriers, 16 non-carriers) participated in this study, which was performed at the Semel Institute for Neuroscience and Human Behavior and the Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles. All participants gave written informed consent in accordance with the UCLA Human Subjects Protection Committee procedures. Participants were selected from a pool of 130 control, MCI and AD subjects recruited though advertisements that underwent
Results
There were no significant differences in the neuropsychological test scores between groups at baseline. As shown in Table 1, 2 years later no performance changes could be detected. APOE-4 carriers and non-carriers were equivalent in cortical thickness at baseline, which allowed us to specifically examine the effects of genotype on longitudinal change. We did not find an association between cortical thickness change and cognitive change.
Within-group cortical thickness results: subjects not
Discussion
Our data indicate that among cognitively healthy APOE-4 carriers the rate of cortical thinning over time is significantly greater in SUB and ERC when compared to non-carriers of the APOE-4 allele. Global cortical thinning (average across subregions) was also significantly greater among APOE-4 carriers. Within group, non-APOE-4 carriers did not show cortical thinning over time whereas APOE-4 carriers showed decrease in cortical thickness in all subregions except CA23DG.
The APOE-4 allele is
Disclosure statement
Dr. Small reports having served as a consultant and/or having received lecture fees from Abbott, Brainstorming Co., Dakim, Eisai, Forest, Myriad Genetics, Novartis, Ortho-McNeil, Pfizer, Radica, Siemens, and Medivation. Dr. Small also reports having received stock options from Dakim. Dr. Ercoli reports having received lecture fees from the Alzheimer's Association Speakers Bureau and Keiro Senior Health Services. Other investigators have no financial interests.
Acknowledgments
The authors thank Ms. Andrea Kaplan and Ms. Debbie Dorsey for help in subject recruitment, data management, and study coordination. Supported by NIH grants P01-AG025831, AG13308, P50 AG 16570, MH/AG58156, MH52453, AG10123, and M01-RR00865; General Clinical Research Centers Program; Fran and Ray Stark Foundation Fund for Alzheimer's Disease Research; and Larry L. Hillblom Foundation. Markus Donix was funded by the Max Kade Foundation. No company provided support of any kind for this study.
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