Longitudinal changes in medial temporal cortical thickness in normal subjects with the APOE-4 polymorphism

David Geffen School of Medicine at UCLA, Center for Cognitive Neurosciences, Semel Institute, Los Angeles, CA 90095, USA.
NeuroImage (Impact Factor: 6.36). 10/2010; 53(1):37-43. DOI: 10.1016/j.neuroimage.2010.06.009
Source: PubMed


People with the apolipoprotein-Eepsilon4 (APOE-4) genetic risk for Alzheimer's disease show morphologic differences in medial temporal lobe regions when compared to non-carriers of the allele. Using a high-resolution MRI and cortical unfolding approach, our aim was to determine the rate of cortical thinning among medial temporal lobe subregions over the course of 2 years. We hypothesized that APOE-4 genetic risk would contribute to longitudinal cortical thickness change in the subiculum and entorhinal cortex, regions preferentially susceptible to Alzheimer's disease related pathology. Thirty-two cognitively intact subjects, mean age 61 years, 16 APOE-4 carriers, 16 non-carriers, underwent baseline and follow-up MRI scans. Over this relatively brief interval, we found significantly greater cortical thinning in the subiculum and entorhinal cortex of APOE-4 carriers when compared to non-carriers of the allele. Average cortical thinning across all medial temporal lobe subregions combined was also significantly greater for APOE-4 carriers. This finding is consistent with the hypothesis that carrying the APOE-4 allele renders subjects at a higher risk for developing Alzheimer's disease.

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Available from: Arne D Ekstrom, Oct 05, 2015
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    • "In a subsequent study from the same group, Donix et al. (2010b) found that a family history of AD and APOE4 status were independently associated with a thinner subiculum, with an additive effect of these two AD risk factors. In a longitudinal study of subfield thickness over two years, the same authors showed a stronger rate of atrophy in the subiculum (Donix et al., 2010b). By contrast, Kerchner et al. (2014) found a selective , dose-dependent effect on the CA1-SRLM width (yet, controls were pooled with MCI and demented patients in this analysis), while Mueller et al. reported a detrimental effect of the e4 allele on CA3/DG volume in healthy elderly, but not in middle aged individuals (Mueller et al., 2008; Mueller and Weiner, 2009). "
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    ABSTRACT: Hippocampal atrophy, as evidenced using magnetic resonance imaging (MRI), is one of the most validated, easily accessible and widely used biomarkers of Alzheimer's disease (AD). However, its imperfect sensitivity and specificity have highlighted the need to improve the analysis of MRI data. Based on neuropathological data showing a differential vulnerability of hippocampal subfields to AD processes, neuroimaging researchers have tried to capture corresponding morphological changes within the hippocampus. The present review provides an overview of the methodological developments that allow the assessment of hippocampal subfield morphology in vivo, and summarizes the results of studies looking at the effects of AD and normal aging on these structures. Most studies highlighted a focal atrophy of the CA1 subfield in the early (predementia or even preclinical) stages of AD, before atrophy becomes more widespread at the dementia stage, consistent with the pathological literature. Preliminary studies have indicated that looking at this focal atrophy pattern rather than standard whole hippocampus volumetry improves diagnostic accuracy at the Mild Cognitive Impairment (MCI) stage. However, controversies remain regarding changes in hippocampal subfield structure in normal aging and regarding correlations between specific subfield volume and memory abilities, very likely because of the strong methodological variability between studies. Overall, hippocampal subfield analysis has proven to be a promising technique in the study of AD. However, harmonization of segmentation protocols and studies on larger samples are needed to enable accurate comparisons between studies and to confirm the clinical utility of these techniques. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 08/2015; DOI:10.1016/j.neuroscience.2015.08.033 · 3.36 Impact Factor
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    • "The ApoE-E4 allele is the major genetic risk factor for late-onset AD [Corder et al., 1993; Farrer et al., 1997]. Some cross-sectional studies have reported smaller MRI volumes and greater rates of atrophy of MTL structures among cognitively normal ApoE-E4 carriers than in E4 non-carriers [Burggren et al., 2008; Chiang et al., 2011; Cohen et al., 2001; Donix et al., 2010; Honea et al., 2009; Lu et al., 2011]. However, these studies did not include long-term clinical follow-up and diagnostic outcomes that are necessary for determining whether these changes were related to the subsequent diagnosis of MCI. "
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    ABSTRACT: This study evaluated the utility of baseline and longitudinal magnetic resonance imaging (MRI) measures of medial temporal lobe brain regions collected when participants were cognitively normal and largely in middle age (mean age 57 years) to predict the time to onset of clinical symptoms associated with mild cognitive impairment (MCI). Furthermore, we examined whether the relationship between MRI measures and clinical symptom onset was modified by apolipoprotein E (ApoE) genotype and level of cognitive reserve (CR). MRI scans and measures of CR were obtained at baseline from 245 participants who had been followed for up to 18 years (mean follow-up 11 years). A composite score based on reading, vocabulary, and years of education was used as an index of CR. Cox regression models showed that lower baseline volume of the right hippocampus and smaller baseline thickness of the right entorhinal cortex predicted the time to symptom onset independently of CR and ApoE-ɛ4 genotype, which also predicted the onset of symptoms. The atrophy rates of bilateral entorhinal cortex and amygdala volumes were also associated with time to symptom onset, independent of CR, ApoE genotype, and baseline volume. Only one measure, the left entorhinal cortex baseline volume, interacted with CR, such that smaller volumes predicted symptom onset only in individuals with lower CR. These results suggest that MRI measures of medial temporal atrophy, ApoE-ɛ4 genotype, and the protective effects of higher CR all predict the time to onset of symptoms associated with MCI in a largely independent, additive manner during the preclinical phase of Alzheimer's disease. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Human Brain Mapping 04/2015; 36(7). DOI:10.1002/hbm.22810 · 5.97 Impact Factor
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    • "Regarding longitudinal MRI studies, results in elderly are more consistent. Most studies highlighted a faster rate of grey matter atrophy in APOE4 carriers compared with non-carriers, especially in medial temporal structures (Cohen et al. 2001; Chen et al. 2007; Morra et al. 2009; Donix et al. 2010a; Hua et al. 2010; Risacher et al. 2010; Chiang et al. 2011; Lu et al. 2011; Roussotte et al. 2014), although negative findings have also been reported (Jack et al. 1998; Du et al. 2006; Schuff et al. 2009; Taylor et al. 2014). In contrast, normal elderly APOE2 carriers showed a slower rate of hippocampal grey matter atrophy compared with APOE3 homozygotes (Chiang et al. 2011). "
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    ABSTRACT: The ε4 allele of the apolipoprotein E (APOE4) is associated with an increased risk of developing Alzheimer's disease (AD). Hence, several studies have compared the brain characteristics of APOE4 carriers versus non-carriers in presymptomatic stages to determine early AD biomarkers. The present review provides an overview on APOE4-related brain changes in cognitively normal individuals, focusing on the main neuroimaging biomarkers for AD, i.e. cortical beta-amyloid (Aβ) deposition, hypometabolism and atrophy. The most consistent findings are observed with Aβ deposition as most studies report significantly higher cortical Aβ load in APOE4 carriers compared with non-carriers. Fluorodeoxyglucose-positron emission tomography studies are rare and tend to show hypometabolism in brain regions typically impaired in AD. Structural magnetic resonance imaging findings are the most numerous and also the most discrepant, showing atrophy in AD-sensitive regions in some studies but contradicting results as well. Altogether, this suggests a graded effect of APOE4, with a predominant effect on Aβ over brain structure and metabolism. Multimodal studies confirm this view and also suggest that APOE4 effects on brain structure and function are mediated by both Aβ-dependent and Aβ-independent pathological processes. Neuroimaging studies on asymptomatic APOE4 carriers offer relevant information to the understanding of early pathological mechanisms of the disease, although caution is needed as to whether APOE4 effects reflect AD pathological processes, and are representative of these effects in non-carriers.
    Neuropsychology Review 08/2014; 24(3). DOI:10.1007/s11065-014-9263-8 · 4.59 Impact Factor
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