Copper Hypothesis in the Missing Hereditability of Sporadic Alzheimer's Disease: ATP7B Gene as Potential Harbor of Rare Variants

Department of Neuroscience, AFaR-Fatebenefratelli Hospital, Isola Tiberina, Rome, Italy.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 01/2012; 29(3):493-501. DOI: 10.3233/JAD-2011-111991
Source: PubMed


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.

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Available from: Renato Polimanti
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    • "Conversely, AD may be the consequence of interacting mechanisms involving oxidative stress, Aβ brain accumulation, and other unknown factors, such as the recent hypothesis based on copper dyshomeostasis [39]. Furthermore, elevation of serum copper levels seems to discriminate AD patients from VaD patients [40]. "
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    • "The overload of Non-Cp copper in systemic circulation causes brain copper deposits and, in a percentage of WD patients, Kaiser–Fleisher rings surrounding the iris of the eyes (reviewed in [6]). We are now postulating that ATP7B functionality is in part also compromised in AD [35], less severely with respect to WD, but sufficiently enough to cause an overflow of Non-Cp copper to be detected in general circulation, and to feed or accelerate noxious neurodegenerative processes of A␤ toxicity within the brain, as depicted above (Fig. 1). "
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    • "Loss of the Cu transporter ATP7B in Wilson's disease model mice presents as elevated brain copper, neurodegeneration, and inflammation [128]. Interestingly, ATP7B gene polymorphisms have been associated with increased AD risk in certain populations [129] [130]. Moreover, an inflammatory milieu can affect Cu homeostasis via regulation of Cu transport proteins (Figure 2). "
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