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

ABSTRACT 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, Aug 21, 2015
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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 · 6.92 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 · 5.40 Impact Factor
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    • "It is one of the first structures to exhibit neurofibrillary tangles in AD, and exhibits massive neuronal loss in superficial layers as the disease progresses (Van Hoesen et al. 1991; Braak and Braak 1995; Gomez-Isla et al. 1996). Interestingly, EC cortical volume and subregional thickness are reduced in cognitively normal APOE-14 carriers (Shaw et al. 2007; Burggren et al. 2008; Donix et al. 2010), suggesting an early manifestation of cortico-hippocampal dysfunction in prodromal AD. Analyses of Golgi-stained MEC neurons by dendritic compartment reveal that reductions in total dendritic length and spine density of E4 "
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    ABSTRACT: The apolipoprotein E4 (APOE-ε4) allele is the strongest genetic risk factor for developing late-onset Alzheimer's disease, and may predispose individuals to Alzheimer's-related cognitive decline by affecting normal brain function early in life. To investigate the impact of human APOE alleles on cognitive performance in mice, we trained 3-mo-old APOE targeted replacement mice (E2, E3, and E4) in the Barnes maze to locate and enter a target hole along the perimeter of the maze. Long-term spatial memory was probed 24 h and 72 h after training. We found that young E4 mice exhibited significantly impaired spatial learning and memory in the Barnes maze compared to E3 mice. Deficits in spatial cognition were also present in a second independent cohort of E4 mice tested at 18 mo of age. In contrast, cognitive performance in the hidden platform water maze was not as strongly affected by APOE genotype. We also examined the dendritic morphology of neurons in the medial entorhinal cortex of 3-mo-old TR mice, neurons important to spatial learning functions. We found significantly shorter dendrites and lower spine densities in basal shaft dendrites of E4 mice compared to E3 mice, consistent with spatial learning and memory deficits in E4 animals. These findings suggest that human APOE-ε4 may affect cognitive function and neuronal morphology early in life.
    Learning & memory (Cold Spring Harbor, N.Y.) 04/2013; 20(5):256-266. DOI:10.1101/lm.030031.112 · 4.38 Impact Factor
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