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Squitti R.,AFaR Fatebenefratelli Hospital | Squitti R.,Biomedical University of Rome | Polimanti R.,University of Rome Tor Vergata
Journal of Alzheimer's Disease | Year: 2012

Sporadic Alzheimer's disease (LOAD) is the most common form of dementia and has a high heritability. The genes associated with LOAD explain a small proportion of the genetic contribution to LOAD, leaving several genetic risk factors to be identified. Some authors have suggested a shift from the paradigm "common disease-common gene variants", which is currently the basis for genome-wide association studies, to a "common disease-multiple rare gene variants" hypothesis aimed at identifying rarer allele variants with large effect size on LOAD onset, suggesting that they may account for the 'missing' heritability of LOAD. Recent studies have demonstrated the connection between copper imbalance and LOAD. Some studies have pointed out the pivotal role of 'free' copper, the portion of serum copper non-bound to ceruloplasmin. Free copper has been already identified as a biological marker of Wilson's disease (WD), the paradigmatic disease of free copper toxicosis or accumulation. The ATP7B gene controls free copper levels, and its mutations cause WD. The paradigm shift to "common disease-multiple rare variants" may suitably fit the ATP7B gene; the high heterogeneity of the ATP7B gene may have hidden multiple rare variants with large effect sizes for LOAD. Demonstrating that the ATP7B gene harbors rare variants which may account for some of the missing hereditability of LOAD would support previous evidence of copper involvement in LOAD from a new and totally different perspective and would bring almost immediate benefits in the clinical community in terms of early diagnosis, treatment efficacy, LOAD prevention, and cost savings. © 2012-IOS Press and the authors. All rights reserved.


Bucossi S.,Biomedical University of Rome | Polimanti R.,University of Rome Tor Vergata | Mariani S.,Biomedical University of Rome | Ventriglia M.,Biomedical University of Rome | And 7 more authors.
Journal of Alzheimer's Disease | Year: 2012

Copper homeostasis appears abnormal in Alzheimer's disease (AD) patients. The aim of this study was to assess whether loci of susceptibility for AD lie in the Wilson's disease (WD) ATP7B gene. We studied single nucleotide polymorphisms (SNPs) K832R (c.2495 A>G, rs1061472) and R952K (c. 2855 G>A, rs732774) of the WD gene in 251 AD patients and 201 healthy controls. We also evaluated their relation with apolipoprotein E (ApoE) ε4 allele frequency. R allele in K832R [adjusted Odds Ratio (OR) = 1.71 (1.12-2.60); p = 0.012] and the K allele in R952K [adjusted OR = 1.82 (1.19-2.80); p = 0.006] ATP7B SNPs were associated with an increased risk of developing AD, as well as the haplotype R832/K952, containing the 2 risk alleles (X 2 = 4.85; p = 0.028). Conversely, the K832/R952 haplotype appeared to confer protection against the disease (X 2 = 7.21; p = 0.007). No difference in the frequency of the ATP7B alleles between carriers and non-carriers of the ApoE ε4 variant was revealed. The linkage disequilibrium (LD) analysis revealed an association between K832R and R952K substitutions in both AD patients (D' = 0.79) and controls (D' = 0.81). A high LD between K832R and R952K was also confirmed in all HapMap populations. Our investigation demonstrated the presence of loci of susceptibility for AD in the WD ATP7B gene, supporting a role of copper dysfunction in contributing or accelerating neurodegenerative processes leading to AD. © 2012-IOS Press and the authors. All rights reserved.


Squitti R.,Biomedical University of Rome | Polimanti R.,University of Rome Tor Vergata | Bucossi S.,Biomedical University of Rome | Ventriglia M.,Biomedical University of Rome | And 7 more authors.
Rejuvenation Research | Year: 2013

Copper dyshomeostasis leading to a labile Cu2+ not bound to ceruloplasmin ("free" copper) may influence Alzheimer's disease (AD) onset or progression. To investigate this hypothesis, we investigated ATP7B, the gene that controls copper excretion through the bile and concentrations of free copper in systemic circulation. Our study analyzed informative ATP7B single-nucleotide polymorphisms (SNPs) in a case-control population (n=515). In particular, we evaluated the genetic structure of the ATP7B gene using the HapMap database and carried out a genetic association investigation. Linkage disequilibrium (LD) analysis highlighted that our informative SNPs and their LD SNPs covered 96% of the ATP7B gene sequence, distinguishing two "strong LD" blocks. The first LD block contains the gene region encoding for transmembrane and copper-binding, whereas the second LD block encodes for copper-binding domains. The genetic association analysis showed significant results after multiple testing correction for all investigated variants (rs1801243, odds ratio [OR]=1.52, 95% confidence interval [CI]=1.10-2.09, p=0.010; rs2147363, OR=1.58, 95% CI=1.11-2.25, p=0.010; rs1061472, OR=1.73, 95% CI=1.23-2.43, p=0.002; rs732774, OR=2.31, 95% CI=1.41-3.77, p<0.001), indicating that SNPs in transmembrane domains may have a stronger association with AD risk than variants in copper-binding domains. Our study provides novel insights that confirm the role of ATP7B as a potential genetic risk factor for AD. The analysis of ATP7B informative SNPs confirms our previous hypothesis about the absence of ATP7B in the significant loci of genome-wide association studies of AD and the genetic association study suggests that transmembrane and adenosine triphosphate (ATP) domains in the ATP7B gene may harbor variants/haplotypes associated with AD risk. © 2013, Mary Ann Liebert, Inc.


Ventriglia M.,AFaR Fatebenefratelli Hospital | Zanardini R.,Neuropsychopharmacology Unit | Bonomini C.,Alzheimers disease Unit | Zanetti O.,Alzheimers disease Unit | And 5 more authors.
BioMed Research International | Year: 2013

Consistent evidence indicates the involvement of the brain-derived neurotrophic factor (BDNF) in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). In the present study, we compared serum BDNF in 624 subjects: 266 patients affected by AD, 28 by frontotemporal dementia (FTD), 40 by Lewy body dementia (LBD), 91 by vascular dementia (VAD), 30 by PD, and 169 controls. Our results evidenced lower BDNF serum levels in AD, FTD, LBD, and VAD patients (P < 0.001) and a higher BDNF concentration in patients affected by PD (P = 0.045). Analyses of effects of pharmacological treatments suggested significantly higher BDNF serum levels in patients taking mood stabilizers/antiepileptics (P = 0.009) and L-DOPA (P < 0.001) and significant reductions in patients taking benzodiazepines (P = 0.020). In conclusion, our results support the role of BDNF alterations in neurodegenerative mechanisms common to different forms of neurological disorders and underline the importance of including drug treatment in the analyses to avoid confounding effects. © 2013 Mariacarla Ventriglia et al.


Bucossi S.,Biomedical University of Rome | Ventriglia M.,Biomedical University of Rome | Panetta V.,Medical Statistics and Information Technology | Salustri C.,CNR Institute of Neuroscience | And 5 more authors.
Journal of Alzheimer's Disease | Year: 2011

There is an ongoing debate on the involvement of systemic copper (Cu) dysfunctions in Alzheimer's disease (AD), and clinical studies comparing Cu levels in serum, plasma, and cerebrospinal fluid (CSF) of AD patients with those of healthy controls have delivered non-univocal and often conflicting results. In an attempt to evaluate whether Cu should be considered a potential marker of AD, we applied meta-analysis to a selection of 26 studies published in the literature. Meta-analysis is a quantitative method that combines the results of independent reports to distinguish between small effects and no effects, random variations, variations in sample used, or in different analytical approaches. The subjects' sample obtained by merging studies was a pooled total of 761 AD subjects and 664 controls for serum Cu studies, 205 AD subjects and 167 controls for plasma Cu, and of 116 AD subjects and 129 controls for CSF Cu. Our meta-analysis of serum data showed that AD patients have higher levels of serum Cu than healthy controls. Plasma data did not allow conclusions, due to their high heterogeneity, but the meta-analysis of the combined serum and plasma studies confirmed higher Cu levels in AD. The analysis of CSF data, instead, revealed no difference between AD patients and controls. © 2011 - IOS Press and the authors. All rights reserved.

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