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

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.