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: 3.61). 01/2012; 29(3):493-501. DOI: 10.3233/JAD-2011-111991
Source: PubMed

ABSTRACT 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.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia. A myriad of complex factors contribute to AD, promoting the deposition in plaques of Amyloid-beta (Aβ), which is the main constituent of this pathognomonic sign of AD at autopsy brain inspection. Aβ toxicity is related to oxidative stress, which results in synaptic loss in specific brain areas, eventually leading to cognitive decline. Metal, and especially copper, dyshomeostasis is a key factor in these processes. Recent studies have demonstrated that the serum fraction of copper that is not bound to ceruloplasmin (Non-Cp copper, also known as ‘free’ or labile copper) increases in a percentage of AD patients and mild cognitive impairment (MCI) subjects; this is considered a precursor of AD. Non-Cp copper is the exchangeable fraction of low molecular weight copper in serum. It is distinguished from the copper structurally bound to the ceruloplasmin protein, a master protein of iron metabolism. Non-Cp copper levels are higher than normal reference values (range 0-1.6 μmol/L) in about 50% of amnestic MCI subjects and 60% of AD patients, typifying them in a subset of AD. Meta-analyses, genetic studies and a prognostic study evaluating the predictive value of Non-Cp copper in MCI conversion to full AD demonstrate the existence of this copper phenotype of AD.
    Journal of Trace Elements in Medicine and Biology 10/2014; DOI:10.1016/j.jtemb.2014.06.018 · 2.49 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurodegenerative diseases, Alzheimer’s disease (AD) and Parkinson’s disease (PD), constitute a major worldwide health problem. Several hypothesis have been put forth to elucidate the basis of onset and pathogenesis of AD and PD; however, till date, none of these seems to clearly elucidate the complex pathoetiology of these disorders. Notably, copper dyshomeostasis has been shown to underlie the pathophysiology of several neurodegenerative diseases including AD and PD. Numerous studies have concluded beyond doubt that imbalance in copper homeostatic mechanisms in conjunction with aging causes an acceleration in the copper toxicity elicited oxidative stress, which is detrimental to the central nervous system. Amyloid precursor protein and α-synuclein protein involved in AD and PD are copper binding proteins, respectively. In this review, we have discussed the possible association of copper metabolism proteins with AD and PD along with briefly outlining the expanding proportion of “copper interactome” in human biology. Using network biology, we found that copper metabolism proteins, superoxide dismutase 1 and ceruloplasmin may represent direct and indirect link with AD and PD, respectively.
    BioMetals 02/2014; 27(1). DOI:10.1007/s10534-013-9702-7 · 2.69 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Copper is an essential micronutrient for physiological cell functioning and central nervous system (CNS) development. Indeed, it is a cofactor of many proteins and enzymes in a number of molecular pathways, including energy generation, oxygen transportation, hematopoiesis, cellular growth and metabolism, and signal transduction. This is because it serves as a catalyst of reduction-oxidation (redox) reactions in these processes. When copper is kept under control, bound to special proteins, it yields key properties. However, when it spirals out of control, it is exchanged among small compounds (it is loosely bound to them), and its redox activity makes it dangerous for cell viability, promoting oxidative stress. Copper homeostasis in the CNS is securely synchronized, and perturbations in brain copper levels are known to underlie the pathoetiology of wide a spectrum of common neurodegenerative disorders, including Alzheimer's disease. The main objective of this review is to provide some of the most relevant evidence gleaned from recent studies conducted on animal models and humans, and to discuss the evidence as it pertains to a new concept: Aberrant copper metabolism, which appears to have a genetic basis, is a modifiable risk factor accelerating Alzheimer's disease and initiation/progression of cognitive deficits in a percentage of susceptible persons.
    Journal of Alzheimer's disease: JAD 09/2014; 44(2). DOI:10.3233/JAD-141194 · 3.61 Impact Factor


Available from
May 19, 2014