APOE and modulation of Alzheimer's and frontotemporal dementia.
ABSTRACT To investigate the difference in the morphologic expression of frontotemporal dementia (FTD) and Alzheimer's disease (AD) in patients carrying and not carrying the epsilon4 allele of APOE, MR images of 26 controls, 18 AD patients (11 carrying the epsilon4 allele, seven non-carriers), and eight FTD (two carriers, six non-carriers) were compared using voxel by voxel analysis. Greater atrophy was found in the disease-specific regions of the epsilon4 carriers vs the non-carriers at P < 0.05 corrected: medial temporal atrophy was greater in the AD carrying the epsilon4 allele, right ventral striatal atrophy in the FTD carrying the allele. The non-carriers did not have atrophic regions compared to the carriers. The epsilon4 allele of the APOE might modulate the expression of degenerative dementias by enhancing the specific effects of neurodegenerative diseases on the brain.
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ABSTRACT: Primary progressive aphasia (PPA) is a heterogeneous disorder characterized by progressive language impairment. Polymorphisms within forkhead box P2 gene (FOXP2) gene have been associated with speech and language impairment. Apolipoprotein E (APOE) genotype and PRNP 129 codon status have been demonstrated to increase the risk of PPA, but with contrasting results. In the present study, we have evaluated the impact of FOXP2, APOE and PRNP genetic variations as risk factors and/or disease-modulators in PPA. 94 PPA patients and 200 age-matched healthy controls were considered and FOXP2 polymorphisms (rs1456031, rs17137124), APOE genotype, and PRNP codon 129 polymorphism analyzed. In 34 PPA patients, SPECT imaging data were analyzed by Statistical Parametric Mapping (SPM8). Genetic distributions and allele frequencies of FOXP2 and PRNP polymorphisms did not differ between groups while APOE ε4 was more represented in PPA as compared to controls. PPA patients carrying at-risk FOXP2 polymorphisms (rs1456031 and/or rs17137124) showed greater hypoperfusion in the frontal areas, namely the left inferior frontal gyrus and the right cingulated gyrus compared to non-carriers (p < 0.005). PPA patients carrying at least one ε4 allele had greater hypoperfusion in orbitofrontal regions (superior frontal gyrus and orbital gyrus) as compared to non-carriers ε4 (p < 0.005). PRNP codon 129 homozigosity correlated with left frontotemporal hypoperfusion (p < 0.005). Genetic variations within FOXP2, APOE, and PRNP modulate PPA disease, leading to a specific regional hypoperfusion according to different molecular pathways. APOE ε4 is overrepresented in PPA, thus likely acting as genetic risk factor on disease development.Journal of Alzheimer's disease: JAD 11/2011; 28(4):941-50. · 4.17 Impact Factor
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ABSTRACT: OBJECTIVE: Case-control studies have not been consistent in showing association between apolipoprotein E (APOE) polymorphisms and frontotemporal lobar degeneration (FTLD), producing contradictory findings. The study objective was to define and quantify further the disease risk associated with the carriage of different APOE alleles to determine whether APOE gene polymorphism is a risk factor for FTLD. METHODS: A systematic review of all case-control studies investigating the association between the APOE gene and FTLD up to December 2011 was conducted. Case-control studies using clinical or pathological criteria for FTLD and reporting APOE allelic or genotypic data were included. Pooled odds ratios (ORs) were estimated using a random effects model, and 95% confidence intervals (CIs) were calculated. RESULTS: Twenty-eight case-control studies met the inclusion criteria. Carriage of the ε2 allele had no effect on disease risk. On the contrary, carriage of the ε4 allele was associated with a significantly increased disease risk (ε4 carriers vs non-ε4 carriers: OR, 1.94; 95% CI, 1.43-2.64; ε4 vs ε3 allele: OR, 1.83; 95% CI, 1.34-2.52). Furthermore, a gene-dosage effect for the ε4 allele was found. There was no evidence of publication bias, but heterogeneity between the studies was high. CONCLUSIONS: Our study provides evidence for an association between the APOE ε4 allele and frontotemporal lobar degeneration.Alzheimer's & dementia: the journal of the Alzheimer's Association 05/2013; · 14.48 Impact Factor
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ABSTRACT: Replications of the association between APOE-ε4 allele load and regional brain atrophy in Alzheimer's disease (AD) patients hold promise for future studies testing relationships between other disease risk gene variants and brain structure. A polymorphism, rs10868366, in the Golgi phosphoprotein 2 gene, GOLM1, was recently identified as an AD risk factor in a genome-wide association study. In a subset of the same AD cohort, we used voxel-based morphometry to test for association between the disease risk genotype and reduced regional gray matter (GM) volume in AD patients (n = 72). A mean 14% reduction in GM volume was observed in the left frontal gyrus with the higher risk GG genotype. A similar association was observed in an independent, dataset of nondemented subjects (n = 278), although with a smaller effect (1%). This replicated association with GM structural variation suggests that GOLM1 polymorphisms may be related to cognitive phenotypes. The greater effect size in AD patients also suggests that the GG genotype could be a risk factor for the expression of cognitive deficits in AD.Neurobiology of aging 03/2012; 33(3):457-65. · 5.94 Impact Factor