Reduced gray matter volume in normal adults with a maternal family history of Alzheimer disease

University of Kansas School of Medicine, Department of Neurology, 2100 West 36th Ave., Suite 110, Kansas City, KS 66160, USA.
Neurology (Impact Factor: 8.29). 01/2010; 74(2):113-20. DOI: 10.1212/WNL.0b013e3181c918cb
Source: PubMed


A consistently identified risk factor for Alzheimer disease (AD) is family history of dementia, with maternal transmission significantly more frequent than paternal transmission. A history of maternal AD may be related to AD-like glucose consumption in cognitively healthy subjects. In this cross-sectional study, we tested whether cognitively healthy people with a family history of AD have less gray matter volume (GMV), an endophenotype for late-onset AD, than individuals with no family history, and whether decreases in GMV are different in subjects with a maternal family history.
As part of the Kansas University Brain Aging Project, 67 cognitively intact individuals with a maternal history of late-onset AD (FHm, n = 16), a paternal history of AD (FHp, n = 8), or no parental history of AD (FH-, n = 43), similar in age, gender, education, and Mini-Mental State Examination score, were scanned at 3 T. We used voxel-based morphometry to examine GMV differences between groups, controlling for age, gender, and apoE4.
Cognitively healthy individuals with a family history of late-onset AD had significantly decreased GMV in the precuneus, middle frontal, inferior frontal, and superior frontal gyri compared with FH- individuals. FHm subjects had significantly smaller inferior frontal, middle frontal, precuneus, and lingual gyri compared with FH- and FHp subjects.
Overall, maternal family history of Alzheimer disease (AD) in cognitively normal individuals is associated with lower gray matter volume in AD-vulnerable brain regions. These data complement and extend reports of cerebral metabolic differences in subjects with a maternal family history.

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Available from: Jeffrey M Burns, Apr 09, 2014
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    • "Indeed, unknown genegene and gene-environment interactions are likely to modulate the effect of this genetic factor on brain structure and function, potentially resulting in both overestimation and masking of APOE4 effects (see Donix et al. 2012 for review). In this respect, APOE genotype and family history risk were shown to have independent and/or additive contributions to brain structure (Donix et al. 2010b; Honea et al. 2010, 2011) or metabolism (Mosconi et al. 2007, 2009). "
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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.
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    • "This trend is consistent with recent reports (Mosconi et al., 2010, 2013) in which greater amyloid burden in healthy older adults with maternal FH was described. This is also consistent with reports in which it was suggested that maternal FH is associated with lower cerebral blood flow (Okonkwo et al., 2012b), lower metabolic rate of glucose (Mosconi et al., 2007, 2009), cerebral atrophy (Honea et al., 2010, 2011), and altered white matter microstructure on diffusion tensor imaging scans (Bendlin et al., 2010). Maternal inheritance of AD is significantly more common than paternal inheritance (Edland et al., 1996). "
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    ABSTRACT: To determine the relationship between amyloid burden and neural function in healthy adults at risk for Alzheimer's Disease (AD), we used multimodal imaging with [C-11]Pittsburgh compound B positron emission tomography, [F-18]fluorodeoxyglucose, positron emission tomography , and magnetic resonance imaging, together with cognitive measurement in 201 subjects (mean age, 60.1 years; range, 46-73 years) from the Wisconsin Registry for Alzheimer's Prevention. Using a qualitative rating, 18% of the samples were strongly positive Beta-amyloid (Aβ+), 41% indeterminate (Aβi), and 41% negative (Aβ-). Aβ+ was associated with older age, female sex, and showed trends for maternal family history of AD and APOE4. Relative to the Aβ- group, Aβ+ and Aβi participants had increased glucose metabolism in the bilateral thalamus; Aβ+ participants also had increased metabolism in the bilateral superior temporal gyrus. Aβ+ participants exhibited increased gray matter in the lateral parietal lobe bilaterally relative to the Aβ- group, and no areas of significant atrophy. Cognitive performance and self report cognitive and affective symptoms did not differ between groups. Amyloid burden can be identified in adults at a mean age of 60 years and is accompanied by glucometabolic increases in specific areas, but not atrophy or cognitive loss. This asymptomatic stage may be an opportune window for intervention to prevent progression to symptomatic AD.
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    • "Studies assessing the effect of APOE4 on brain structure using structural MRI are numerous but lead to diverging findings. Thus, several studies have reported a significant atrophy (or cortical thinning) in APOE4 carriers compared to non carriers, most often in brain regions most susceptible to AD, i.e. medial temporal structures (hippocampus, entorhinal cortex, etc; Plassman et al., 1997; Tohgi et al., 1997; Lemaître et al., 2005; Lind et al., 2006; Wishart et al., 2006; Burggren et al., 2008; Honea et al., 2009; Suthana et al., 2010; O'Dwyer et al., 2012). Other regions are also reported such as the lateral temporal and prefrontal cortex (Wishart et al., 2006) or parietal areas (Honea et al., 2009). "
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    ABSTRACT: The E4 allele of the apolipoprotein E (APOE4) is the major known genetic risk factor for Alzheimer's disease (AD), with a dramatic increase in the risk of developing AD as the number of APOE4 alleles increases from 0 to 2. For this reason, asymptomatic APOE4 carriers as a group offer a great opportunity to search for the presence of early biomarkers for AD. The present article reviews neuroimaging studies on APOE4 carriers, focusing on cognitively normal individuals and on the main neuroimaging biomarkers for AD, i.e. atrophy with structural MRI, hypometabolism with FDG-PET, and amyloid deposition with amyloid-PET imaging. There are a great number of studies on the effect of APOE4 on brain structures, and they tend to show significant atrophy in APOE4 carriers compared to non-carriers especially in regions susceptible to AD pathology such as the hippocampus. However, results are rather discrepant which suggests that the effect of APOE4 on brain structure is subtle. As for FDG-PET metabolism, the few available studies show decreased metabolism, again especially in AD-sensitive regions such as posterior associative parietal areas, with a dose-dependent effect (i.e. worsening as the number of APOE4 alleles increases). Finally, there is a unanimous and major effect of APOE4 on amyloid deposition with an increase in Aβ load as the number of APOE4 alleles increases and a decrease in the age of predicted amyloid-positivity in APOE4 carriers. This graded effect of APOE4 on atrophy, hypometabolism, and amyloid deposition is consistent with multimodal neuroimaging studies suggestive of a predominant effect of APOE4 on amyloid rather than tau-related injury and on brain metabolism rather than brain structure. Neuroimaging studies also suggest that APOE4 effects may be mediated by both Aβ-dependent and Aβ-independent pathological processes. This contradicts the view that Aβ pathology is a necessary upstream event to neuronal injury in AD. Future studies should tell whether the mechanisms and sequences evidenced in carriers are comparable to those found in non-carriers, but it is likely that APOE4 not only influences the risk for AD, but also modulates the pathophysiological cascade. Altogether, APOE4 carriers offer a great opportunity to investigate brain changes in the asymptomatic stages of AD and to further our understanding of the pathophysiology of the disease, although precaution is needed for interpretation in AD at large.
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