title: Non-Ceruloplasmin Copper Distincts Subtypes in Alzheimer's Disease: a Genetic Study of ATP7B Frequency.
abstract: Meta-analyses show that serum copper non-bound-to-ceruloplasmin (non-Cp-Cu) is higher in patients with Alzheimer's disease (AD). ATP7B gene variants associate with AD, modulating the size of non-Cp-Cu pool. However, a dedicated genetic study comparing AD patients after stratification for a copper biomarker to demonstrate the existence of a copper subtype of AD has not yet been carried out. An independent patient sample of 287 AD patients was assessed for non-Cp-Cu serum concentrations, rs1801243, rs1061472, and rs732774 ATP7B genetic variants and the APOE4 genotype. Patients were stratified into two groups based on a non-Cp-Cu cutoff (1.9 μM). Single-locus and haplotype-group analyses were performed to define their frequencies in dependence of the non-Cp-Cu group. The two AD subgroups did not differ regarding age, sex, MMSE score, or APOE4 frequency allele, while they did differ regarding non-Cp-Cu concentrations in serum, allele, genotype, and haplotype frequencies of rs1061472 A > G and rs732774 C > T after multiple testing corrections. AD patients with a GG genotype had a 1.76-fold higher risk of having a non-Cp-Cu higher than 1.9 μmol/L (p = 0.029), and those with a TT genotype for rs732774 C > T of 1.8-fold (p = 0.018). After 100,000 permutations for multiple testing corrections, the haplotype containing the AC alleles appeared more frequently in AD patients with normal non-Cp-Cu [43 vs. 33 %; Pm = 0.03], while the haplotype containing the GT risk alleles appeared more frequently in the higher non-Cp-Cu AD (66 vs. 55 %; Pm = 0.01). Genetic heterogeneity sustains a copper AD metabolic subtype; non-Cp-Cu is a marker of this copper AD.
authors.affiliation: Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome, Italy. rosanna.squitti@afar.it.|Institute of Cognition Sciences and Technologies (CNR), Fatebenefratelli Hospital, Isola Tiberina, Rome, Italy. rosanna.squitti@afar.it.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Squitti
authors.affiliation: Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome, Italy.
authors.forename: Mariacarla
authors.initials: M
authors.lastname: Ventriglia
authors.affiliation: Genetic Unit, IRCCS Centro San Giovanni di Dio, Fatebenefratelli, Brescia, Italy.|Departement of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Gennarelli
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro", via Orabona 4, 70125, Bari, Italy.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.affiliation: Biofordrug srl, Spin-off, Università degli studi di Bari "A. Moro", via Orabona 4, 70125, Bari, Italy.
authors.forename: Imane Ghafir
authors.initials: IG
authors.lastname: El Idrissi
authors.affiliation: Institute of Cognition Sciences and Technologies (CNR), Fatebenefratelli Hospital, Isola Tiberina, Rome, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Bucossi
authors.affiliation: Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Mariani
authors.affiliation: Unità Biomolecolare - Fatebenefratelli Hospital, Isola Tiberina, Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Rongioletti
authors.affiliation: Alzheimer Unit, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Zanetti
authors.affiliation: Alzheimer Unit, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Congiu
authors.affiliation: Institute of Neurology, Department of Geriatrics, Neuroscience and Orthopedics, Catholic University, Policlinic A. Gemelli, Rome, Italy.
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Rossini
authors.affiliation: Genetic Unit, IRCCS Centro San Giovanni di Dio, Fatebenefratelli, Brescia, Italy.
authors.forename: Cristian
authors.initials: C
authors.lastname: Bonvicini
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D002570:Ceruloplasmin; D015331:Cohort Studies; D003300:Copper; D000073840:Copper-Transporting ATPases / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male
chemical_list: D003300:Copper; D002570:Ceruloplasmin; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases
keywords: ATP7B; Alzheimer’s disease; Ceruloplasmin; Copper; Free copper; Non-ceruloplasmin-copper