Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease
ABSTRACT To examine the influence of the APOE genotype on levels of beta-amyloid (Abeta) plaque load and atrophy in patients with Alzheimer disease (AD) in vivo.
Thirty-two patients with moderate AD were divided into carriers and noncarriers of the epsilon4 allele. These groups were matched for age, disease duration, education, and cognitive impairment. In all subjects, [11C]PIB-PET was performed for measurement of cerebral Abeta plaque deposition and cranial MRI for the assessment of gray matter volume by voxel-based morphometry (VBM) and for correction of partial volume effects (PVE) in the PET data. Voxel-based comparisons (SPM5) were performed between patient groups and healthy control populations and completed with multiple regression analyses between imaging data and epsilon4 allele frequency.
Compared to controls, AD-typical patterns of [11C]PIB retention and atrophy were detected in both epsilon4-positive and epsilon4-negative patient groups. In direct comparison, significantly stronger and more extended [11C]PIB uptake was found in epsilon4-positive patients in bilateral temporoparietal and frontal cortex, surviving PVE correction. VBM analysis demonstrated comparable levels of atrophy in both patient groups. Regression analyses revealed a linear association between higher epsilon4 allele frequency and stronger temporoparietal Abeta plaque deposition, independently of other confounds. No major correlation between epsilon4 allele frequency and gray matter decrease was observed.
These results indicate that the epsilon4-positive APOE genotype not only represents a risk factor for Alzheimer disease (AD), but also results in higher levels of Abeta plaque deposition in epsilon4-positive patients with AD compared to age-matched epsilon4-negative patients with similar levels of cognitive impairment and brain atrophy. The potential role of Abeta plaque imaging for patient inclusion and follow-up in anti-amyloid therapy trials is strengthened by these findings.
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ABSTRACT: The apolipoprotein E (APOE) ɛ4 allele is a well-established genetic risk factor for Alzheimer's disease (AD). Recent research has demonstrated an APOE ɛ4-mediated modulation of intrinsic functional brain networks in cognitively normal individuals. However, it remains largely unknown whether and how APOE ɛ4 affects the brain's functional network architecture in patients with AD. Using resting-state functional MRI and graph-theory approaches, we systematically investigated the topological organization of whole-brain functional networks in 16 APOE ɛ4 carriers and 26 matched noncarriers with AD at three levels: global whole-brain, intermediate module, and regional node/connection. Neuropsychological analysis showed that the APOE ɛ4 carriers performed worse on delayed memory but better on a late item generation of a verbal fluency task (associated with executive function) than noncarriers. Whole-brain graph analyses revealed that APOE ɛ4 significantly disrupted whole-brain topological organization as characterized by (i) reduced parallel information transformation efficiency; (ii) decreased intramodular connectivity within the posterior default mode network (pDMN) and intermodular connectivity of the pDMN and executive control network (ECN) with other neuroanatomical systems; and (iii) impaired functional hubs and their rich-club connectivities that primarily involve the pDMN, ECN, and sensorimotor systems. Further simulation analysis indicated that these altered connectivity profiles of the pDMN and ECN largely accounted for the abnormal global network topology. Finally, the changes in network topology exhibited significant correlations with the patients' cognitive performances. Together, our findings suggest that the APOE genotype modulates large-scale brain networks in AD and shed new light on the gene-connectome interaction in this disease. Hum Brain Mapp, 2015. © 2014 Wiley Periodicals, Inc.Human Brain Mapping 01/2015; DOI:10.1002/hbm.22740 · 6.92 Impact Factor
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ABSTRACT: We conducted a meta-analysis of positron emission tomography (PET) findings in Alzheimer's disease (AD) and mild cognitive impairment (MCI) to clarify the changes underpinning these conditions. All studies that utilised the PET tracers Pittsburgh Compound-B (PIB) or 2-[18F]fluoro-2-deoxy-D-glucose (FDG) to investigate patients with MCI or AD, were considered for the meta-analysis. Meta-analyses of PIB-PET and FDG-PET changes between patients and controls were undertaken with the effect-size signed differential mapping (ES-SDM) voxel-based meta-analytic method. A total of 24 studies were included involving 728 AD patients, 211 MCI patients and 658 healthy controls. Individuals with AD showed a significant PIB retention in bilateral precuneus and temporal, supramarginal, cingulate and fusiform gyri, as well as right insula and putamen. In addition, AD patients showed significant glucose hypometabolism in bilateral precuneus and temporal, supramarginal, cingulate, fusiform, angular, inferior parietal and middle frontal gyri, as well as left precentral and parahippocampal gyri and right superior frontal gyrus and thalamus. An exploratory meta-analysis of the few studies on MCI showed mildly decreased glucose metabolism with a similar regional distribution than in patients with AD. We suggest that our results can be used for further region-of-interest studies of AD and MCI patients.Cell Biochemistry and Biophysics 11/2014; 71(1). DOI:10.1007/s12013-014-0138-7 · 2.38 Impact Factor
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ABSTRACT: The aging brain is characterized by the simultaneous presence of multiple pathologies, and the prevalence of cerebral multi-morbidity increases with age. To understand the impact of each subtype of pathology and the combined effects of cerebral multi-morbidity on clinical signs and symptoms, large clinico-pathological correlative studies have been performed. However, such studies are often based on semi-quantitative assessment of neuropathological hallmark lesions. Here, we discuss some of the new methods for high-throughput quantitative neuropathological assessment. These methods combine increased quantitative rigor with the added technical capacity of computers and networked analyses. There are abundant new opportunities - with specific techniques that include slide scanners, automated microscopes, and tissue microarrays - and also potential pitfalls. We conclude that quantitative and digital neuropathologic approaches will be key resources to further elucidate cerebral multi-morbidity in the aged brain and also hold the potential for changing routine neuropathologic diagnoses.Alzheimer's Research and Therapy 12/2014; 6(9):85. DOI:10.1186/s13195-014-0085-y · 3.50 Impact Factor