title: ATP7B variants as modulators of copper dyshomeostasis in Alzheimer's disease.
abstract: To understand the role of the key copper-regulating gene, ATP7B, in copper dyshomeostasis associated with Alzheimer's disease (AD), we analyzed the serum levels of copper, ceruloplasmin and 'free' (i.e., non-ceruloplasmin bound) copper in 399 patients with AD and 303 elderly healthy controls. We also performed analyses of informative variants of ATP7B. AD patients had higher levels of copper and free copper than controls. Individuals with free copper levels higher than 1.6 μmol/L (the upper value of the normal reference range) were more frequent among cases (p < 0.001). Among these individuals, those who were carriers of the ATP7B variants accounted for a large proportion of the free copper levels, specifically in the AD group (p < 0.01). Our results suggest the existence of a 'copper dysfunction' phenotype of sporadic AD which has a genetic basis. They also suggest that free copper is a risk factor for this disorder, modulating additional pathways leading to the disease cascade.
authors.affiliation: Department of Neuroscience, AFaR-Ospedale Fatebenefratelli Hospital, 00186, Rome, Italy. rosanna.squitti@afar.it
authors.forename: Rosanna
authors.initials: R
authors.lastname: Squitti
authors.forename: Renato
authors.initials: R
authors.lastname: Polimanti
authors.forename: Mariacristina
authors.initials: M
authors.lastname: Siotto
authors.forename: Serena
authors.initials: S
authors.lastname: Bucossi
authors.forename: Mariacarla
authors.initials: M
authors.lastname: Ventriglia
authors.forename: Stefania
authors.initials: S
authors.lastname: Mariani
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vernieri
authors.forename: Federica
authors.initials: F
authors.lastname: Scrascia
authors.forename: Laura
authors.initials: L
authors.lastname: Trotta
authors.forename: Paolo Maria
authors.initials: PM
authors.lastname: Rossini
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000502:physiology*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics / Q000502:physiology*; D002570:Ceruloplasmin / Q000032:analysis*; D003300:Copper / Q000097:blood*; D000073840:Copper-Transporting ATPases; D005260:Female; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D008297:Male; D008959:Models, Neurological; D020641:Polymorphism, Single Nucleotide
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D027682:Cation Transport Proteins; D003300:Copper; D002570:Ceruloplasmin; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases